Datasets:

turingmachine

/

hupd-npe-balanced-same-year-same-class-subset

like 0

ACCEPTED

Map display method

A map display method whereby the contents of a road map displayed can be easily and clearly grasped regardless of the running conditions of a vehicle. In a summarized map displayed on a display screen 10, an area including a vehicle position 11, a destination 13 and a guide route 12 between them is displayed in simplified fashion. At a position far from the destination, as shown in FIG. 2A, a summarized map of a wide area is displayed and objects including a road 14 and a facility 15 are limited to a greater degree. With the approach of the vehicle position 11 to the destination 13, as shown in FIG. 2B, the contraction scale is decreased and a summarized map of a middle area is displayed, while at the same time increasing the objects displayed. With a further approach of the vehicle position 11 to the destination 13, as shown in FIG. 2C, a narrower area is displayed in summarization, while at the same time displaying substantially all the objects, thereby making it possible to grasp the neighborhood of the destination 13 in detail.

1. A map display method for detecting the present position of a vehicle and displaying a road map including a vehicle position mark indicating the present position of the vehicle and a guide route along which the vehicle runs, characterized in that a summarized map indicating the guide route from the present position of the vehicle to the destination is displayed, and the summarized map is a map summarized with a summarization degree corresponding to the distance from the present position of the vehicle to the destination. 2. A map display method according to claim 1, characterized in that the limited number of the roads and the display elements to be displayed in the summarized map is changed in accordance with the summarization degree. 3. A map display method according to claim 2, characterized in that the priority is set for each type of the roads and the display elements, and the roads and the display elements displayed in the summarized map are selected based on the priority in accordance with the summarization degree. 4. A map display method according to claim 1, characterized in that a two-screen display of the summarized map and a road map of another form is possible. 5. A map display method according to claim 2, characterized in that a two-screen display of the summarized map and a road map of another form is possible. 6. A map display method according to claim 3, characterized in that a two-screen display of the summarized map and a road map of another form is possible. 7. A map display method according to claim 4, characterized in that the road map of another form of display is a local plane map of the neighborhood of the present position of the vehicle. 8. A map display method according to claim 7, characterized in that the contraction scale of the local plane map can be changed. 9. A map display method for detecting the present position of a vehicle and displaying a road map including a vehicle position mark indicating the present position of the vehicle and a guide route along which the vehicle runs, characterized in that a summarized map indicating a local area including the guide route from the present position of the vehicle is displayed, and the limited amount of the roads and the display elements to be displayed in the summarized map is changed in accordance with the running speed of the vehicle. 10. A map display method according to claim 9, characterized in that the range of the map display area of the summarized map is changed in accordance with the running speed of the vehicle.

TECHNICAL FIELD This invention relates to a map display method for measuring the present position of an automotive vehicle, displaying, on a display screen, a map including the present position and the present vehicle position on the map and guiding an occupant of the vehicle to a destination. BACKGROUND ART In the prior art, a car navigation apparatus for permitting the occupant to easily view the route to a destination and guiding the vehicle positively to the destination has been proposed (for example, JP-A-7-103779). Patent Document 1: JP-A-7-103779 In the car navigation apparatus described in this Patent Document 1, the contraction scale of the road map displayed is changed with the progression of the vehicle to the destination, and the road map on display is progressively enlarged with the approach to the destination. In this conventional apparatus, the contraction scale of the road map on display is determined in such a manner that the present vehicle position is always displayed in the neighborhood of a corner of the display screen and the destination is displayed in the neighborhood of the diagonally opposite corner of the display screen in accordance with the ratio of the linear distance between the present vehicle position and the destination to the length of the diagonal line of the display screen,. DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention In the car navigation apparatus described in Patent Document 1, the road map is displayed in more detail with the approach to the destination. In the case where the vehicle is running in an area somewhat distant from the destination, however, the marks indicating roads and facilities are displayed in fine detail on the road map covering a wide area, and so are the names of places, roads and facilities, which are very hard to read, especially, for an occupant driving the vehicle. The present position where the vehicle is running, therefore, may not be easily determined from the road map. In the car navigation apparatus, the road map in the neighborhood of the present position of the vehicle can be also displayed. The road map of the same contraction scale, however, is viewed by the occupant differently on a toll road for high speed running and an ordinary road where the vehicle cannot be driven at high speed. From such a road map, the occupant of the vehicle running at high speed on a toll road may not be able to determine easily where his/her vehicle is located. The object of this invention is to obviate this problem, and to provide a map display method whereby the contents of a road map on display can be easily and clearly grasped without regard to the running conditions of the vehicle. MEANS FOR SOLVING THE PROBLEM In order to achieve the above-mentioned object, according to a typical aspect of the invention, there is provided a map display method for detecting the present position of a vehicle and displaying a road map including a vehicle position mark indicating the detected present vehicle position and a guide route to be followed by the vehicle, wherein a summarized map indicating the guide route from the present vehicle position to the destination is displayed, which summarized map is summarized to a summarization degree corresponding to the distance from the present vehicle position to the destination. Also, in this summarized map, the display amount of the roads and other display elements constituting the summarized map is changed in accordance with the summarization degree. Also, according to this invention, there is provided a map display method for detecting the present position of a vehicle and displaying a road map including a vehicle position mark indicating the detected present vehicle position and a guide route to be followed by the vehicle, wherein a summarized map indicating a local area including the guide route from the present vehicle position is displayed, and in the local summarized map, the display amount of the roads and other display elements constituting the summarized map is changed in accordance with the vehicle running speed. Also, in this local summarized map, the range of the display area is changed in accordance with the vehicle running speed. ADVANTAGES OF THE INVENTION According to this invention, a summarized map indicating the running route can be displayed in simplified fashion as compared with a plane map, and the contraction scale of the summarized map is changed to change the range of a display area in accordance with the distance from the present vehicle position to the destination, wherein the summarized map is easy to view and the relative position of the vehicle can be intuitively grasped wherever the vehicle may be located on the guide route. Also, in view of the fact that the display amount of objects on the summarized map is changed in accordance with the distance between the vehicle position and the destination, the summarized map is easier to view wherever the vehicle is located on the guide route. The other objects, features and advantages of the invention will be made apparent by the description of embodiments of the invention taken in conjunction with the accompanying drawings. BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the invention are described below with reference to the drawings. FIG. 1 is a block configuration diagram showing a car navigation apparatus using the map display method according to an embodiment of the invention. Reference numeral 1 designates a control unit, numeral 2 a position detector, numeral 3 a vehicle speed detector, numeral 4 a communication unit, numeral 5 a memory, numeral 6 a map data base, numeral 7 a display unit, numeral 8 a voice input/output unit and numeral 9 an input unit. In this diagram, the map data of each area are stored in the map data base 6 and downloaded to the memory 5 provisionally from an external source through the communication unit 4. The map data stored in the memory 5 are stored in the map data base 6 under the control of the control unit 1. The map data of the whole nation is not initially required to be stored, but in the absence of the map data on the area where the vehicle with the car navigation apparatus mounted thereon (hereinafter referred to simply as the vehicle) is running, the map data of the particular area can be requested from a server (not shown) through the communication unit 4 and distributed from the server. Nevertheless, the whole map data can of course be stored in the map data base 6 in advance. The map data base 6 has stored therein the road data and the display element data as the component elements of the map data, and by reading and combining the data of the component elements from the map data base 6, the road map data is obtained, whereby a road map is displayed on the display screen of the display unit 7. The display elements include the elements (symbols and names) of the facilities such as railroads, schools, convenience stores and bridges and the equipment including traffic signals. The position detector 2 is a device such as a GPS (Global Positioning System) for detecting the position of the vehicle, and the vehicle speed detector 3 is a device for detecting the moving speed of the vehicle. In the position detector 2, the position of the vehicle (hereinafter referred to as the vehicle position) is detected at predetermined time intervals. The vehicle position is detected by the position detector 2 at the position detection timing based on the detection result of the vehicle speed detector 3. The input unit 9 includes a mechanical switching means operated by the occupant and a touch switch displayed on the display screen of the display unit 7. The occupant, by operating the input unit 9, can input a command for the desired operation of the car navigation apparatus. The control unit 1 is for controlling the various parts for navigation based on the command from the input unit 9. The road map data corresponding to the vehicle position based on the position information from the position detector 2 and the vehicle speed information from the vehicle speed detector 3 is read from the map data base 6 and displayed on the display unit 7 together with a mark indicating the present vehicle position (i.e. the vehicle position mark). According to this embodiment, the road map data can be displayed on the display unit 7, though not explained in detail, in any of various forms including a normal plane display in which the road map is displayed in the normal two-dimensional way, a bird's-eye display in which a two-dimensional road map is displayed as if viewed from a high view point, and a steric display in which, as a kind of a bird's-eye display, buildings, three-dimensional objects like buildings and ups and downs of the ground are displayed stereoscopically. Other display forms available include, as described later, a summarized display in which the required information is selectively picked up from a two-dimensional road map and roads, etc. are geometrically processed and displayed in a simplified fashion, and a two-screen display combining any of the display forms described above. In the case where a road map is displayed by other than the plane display, the control unit 1 processes the road map data read from the map data base 6 and displays it on the display unit 7. Incidentally, the voice input/output unit 8 includes a speaker for outputting a voice guide or the like is output in operatively interlocked relation with the operation of guiding the vehicle on the road map displayed on the display screen of the display unit 7 and a reproducing device for a recording medium such as a disk. Next, the display forms according to this invention are explained. FIGS. 2A to 2C show a map display method according to an embodiment of the invention, in which summarized maps corresponding to the distance from the vehicle position to the destination are shown. Numeral 10 designates a display screen of the display unit 7, numeral 11 a vehicle position, numeral 12 a vehicle guide route, numeral 13 a destination, 14 roads other than the guide route 12, numeral 15 a symbol of a facility, and numeral 16 names of roads or facilities. The summarized map according to this embodiment displays by summarizing the area from the present vehicle position to the destination. With the approach of the vehicle position to the destination, the contraction scale is increased while the map area displayed on the display screen of the display unit 7 is reduced. The “contraction scale” is defined as the degree of contracting the map displayed on the display screen. Assume that the contraction scale of the map displayed without contraction on the display screen of the display unit 7 is 1. In the case where a map of a wider area is displayed on the display screen, the map is required to be contracted to the size of the display screen with a contraction scale of less than 1. For example, a map having an area four times as large as a map having the contraction scale α of 1, if to be displayed on the display screen, is reduced to one fourth with the contraction scale α of ¼. The roads and the display elements in the summarized map are limited more, the longer the distance from the vehicle position to the destination and hence the larger the area to be displayed. Specifically, the summarized map facilitates the viewing of roads and display elements in spite of the change in contraction scale. The same roads and the same display elements are displayed, therefore, in substantially the same size for different contraction scales, without being superposed one on another. In order to display roads and display elements in this way, the display amount of the roads and the display elements is required to be limited and processed to improve the visibility depending on the contraction scale of the map. The degree of this limitation and the processing is determined by the degree of summarization indicating the degree to which the summarized map is summarized, i.e. the summarization degree. In the case where a map (contraction scale α of ¼) of an area four times larger than the area of a map having the contraction scale α of 1 (hereinafter referred to as a reference map) and including the area of the reference map is displayed by being contracted to one fourth, for example, the roads and the display elements are also displayed by being contracted and become very difficult to view. In a summarized map, the display amount is reduced by reducing the number of roads and display elements displayed to one forth and the roads and the display elements after reduction are enlarged in a manner not superposed one on another to facilitate the viewing. The degree to which the number of roads and display elements is reduced and enlarged is determined by the summarization degree of the summarized map. FIGS. 2A to 2C show examples of summarized map displayed on the display screen 10 of the display unit 7 (FIG. 1). In these summarized maps, symbols 15 of roads 14 or facilities and characters indicating the names of places or facilities (names 16) are displayed, together with a mark Δ indicating the present vehicle position 11 (vehicle mark), an asterisk indicating the destination 13 (destination mark) and a vehicle guide route 12 from the vehicle position to the destination. According to this embodiment, the summarized map is displayed on the display screen 10 in such a manner as to include the guide route from the present vehicle position to the destination. Therefore, the contraction scale of the summarized map and the area displayed are changed in accordance with the distance from the present vehicle position to the destination. FIG. 2A shows a summarized map with a long distance from the present vehicle position to the destination. In this case, the contraction scale is small and a wide area is displayed by being summarized. In this wide-area summarized map, the guide route 12 is displayed, together with a main road 14, a railroad 17, a symbol 15 indicating a river and a main facility and names 16 thereof which provide easily visible marks for the occupant driving the vehicle. Also, on the summarized map, the roads and display elements are limited and processed to facilitate the viewing without difficulty. According as the distance from the present vehicle position to the destination is shortened and the contraction scale is increased while the area indicated by the summarized map is narrowed, the display amount of the roads and the display elements is limited to lesser degree. In a summarized map for a middle area as shown in FIG. 2B, for example, a road 14a crossing the guide route 12 also comes to be displayed. Further, with the approach of the guided vehicle to the destination 13, as shown in FIG. 2C, a road map of a narrow area is displayed. This narrow-area road map, if 1 in contraction scale α, is not summarized, and all the roads and display elements are displayed together with the guide route 12. In this case, these roads are displayed realistically with the same width, length and shape (curve, etc.) as in the ordinary road map. Also, the display elements including facilities and the names thereof displayed on this summarized map are increased in number, thereby facilitating the detection of the destination 13. The map having the contraction scale α of 1 is based on the map data obtained by cutting out an area that can be displayed on the display screen of the display unit 7 as it is from the map data base 6 (FIG. 1). Also in this case, the roads and display elements may be appropriately limited and processed. In the series of summarized maps described above, with the change in distance between the running vehicle position 11 and the destination 13, the contraction scale is progressively increased and the display area narrowed, so that the summarized map is displayed in increasingly enlarged form. In this case, the vehicle position is detected at intervals of about one to several seconds by the position detector 2 and the vehicle speed detector 3 (FIG. 1), and based on this detection result, a summarized map is produced. In this case, therefore, the contraction scale of the summarized map is changed and the display area is narrowed at these time intervals, so that the summarized road map progressively enlarged is displayed on the display screen 10. FIGS. 3A to 3C are diagrams showing the map display method according to another embodiment of the invention, and represent an example of two-screen display. Numeral 20 designates a summarized map, numeral 21 a plane map and 22 a traffic signal. The parts corresponding to those in FIGS. 2A to 2C are designated by the same reference numerals and not explained again. FIG. 3A shows the two-screen display in the case where the distance from the vehicle position 11 to the destination 13 is long (far in distance). The display unit 7 (FIG. 1), together with the display screen 10, includes operation means such as a “two-screen” button 25, a “vehicle position” button 26, a “scale” button 27 and a “total route” button 28. By operating the “two-screen” button 25, the summarized map 20 is displayed in the left half and the plane map 21 in the right half, for example, of the display screen 10. Although the component elements (roads and display elements) of the summarized map 20 are similar to those of the summarized maps shown in FIGS. 2A to 2C, a summarized map of the neighborhood of the vehicle position is displayed by operating the “vehicle position” button 26. The plane map 21 is an ordinary road map. By operating the “total route” button 28, however, the plane map 21 of the total route from the present vehicle position 11 to the destination 13 is displayed. Also, by operating the “scale” button 28 with the prevailing contraction scale as a minimum one, the contraction scale of the plane map 21 can be changed. As a result, with the increase in contraction scale, a narrower area is displayed in progressively enlarged form by the plane map 21. The plane map 21 thus displayed, however, always covers an area including the present vehicle position 11, and therefore the situation in the neighborhood of the vehicle position can be known in detail. With the approach of the running vehicle 11 to the destination 13 and arrival at the position of a middle distance from the destination 13, as shown in FIG. 3B, the roads and display elements not displayed in the summarized map 20 shown in FIG. 3A come to be newly displayed in the summarized map 20, like in the summarized map 10 shown in FIG. 2B. The plane map 21, in contrast, is displayed in the same contraction scale unless the “scale” button 27 or the “total route” button 28 is operated. According as the vehicle runs, however, the area displayed is changed. With the approach of the vehicle position 11 to the range of a predetermined distance from the destination 13, as shown in FIG. 3C, only the plane map 21 including the vehicle position 11 to the destination 13 is displayed in a one-screen display mode. As described above, a local plane map of neighborhood of the vehicle position can also be displayed in two-screen display mode together with the summarized map. Further, in view of the fact that the contraction scale of the plane map can be changed, the vehicle position in terms of the approximate distance to the destination can be grasped on the summarized map, and by displaying the local plane map, the situation in the neighborhood of the present vehicle position can be known in detail, thereby making it possible to drive the vehicle more smoothly as guided by the apparatus. As described above, the summarized map can be combined also with a bird's-eye display or a steric display in place of a plane map. In this case, the information on the neighborhood of the vehicle position in line with a more realistic visual field can be provided. Also, the display can be switched by the provision of a button to switch the screen in the menu bar. With reference to FIG. 4, a specific example of the operation for display of a summarized map by the control unit 1 shown in FIG. 1 is explained. In this drawing, first, a power switch not shown is turned on. Then, the vehicle position is measured by the detection output of the position detector 2 (step 100). When the destination is input from the input unit 9 (step 101), the route (guide route) from the vehicle position to the destination is retrieved using the map data including the data on the roads and display elements in the map data base 6 (step 102). From the vehicle position, the destination and the guide route thus retrieved, a display range including these factors to be displayed on the display screen 10 of the display unit 7 is determined (step 103). A specific example of the method of determining this display range is explained with reference to FIG. 5. In this drawing, from the vehicle position information obtained by the detection output of the position detector 2 and the destination information input from the input unit 9, the map data 30 including them is retrieved from the map data base 6, and the vehicle position 11 and the destination 13 are determined on the map data 30. Under predetermined conditions, the guide route 12 from the vehicle position 11 to the destination 13 is retrieved. Then, a square or rectangular area having four sides including a north-to-south straight line 32a passing through the vehicle position 11, the destination 13 or the guide route 12, whichever is located at the easternmost position, a west-to-east straight line 32b passing through the northernmost position, a north-to-south straight line 32c passing through the westernmost position and a west-to-east straight line 32d passing through the southernmost position, is detected as a route area 31. Further, an area including the route area 31 and having the same aspect ratio as the display screen 10 of the display unit 7 is determined as a map display area 33. This map display area 33 is determined as a display range at step 103 shown in FIG. 4. On the other hand, a table is set for determining the display limit amount for each type of object (a display element such as character/symbol and a road) in accordance with the screen size of the display unit 7. This limit amount may be set in terms of the number or the ratio of the occupied area to the area of the display screen 10 (=Total area (number of pixels) occupied by display elements/Area of display screen 10 (number of pixels)). Table 1 shown below is an example in which the display limit amount of characters/symbols and roads is expressed by the number, and Table 2 by the ratio of occupied area. TABLE 1 Screen size Characters/symbols Roads 6 inches 30 50 7 inches 35 60 TABLE 2 Screen size Characters/symbols Roads (pixels) (%) (%) 800 × 480 20 30 1440 × 234 30 35 In the case where the screen size of the display screen is 6 inches, for example, a maximum of 30 characters/symbols (or maximum of 20% in occupied area ratio) can be displayed, and a maximum of 50 roads (or maximum of 30% in occupied area ratio) can be displayed. Returning to FIG. 4, upon determination of the display range as described above (step 103), the display limit amount of each object (road and display element making up the component elements of the map) shown in Tables 1 and 2 is read (step 104). Also, the map data of the display range (the map display area 33 determined in the manner described with reference to FIG. 5) is read from the map data base 6 and temporarily stored in the memory 5 (step 105). This map data include object data as described above. The number of each type of objects read from the map data base 6 is determined (this number of each type of objects is called the number of objects in the initial value layer). This number of objects in the initial value layer is compared with the display limit amount obtained at step 104, and the maximum number of each type of objects actually displayed in the summarized map is adjusted to be equal to the display limit value. In this way, the roads and display elements actually displayed are determined from the objects in the initial value layer (step 106). In this specific example, the display amount of objects is limited to the display limit amount shown in Tables 1 and 2. Based on this display limit amount, the degree to which the map is summarized, i.e. the summarization degree is changed in accordance with the contraction scale of the summarized map. Specifically, in the case where a summarized map is displayed on the contraction scale α1, for example, assume that n1 is the number of object “roads” (number of objects in the initial value layer) read from the map data base 6 to display the summarized map, and that M is the display limit value of this object (“50”, for example, for the screen size shown in Table 1). In this summarized map, only M roads are displayed out of actually existing n1 roads. Thus, this summarized map is summarized in this way as far as the object “roads” are concerned. The ratio y1 of the roads displayed in this summarized map is given as y1=M/n1, which indicates the degree to which the map is summarized, i.e. the summarization degree. In the case where the summarized map is displayed on the contraction scale α2 (<α1), on the other hand, assume that the number of object “roads” in the initial value layer read from the map data base 6 is n2 (n2>n1, since α2<α1 and therefore this summarized map has a wider area than the summarized map of contraction scale α1). Then, the summarization degree y2 of this summarized map is given as y2=M/n2. Since y1>y2, the summarization degree y of the summarized map is varied with the contraction scale α of the summarized map. In other words, the amount of objects displayed in the summarized map is limited in accordance with the summarization degree y. Thus, the map is summarized in accordance with the summarization degree. In one method of determining the objects actually displayed from the objects in the initial value layer, the priority is set for each type of object, and the number of objects equal to the determined value is selected in the descending order of priority. Next, this is explained with reference to FIGS. 6 to 8 taking the road data as an example. As shown in FIG. 6, assume that the object “roads” displayed in the summarized map are classified, as road types, into a road constituting the guide route 12, main roads 14a including a toll road and national and prefectural roads, and branch roads 14b connected as a branch to the guide route 12 such as a road 14c named for the purpose of tourism or the like, a straight connected road 14d connected linearly with a branch road and other types of roads. The priority is set for each type of these roads. In setting the object “roads” actually displayed at step 106 in FIG. 4, the priority set for each type of the “road” as described above is used. An example of this priority is explained with reference to FIG. 7. First, the road constituting the guide route 12 is set to priority p1 (step 200), the main roads 14a are set to priority p2 (step 201), the branch roads 14b are set to priority p3 (step 202), the named roads 14c are set to priority p4 (step 203), the straight roads 14d connected to the branch roads are set to priority p5 (step 204), and the other roads are not set to any priority. FIG. 8 is a diagram showing the road data to which priority is set in this way. In this drawing, the road data include an ID (identification) 41 for identifying the road data, a layer 42 indicating that the type of an object is the “road”, a category 43 indicating the road type (the route road, main road, etc. shown in FIG. 7), a pattern type 45 indicating the shape of the pattern for display of the road and a name 46 of the display elements. Further, the priority 47 is also included in the case where priority is set as described above. In this case, the road data is taken as an example, and the type is assumed to be indicated by the layer “100”. The category is expressed as “500” in the case where the type of the object “road” is the guide route 12, “400” for the main roads 14a, and “200” for the named roads 14c. Also, for other types of roads, the category is determined in accordance with each type thereof. The pattern type 44 indicates a polygonal line as “polyline” including a multiplicity of straight lines, and may be expressed, for example, as a “polygon”. The pattern data 45 represents the road position indicated by latitude and longitude (or the ordinate and abscissa on an orthogonal coordinate system). A road, for example, is expressed by the coordinates of a train of constituent points thereof. Also, in the case where a road has a name (◯◯ toll road, national road No. XX, ΔΔ line, etc.), the particular name 46 is added. Incidentally, although all the data shown in FIG. 8 are not essential, at least one of the layer 42 and the category 43 is required to specify the type. The pattern type 44 and the pattern data 45 represent the classification of the pattern type (dot, polygonal line, polygon, etc.) and the pattern data, and if capable of expressing the same contents, may be described collectively as one item. The name 46 is essential for indicating the name of the road along which the vehicle is running and the crossing roads. The priority 47 is added, if determined at the time of preparation of the map data base 6 (FIG. 1). By doing so, the priority setting process is simplified. Returning to FIG. 4, in the case of the road data, the determined value obtained at step 104 may be the ratio (%) of the total display area of the roads to the display screen 10. At step 106, while adjusting to this determined value, the limit of the priority of the roads displayed is determined (step 106). In this case, “adjust” is defined as a process in which with the advance of priority to one lower order, the number of the roads or the area (number of pixels) occupying the display screen 10 before the particular priority is calculated, the ratio (%) between this area and the area of the display screen 10 is determined, the number of the roads or the occupied area is compared with the display limit amount, and then it is determined whether the display limit amount is exceeded or not. In the case where the display limit amount is not exceeded, the priority is further advanced to one lower order and the number or the occupied area of roads to be displayed is increased, while in the case where the display limit amount is exceeded, the prevailing number of the roads on the lowest order of priority is reduced. As an alternative, the road data read from the map data base 6 are removed in the ascending order of priority to adjust to the display limit amount. Incidentally, at step 106, the priority of the roads may be changed and the roads to be displayed can be adjusted in accordance with the situation of the guide route or the crossing roads. At step 104 of FIG. 4, the display limit amount of each object is uniquely determined by the size (Table 1) or the occupied area ratio (Table 2) of the display screen 10. Alternatively, the map data base 6 is provided for each of the wide area, middle area and the narrow area shown in FIGS. 2A to 2C into which the contraction scale is divided, and the display limit amount of each object is set for each division map data base (in short, the map data is divided into the map data for the wide area, middle area and the narrow area, and the display limit amount of each object is set for each division map data). Then, in accordance with the contraction scale of the road map to be displayed, the display limit amount of an object is changed. Also within this contraction scale classification, the display limit amount may of course be changed in accordance with either the sizes shown in Tables 1 and 2 or the size of the display screen 10. Once an object to be displayed is determined in this way, as described later, the data processing is executed for processing the shape (thickness of roads, size of characters or symbols, etc.) of the particular object, i.e. a road or a display element. Further, the data processing is executed for arranging the processed display elements on the processed roads in such a manner as not to be superposed one on another (step 107). Thus, a summarized map having the display elements geometrically processed as shown in FIGS. 2A to 2C, FIGS. 3A to 3C is displayed on the display screen 10 of the display unit 7 as shown in FIGS. 2A to 2C, FIGS. 3A to 3C (step 108). Next, the vehicle position 11 is measured (step 109), it is determined whether the vehicle is located on the guide route 12 or not (step 110), and in the case where the vehicle is so located, the display range is determined from the measured vehicle position 11 and the destination 13 (step 103). For the display range thus determined, the operation from step 104 is repeated. In the case where the vehicle is not located on the guide route 12 (i.e. in the case where the route is changed), a new guide route is retrieved (step 102) and the operation from step 103 is repeated. By doing so, the vehicle position is detected at intervals of about one or several seconds at step 110, and the operation from step 103 or 102 is repeated. For each repetitive operation, a new summarized map updated is displayed on the display screen 10. By the way, according to this specific example, the process of reading the map data from the map data base 6 is executed (step 105) after the process of step 104 in FIG. 4. Nevertheless, following step 103, the process of step 105 for reading the map data from the map data base 6 is executed, after which the process of step 104 may be executed. In this specific example, the number or the occupied area ratio of objects displayed is constant regardless of the contraction scale of the summarized map. Next, another example in which they are not constant but variable is explained with reference to FIG. 9. In FIG. 9, steps 100 to 103 are similar to steps 100 to 103 in FIG. 4, and steps 107 to 110 similar to steps 107 to 110 in FIG. 4. Specifically, the process of steps 104 to 106 in the flowchart shown in FIG. 4 is replaced by the process of steps 300 to 307 in the flowchart shown in FIG. 9. Therefore, the parts included in the flowchart of FIG. 4 are not explained, and the processing operation of steps 300 to 304 is explained. In FIG. 9, as explained with reference to FIG. 4, once the display range of the map to be displayed on the display screen 10 of the display unit 7 is determined (step 103), the contraction scale α (0 <α≦1) for displaying the map in this display range on the display screen 10 is determined (step 300). This contraction scale α is multiplied by a coefficient k (0≦k≧1) to determine an adjust value z (=k·α) (step 301). This coefficient k is preset and can be determined in accordance with the size of the display screen 10, for example, shown in Tables 1 and 2. The number of objects to be displayed on the display screen 10 is determined by this adjust value z. In the case where there are too many objects to be displayed on the display screen 10, however, k can be reduced, and vice versa. This adjust value z has a tolerable minimum value zmin set therein. The adjust value z, when holding the relation zmin≦z (step 302), constitutes the summarization degree y (step 303), while in the case where z<zmin (step 302), the particular tolerable minimum value zmin constitutes the summarization degree y (step 304). In the case where the distance from the present position to the destination is long and the wide-area map is reduced to a great measure (to a sufficiently small contraction scale α) and displayed, for example, only a few objects may be included in this particular area (such as in the case where the number of objects is few and remains substantially unchanged in spite of the fact that the distance to the destination is changed by the running vehicle and the display area is progressively narrowed). In such a case, assume that the coefficient k is small and the wide-area map is displayed by being greatly contracted (to a sufficiently small contraction scale α). Then, the number of objects displayed is reduced in proportion to the adjust value z=k·α, and less information required to guide the vehicle becomes available. For this reason, the tolerable minimum value zmin is determined as described above to prevent the number of objects displayed from being reduced at the distance end (sic). Once the summarization degree y is determined in the aforementioned way, the number of each object in the initial value layer is determined in the display range of the map determined at step 103 from the map data base 6, and the number of the object to be displayed is determined from the number of the object in the initial value layer and the summarization degree y (step 305). Assuming that the number of an object “road” in the initial value layer in this display range is N, for example, the number n of this particular object to be displayed is given as n=N·y. After that, the map data in the display range determined at step 103 is read from the map data base 6, and temporarily stored in the memory 5 (step 306). Then, the objects to be displayed are determined in the number for each object in accordance with the priority order, for example, set from the map data base 6 (step 307), and the process from step 107 is executed for the objects thus determined. FIGS. 10A, 10B show objects in the display range changed by the summarization process shown in FIG. 4. FIG. 10A shows a summarized map 40a of a narrow area, and FIG. 10B a summarized map 40b of a middle area. Comparison between the summarized maps 40a, 40b apparently shows that the summarization process shown in FIG. 4 has the advantage that the number of objects displayed on the summarized maps 40a, 40b is substantially unchanged and always limited to a predetermined number. In contrast, FIGS. 11A, 11B show objects in different display ranges due to the summarization process shown in FIG. 9. FIG. 11A shows a summarized map 41a of a narrow area, and FIG. 11B a summarized map 41b of a middle area. Comparison between the summarized maps 41a, 41b apparently shows that the summarization process shown in FIG. 9 results in a greater number of objects to be displayed for the middle-area summarized map 41b than for the narrow-area summarized map 41a. Of course, in accordance with the number of objects in the display range in the initial value layer, the number of objects to be displayed is greater for the narrow-area summarized map 41a than for the middle-area summarized map 41b in some cases, or the number of objects to be displayed is substantially equal between the narrow-area summarized map 41a and the middle-area summarized area 41b in other cases. In the summarization process shown in FIG. 9, however, the number of objects to be displayed is limited and therefore the road map displayed on the display screen 10 becomes also very easy to see as in the summarized map produced by the summarization process shown in FIG. 4. Nevertheless, this embodiment has another advantage that the relative positions of the objects in each area are maintained and the surrounding situation is easy to grasp. As described above, in this specific example of display, the contraction scale of the summarized map is changed in accordance with the distance between the vehicle position and the destination, while at the same time changing the number of objects to be displayed thereon. Further, the number of objects to be displayed may be changed in accordance with the running speed of the vehicle. The display screen of the car navigation apparatus is viewed differently when running on a toll road at high sped and when running on an ordinary road slowly. While the vehicle is running on a toll road at high speed, the contents of the display screen are desirably understood by instantaneous viewing, while a more detailed situation is desirably grasped while running at low speed. When running at high speed, therefore, the number of objects such as facilities and equipment displayed is reduced as compared with the determined value obtained at step 105 shown in FIG. 4, so that objects high in priority order and easily visible are displayed in the summarized map. Incidentally, whether the vehicle is running at high speed or not is determined by a method in which the vehicle speed is detected from the detection output of the vehicle speed detector 3, and in the case where the detected vehicle speed is higher than a predetermined threshold value, the vehicle is determined as running at high speed, while the vehicle is determined as running at low speed in the case where the detected vehicle speed is not higher than the threshold value, or by a method in which whether the vehicle position detected by the position detector 2 is located on a toll road or not is determined based on the road data 40 (FIG. 8) stored in the map data base 6, and in the case where the vehicle is located on a toll road, the vehicle is determined as running at high speed, while the vehicle is otherwise determined as running at low speed. As described above, in the case where a local summarized map is displayed, the display limit amount of objects on this summarized map is changed in accordance with the vehicle running speed. Therefore, a road map summarized in a manner easily visible in accordance with the vehicle running speed is provided, and the vehicle position can be intuitively grasped even when running at high speed. Further, the contraction scale of the summarized map is locally changed in accordance with the vehicle running speed, and so is the range of the display area. While the vehicle is running at high speed, therefore, even the situation comparatively far ahead can be grasped thereby facilitating the driving. Further, when the vehicle comes to a stop, the screen is easily visible and therefore the display limit amount of objects may be increased to display more objects. In this case, a summarized map having a larger contraction scale or a map having the contraction scale α=1 (narrow-area map) can be displayed, whereby the situation in the neighborhood of the vehicle position can be grasped in more detail. Also, according to this embodiment, a summarized map includes the whole guide route from the vehicle position to the destination. According to another embodiment, however, a local summarized map of the neighborhood of the vehicle position can be displayed (this corresponds to a summarized map of the plane map 21 shown in FIGS. 3A, 3B, for example). In this case, the contraction scale of the summarized map can be either fixed or, like in the plane map 21 shown in FIGS. 3A, 3B, can be changed by the operation of the occupant. With the change in contraction scale, the display range of the local summarized map is also changed (the smaller the contraction scale, the wider the display range displayed in the summarized map). The number of objects (or the occupied area ratio) displayed in this case, which is constant regardless of the contraction scale, may alternatively be switched continuously or in steps in accordance with the change in contraction scale. Further, also in a local summarized map, the number of objects displayed (or the occupied area ratio) can be changed in accordance with the vehicle speed. For this purpose, as shown in FIG. 12, the defined data including the number a of characters or symbols displayed while the vehicle is running at high speed, the ratio c % which the road display area represents of the background of the display screen 10, the number b (a<b) of the characters or symbols displayed while the vehicle is running at low speed, and the ratio d % (c<d) which the road display area represents of the background of the display screen 10, are held in the map data base 6 (FIG. 1), and in accordance with the result of determination by the determination method for high-speed and low-speed running, the objects displayed are changed. Also, in this case, the display range of the local summarized map can be changed at the time of high-speed and low-speed running, so that while the vehicle is running at high speed, a summarized map of a wider area than the summarized map for the low-speed running shown in FIG. 13B can be displayed as shown in FIG. 13A. Also in this case, the contraction scale of the local summarized map can be changed continuously or in steps in accordance with the running speed, so that the higher the running speed, the wider the area displayed in the summarized map. As a result, the occupant can know the situation even at a position comparatively far ahead while the vehicle is running at high speed and covers a long distance within a short time. Now, the geometric process (step 108) shown in FIG. 4 for preparing a summarized map is explained. FIG. 14 is a diagram showing a specific example of the linearization process of a polygonal pattern. In the linearization process according to this specific example, the linear pattern of a road or a railroad is expressed by a polygonal line and approximated by a straight line thereby to reduce the amount of the map information data. Now, the road linearization process is explained as an example. A road is recognized as a polygonal line with the ends thereof constituting an intersection or a dead end. First, as shown in FIG. 14(a), the tilt angles θ1, θ2 of the line segments w1, w2 of the polygonal line with respect to X axis are determined, and by calculating the error between adjacent tilt angles, the linearity is detected. Based on the result of this processing, the line segments are classified into groups of high linearity, and as shown in FIG. 14(b), can be divided into a dotted line, a dashed line and a one-dot chain. Finally, as shown in FIG. 14(c), the line segments of each group are connected and linearized. FIG. 15 is a diagram showing another specific example of the linearization process of a polygonal pattern. FIG. 15(a) shows a starting point S, an ending point G and nodes P of a road. For this road, as shown in FIG. 15(b), a straight line SL is drawn to connect the starting point S and the ending point G, and let L1 be the length thereof. From each node P, a normal PL is drawn to the straight line SL, and let d1max be the length of the longest normal PL. It is determined whether the evaluation formulae described below hold or not. F1=d1max/L1<ε1 (1) F2=d1max<ε2 (2) where ε1, ε2 are evaluation functions. The first evaluation function ε1 is a threshold value of the ratio between the length of the longest normal PL and the distance between starting point S and ending point G, and used for the number reduction process not dependent on scale. Therefore, the first evaluation function ε1 remains the same for different scales, as long as the polygonal line is in the same shape. The second evaluation function ε2, on the other hand, is a threshold value of the length of the longest normal PL, and in the case where the scale range (maximum magnification) is determined, provides an effective number reduction process. This process is effective for removing minor unevennesses. In the case where the evaluation formulae (1), (2) hold, the polygonal line is replaced by the straight line SL and the process is finished. In the case where at least one of the evaluation formulae (1), (2) fails to hold, on the other hand, as shown in FIG. 15(c), the straight lines SL1, SL2 connecting the node P1 associated with the longest normal PL and the starting point S and the ending point G are drawn, and further, the normal PL is drawn from each node P to these two straight lines SL1, SL2. Then, let d2max, d3max, be the length (nodes P2, P3) of the longest normal PL for each of the straight lines SL1, SL2, and it is determined whether the evaluation formulae (1), (2) hold or not. In the case where the evaluation formulae (1), (2) hold, the nodes P are removed and each polygonal line segment is replaced by a straight line. In the example shown in FIG. 15(c), the evaluation formulae (1), (2) fail to hold for the longer polygonal line segment for which the straight line SL1 is set, while the evaluation formulae (1), (2) hold for the shorter polygonal line segment for which the straight line SL2 is set. For the shorter polygonal line segment, therefore, the node P is removed and replaced by the straight line SL2. With regard to the longer polygonal line segment, as shown in FIG. 15(d), the straight lines SL3, SL4 connecting the node P2 associated with the longest normal PL, the starting point S and the node P1 are drawn, and a similar process is executed for the two polygonal line segments of the straight lines SL3, SL4. In the case where this process satisfies the evaluation formulae (1), (2) hold, as shown in FIG. 15(e), the nodes P are removed, and each polygonal line segment is replaced by a straight line. Comparison between FIGS. 15(a) and 15(b) apparently shows that in this specific example, a polygonal line having a multiplicity of nodes is replaced by a polygonal line having a fewer number of nodes. Thus, a complicated road is replaced by a road of a simple shape, and therefore the data amount of the map information is reduced. Although embodiments are described above, this invention is not limited to them, and it is apparent to those skilled in the art that the invention can be variously altered or modified without departing from the spirit and the scope of the invention defined in the attached claims. BRIEF DESCRIPTION OF THE DRAWINGS [FIG. 1] A block configuration diagram showing an on-vehicle navigation apparatus using the map display method according to this invention. [FIG. 2A] A diagram showing a map display method according to an embodiment of the invention. [FIG. 2B] A diagram showing a map display method according to an embodiment of the invention. [FIG. 2C] A diagram showing a map display method according to an embodiment of the invention. [FIG. 3A] A diagram showing a map display method according to an embodiment of the invention. [FIG. 3B] A diagram showing a map display method according to an embodiment of the invention. [FIG. 3C] A diagram showing a map display method according to an embodiment of the invention. [FIG. 4] A diagram showing a specific example of the processing operation for displaying the summarized maps according to the embodiments shown in FIGS. 2A to 2C, 3A to 3C. [FIG. 5] A diagram showing a specific example of the method of setting the display range of a summarized map at step 103 in FIG. 4. [FIG. 6] A diagram schematically showing the types of road as an object in a summarized map. [FIG. 7] A flowchart showing a specific example of the method of setting the priority for each type of road shown in FIG. 6. [FIG. 8] A diagram showing a specific example of the road data in the map data base shown in FIG. 1. [FIG. 9] A diagram showing another specific example of the processing operation for displaying the summarized maps according to the embodiments shown in FIGS. 2A to 2C, 3A to 3C. [FIG. 10A] A diagram showing the objects in a summarized map in a different display range due to the summarization process shown in FIG. 4. [FIG. 10B] A diagram showing the objects in a summarized map in a different display range due to the summarization process shown in FIG. 4. [FIG. 11A] A diagram showing the objects in a summarized map in a different display range due to the summarization process shown in FIG. 9. [FIG. 11B] A diagram showing the objects in a summarized map in a different display range due to the summarization process shown in FIG. 9. [FIG. 12] A diagram showing a specific example of the data for restricting the display amount of an object in accordance with the running speed in the map data base shown in FIG. 1. [FIG. 13A] A diagram showing the map display method according to another embodiment of the invention. [FIG. 13B] A diagram showing the map display method according to another embodiment of the invention. [FIG. 14] A diagram for explaining a specific example of the linearization process of a polygonal pattern at step 108 shown in FIG. 4. [FIG. 15] A diagram for explaining another specific example of the linearization process of a polygonal pattern at step 108 shown in FIG. 4.

<SOH> BACKGROUND ART <EOH>In the prior art, a car navigation apparatus for permitting the occupant to easily view the route to a destination and guiding the vehicle positively to the destination has been proposed (for example, JP-A-7-103779). Patent Document 1: JP-A-7-103779 In the car navigation apparatus described in this Patent Document 1, the contraction scale of the road map displayed is changed with the progression of the vehicle to the destination, and the road map on display is progressively enlarged with the approach to the destination. In this conventional apparatus, the contraction scale of the road map on display is determined in such a manner that the present vehicle position is always displayed in the neighborhood of a corner of the display screen and the destination is displayed in the neighborhood of the diagonally opposite corner of the display screen in accordance with the ratio of the linear distance between the present vehicle position and the destination to the length of the diagonal line of the display screen,.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>[ FIG. 1 ] A block configuration diagram showing an on-vehicle navigation apparatus using the map display method according to this invention. [ FIG. 2A ] A diagram showing a map display method according to an embodiment of the invention. [ FIG. 2B ] A diagram showing a map display method according to an embodiment of the invention. [ FIG. 2C ] A diagram showing a map display method according to an embodiment of the invention. [ FIG. 3A ] A diagram showing a map display method according to an embodiment of the invention. [ FIG. 3B ] A diagram showing a map display method according to an embodiment of the invention. [ FIG. 3C ] A diagram showing a map display method according to an embodiment of the invention. [ FIG. 4 ] A diagram showing a specific example of the processing operation for displaying the summarized maps according to the embodiments shown in FIGS. 2A to 2 C, 3 A to 3 C. [ FIG. 5 ] A diagram showing a specific example of the method of setting the display range of a summarized map at step 103 in FIG. 4 . [ FIG. 6 ] A diagram schematically showing the types of road as an object in a summarized map. [ FIG. 7 ] A flowchart showing a specific example of the method of setting the priority for each type of road shown in FIG. 6 . [ FIG. 8 ] A diagram showing a specific example of the road data in the map data base shown in FIG. 1 . [ FIG. 9 ] A diagram showing another specific example of the processing operation for displaying the summarized maps according to the embodiments shown in FIGS. 2A to 2 C, 3 A to 3 C. [ FIG. 10A ] A diagram showing the objects in a summarized map in a different display range due to the summarization process shown in FIG. 4 . [ FIG. 10B ] A diagram showing the objects in a summarized map in a different display range due to the summarization process shown in FIG. 4 . [ FIG. 11A ] A diagram showing the objects in a summarized map in a different display range due to the summarization process shown in FIG. 9 . [ FIG. 11B ] A diagram showing the objects in a summarized map in a different display range due to the summarization process shown in FIG. 9 . [ FIG. 12 ] A diagram showing a specific example of the data for restricting the display amount of an object in accordance with the running speed in the map data base shown in FIG. 1 . [ FIG. 13A ] A diagram showing the map display method according to another embodiment of the invention. [ FIG. 13B ] A diagram showing the map display method according to another embodiment of the invention. [ FIG. 14 ] A diagram for explaining a specific example of the linearization process of a polygonal pattern at step 108 shown in FIG. 4 . [ FIG. 15 ] A diagram for explaining another specific example of the linearization process of a polygonal pattern at step 108 shown in FIG. 4 . detailed-description description="Detailed Description" end="tail"?

20060120

20101123

20061005

68103.0

G08G1123

TANG, SIGMUND N

MAP DISPLAY METHOD

UNDISCOUNTED

ACCEPTED

G08G

ACCEPTED

Drilling method

A method of reducing formation breakdown during the drilling of a wellbore which method comprises: (a) circulating a drilling mud in the wellbore comprising (i) an aqueous or oil based fluid, (ii) at least one fluid loss additive at a concentration effective to achieve a high temperature high pressure (HTHP) fluid loss from the drilling mud of less than 2 ml/30 minutes and (iii) a solid particulate bridging material having an average particle diameter of 25 to 2000 microns and a concentration of at least 0.5 pounds per barrel; (b) increasing the pressure in the wellbore to above the initial fracture pressure of the formation such that fractures are induced in the formation and a substantially fluid impermeable bridge comprising the solid particulate bridging material and the fluid loss additive(s) is formed at or near the mouth of the fractures thereby strengthening the formation; (c) thereafter continuing to drill the wellbore with the pressure in the wellbore maintained at above the initial fracture pressure of the formation and below the breakdown pressure of the strengthened formation.

1-18. (canceled) 19. A method of reducing formation breakdown during the drilling of a wellbore which method comprises: (a) circulating a drilling mud in the wellbore comprising (i) an aqueous or oil based fluid, (ii) at least one fluid loss additive at a concentration effective to achieve a high temperature high pressure (HTHP) fluid loss from the drilling mud of less than 2 ml/30 minutes wherein the HTHP fluid loss is determined using an HTHP test according to the specifications of the American Petroleum Institute (API), as described in API Recommended Practice 13B-2 Third Edition, February 1998, Section 5.2.1 to 5.2.3 or Recommended Practice 13B-1 Second Edition, September 1997, Section 5.3.1 to 5.3.2, and (iii) a solid particulate bridging material having an average particle diameter of 25 to 2000 microns and a concentration of at least 0.5 pounds per barrel (1.43 kg/m3); (b) increasing the pressure in the wellbore to above the initial fracture pressure of the formation such that fractures are induced in the formation and a substantially fluid impermeable bridge comprising the solid particulate bridging material and the fluid loss additive(s) is formed at or near the mouth of the fractures thereby strengthening the formation; (c) thereafter continuing to drill the wellbore with the pressure in the wellbore maintained at above the initial fracture pressure of the formation and below the breakdown pressure of the strengthened formation. 20. A method as claimed in claim 19 wherein the pressure in the wellbore in step (c) is maintained at least 300 psi (2.07 M Pa) above the initial fracture pressure of the formation and below the breakdown pressure of the strengthened formation. 21. A method as claimed in claims 19 or 20 wherein the solid particulate bridging material is added to a circulating drilling mud having an HTHP fluid loss value of less than 2 ml/30 minutes prior to increasing the pressure in the wellbore to above the initial fracture pressure of the formation. 22. A method as claimed in claims 19 or 20 wherein the strengthened formation is a depleted formation. 23. A method as claimed in claims 19 or 20 wherein the strengthened formation is a weak formation in a previously drilled section of wellbore. 24. A method as claimed in claims 19 or 20 wherein the drilling mud has a HTHP fluid loss value of less than 1 ml/30 minutes, preferably less than 0.5 ml/30 minutes. 25. A method as claimed in claims 19 or 20 wherein the concentration of solid particulate bridging material in the circulating drilling mud is at least 10 lb per barrel (26.6 kg/m3), preferably at least 15 lb per barrel (42.9 kg/m3). 26. A method as claimed in claims 19 or 20 wherein the drilling mud is recycled to the wellbore after separating material having a size of greater than 500 microns therefrom using a 35 mesh screen (US sieve series). 27. A method as claimed in claim 26 wherein fresh solid particulate bridging material is added to the drilling mud prior to recycling the drilling mud to the wellbore. 28. A method as claimed in claim 19 wherein the drilling mud is recycled to the wellbore after separating drill cuttings from the drilling mud using a centrifuge or hydrocyclone. 29. A method as claimed in claim 23 wherein a pill of the drilling mud having a concentration of solid particulate bridging material of at least 50 lb per barrel (143 kg/m3) is circulated to the weak formation and is squeezed into the weak formation with the pressure in the wellbore in the vicinity of the weak formation maintained at above the initial fracture pressure of the weak formation. 30. A drilling mud composition comprising (a) an aqueous or oil based fluid; (b) at least one fluid loss additive at a concentration effective to achieve a high temperature high pressure (HTHP) fluid loss from the drilling mud of less than 2 ml/30 minutes wherein the HTHP fluid loss is determined using an HTHP test according to the specifications of the American Petroleum Institute (API), as described in API Recommended Practice 13B-2 Third Edition, February 1998, Section 5.2.1 to 5.2.3 or Recommended Practice 13B-1 Second Edition, September 1997, Section 5.3.1 to 5.3.2; and (c) a solid particulate bridging material having an average particle diameter in the range 50 to 1500 microns and a concentration of at least 0.5 pounds per barrel (1.43 kg/m3). 31. A drilling mud composition as claimed in claim 30 having a specific gravity in the range 0.9 to 2.5. 32. A drilling mud composition as claimed in claims 30 or 31 wherein the solid particulate bridging material comprises at least one substantially crush resistant particulate solid selected from the group consisting of graphite, calcium carbonate (preferably marble), dolomite, celluloses, micas, sand and ceramic particles. 33. A drilling mud composition as claimed in claim 30 wherein the concentration of the solid particulate bridging material is at least 10 pounds per barrel (28.6 kg/m3), preferably at least 15 pounds per barrel (42.9 kg/m3). 34. A drilling mud composition as claimed in claim 30 wherein the solid particulate bridging material has an average particle diameter in the range 250 to 1000 microns. 35. A drilling mud composition as claimed in claim 30 having an HTHP fluid loss value of less than 1 ml/30 minutes, preferably less than 0.5 ml/30 minutes. 36. A drilling mud composition as claimed in claim 30 wherein the fluid loss additive(s) is selected from organic polymers of natural or synthetic origin and finely dispersed clays.

The present invention relates to drilling of wells through a subterranean formation, and more particularly to a method of increasing the resistance of the wellbore wall to fracturing during drilling operations. Conventionally, the drilling of a well into the earth by rotary drilling techniques, involves the circulation of a drilling fluid from the surface of the earth down a drill string having a drill bit on the lower end thereof and through ports provided in the drill bit to the well bottom and thence back to the surface through the annulus formed about the drill string. Commonly, drilling fluids are employed that are either oil or water based. These fluids are treated to provide desired Theological properties which make the fluids particularly useful in the drilling of wells. A problem often encountered in the drilling of a well is the loss of unacceptably large amounts of drilling fluid into subterranean formations penetrated by the well. This problem is often referred to generally as “lost circulation,” and the formations into which the drilling fluid is lost are often referred to as “lost circulation zones” or “thief zones”. Various causes may be responsible for the lost circulation encountered in the drilling of a well. For example, a formation penetrated by the well may exhibit unusually high permeability or may contain fractures or crevices therein. In addition, a formation may simply not be sufficiently competent to support the pressure applied by the drilling fluid and may break down under this pressure and allow the drilling fluid to flow thereinto. It is this latter situation where the formation is broken down by the pressure of the drilling fluid to which the present invention is addressed. One of the limiting factors in drilling a particular portion of a well is the mud weight (density of the drilling fluid) that can be used. If too high a mud weight is used, fractures are created in the wall of the borehole with resulting loss of drilling fluid and other operating problems. On the other hand, if too low a mud weight is used, encroachment of formation fluids can occur, borehole collapse may occur due to insufficient support from the fluid pressure in the wellbore, and in extreme cases safety can be compromised due to the possibility of a well blowout. In many cases, wells are drilled through weak or lost-circulation-prone zones prior to reaching a potential producing zone, requiring use of a low mud weight and installation of sequential casing strings to protect weaker zones above a potential producing zone. If a higher weight mud could be used in drilling through weaker or depleted zones, then there is a potential for eliminating one or more casing strings in the well. Elimination of even one casing string from a well provides important savings in time, material and costs of drilling the well. Thus, there is a need for a method of drilling boreholes using a higher mud weight than could normally be used without encountering formation breakdown problems. Surprisingly, it has now been found that formation breakdown during drilling can be controlled by drilling the borehole using an ultra-low fluid loss mud with the pressure of the drilling mud maintained at above the initial fracture pressure of the formation wherein the fractures that are induced in the wellbore wall are bridged at or near the mouth thereof by a solid particulate material that is added to the drilling mud and the bridge is sealed by the accumulation of fluid loss additives in the voids between the bridging particles and/or the precipitation of fluid loss additives onto the bridging particles. The presence of the fluid impermeable bridge at or near the mouth of the fracture strengthens the near wellbbre region of the formation by generating a stress cage. Thereafter, the drilling of the wellbore is continued with the pressure of the drilling mud maintained at below the breakdown pressure of the strengthened formation. Thus, according to a first aspect of the present invention there is provided a method of reducing formation breakdown during the drilling of a wellbore which method comprises: (a) circulating a drilling mud in the wellbore comprising (i) an aqueous or oil based fluid, (ii) at least one fluid loss additive at a concentration effective to achieve a high temperature high pressure (HTHP) fluid loss from the drilling mud of less than 2 ml/30 minutes and (iii) a solid particulate bridging material having an average particle diameter of 25 to 2000 microns and a concentration of at least 0.5 pounds per barrel; (b) increasing the pressure in the wellbore to above the initial fracture pressure of the formation such that fractures are induced in the formation and a substantially fluid impermeable bridge comprising the solid particulate material and the fluid loss additive(s) is formed at or near the mouth of the fractures thereby strengthening the formation; (c) thereafter continuing to drill the wellbore with the pressure in the wellbore maintained at above the initial fracture pressure of the formation and below the breakdown pressure of the strengthened formation. For avoidance of doubt, the strengthened formation may be a permeable or non-permeable formation. Without wishing to be bound by any theory, the mechanism by which the method of the present invention strengthens the wall of the wellbore and hence reduces formation breakdown is that as a fracture is deliberately induced in the wellbore wall, the solid particulate material enters and bridges the fracture at or near the mouth of the fracture. Additives which are conventionally included in the drilling mud to reduce loss of fluid from the drilling mud into the formation subsequently either precipitate on the solid particulate material that bridges the fracture or fill the voids between the solid particulate material thereby establishing a fluid impermeable immobile mass or bridge at or near the mouth of the fracture. Accordingly, fluid from the drilling mud can no longer pass into the fracture and the pressure within the fracture may begin to dissipate until it is substantially the same as the pressure of the surrounding formation. The rate of reduction in pressure within the fracture beyond the bridge will depend on the rock permeability and other factors such as the supporting action of the bridge which maintains the rock displacement caused by the fracture and the sealing action of the bridge which prevents fluid loss from the drilling mud into the fracture. The rock displacement caused by the fracture places the rock in the near wellbore region of the formation (for example, within a radial distance of up to 5 feet from the wellbore wall) in a state of compression, thereby increasing the “hoop stress” and generating a “stress cage”. If there is a reduction in pressure in the fracture beyond the bridge, the fracture will attempt to close and this will impart stress on the fluid impermeable immobile mass or bridge which, in turn, leads to additional compressive stress being imparted to the rock in the near wellbore region of the formation. The increased compressive stress in the near wellbore region of the formation results in the wall of the wellbore having a greater resistance to further fracturing. The method of the present invention therefore allows a drilling mud of higher density to be employed in drilling the wellbore than could be used in the absence of strengthening of the formation. The method also has a further beneficial effect of reducing loss of fluid from the drilling mud into the formation owing to the sealing of the fractures with the fluid impermeable immobile mass. The method of the first aspect of the present invention differs from a conventional “tip screen out” in that a “tip screen out” requires the use of a high fluid loss drilling mud so that particulate material accumulates rapidly at the fracture tip thereby sealing the fracture and preventing further propagation of the fracture. The person skilled in the art would therefore have concerns that the use of an ultra-low fluid loss drilling mud would slow down deposition of particulate material at the fracture tip. Furthermore, there was no understanding that it may be preferable to bridge at or near the mouth of a fracture. Thus, conventional drilling muds employed in a “tip screen out” are designed so that the particulate material readily penetrates into the fracture to deposit at the fracture tip. Also, a “tip screen out” does not create an effective near wellbore “stress cage”. Although the rock at the fracture tip would be under increased compressive stress (owing to the accumulation of particulate material at the fracture tip), this would not apply to the rock between the fracture tip and the mouth of the fracture. Finally, there was a prejudice against using a low fluid loss drilling mud owing to a belief that a low fluid loss mud would slow down the “rate of penetration” while drilling. It was therefore surprising that an ultra-low fluid loss mud does not significantly reduce the “rate of penetration”. The fluid loss value for the drilling mud is determined using a standard high temperature high pressure (HTHP) fluid loss test, according to the specifications of the American Petroleum Institute (API), as described in “Recommended Practice Standard Procedure for Field Testing Oil-Based Drilling Fluids”, API Recommended Practice 13B-2 Third Edition, February 1998, Section 5.2.1 to 5.2.3; and “Recommended Practice Standard Procedure for Field Testing Water-Based Drilling Fluids”, API Recommended Practice 13B-1 Second Edition, September 1997, Section 5.3.1 to 5.3.2. The test employs a pressurized cell fitted with a standard hardened filter paper as a filtration medium. The filtration behaviour of the drilling mud is determined with a standard pressure differential across the filter paper of 500 psi. A filter cake is allowed to build up on the filter paper for 30 minutes and the volume of filtrate collected after this 30 minute period is then recorded. Because the filtration area (3.5 square inches) of the pressurized cell is half the filtration area of a standard API low temperature low pressure (LTLP) fluid loss test (7 square inches), the filtrate volume after 30 minutes is doubled to give a corrected API fluid loss value. Suitably, the temperature at which the high temperature high pressure (HTHP) fluid loss test is carried out corresponds to the temperature in the borehole. Generally, the test temperature is in the range 50 to 150° C. By “fracture pressure” is meant the minimum fluid pressure in the wellbore at which a fracture is created in the wellbore wall. As would be evident to the person skilled in the art, creation of a near wellbore “stress cage” will increase the fracture pressure of the strengthened formation. Accordingly, by “initial fracture pressure” of a formation is meant the fracture pressure of the formation prior to creation of the “stress cage”. The initial fracture pressure of a formation may be readily determined, for example, from historical data. By “breakdown pressure of the strengthened formation” is meant the maximum fluid pressure that can be sustained within the wellbore without creating a fracture in the strengthened formation and/or without breaking down the fluid impermeable bridge(s) that has been formed at or near the mouth of the fracture(s). Suitably, the pressure in the wellbore in step (c) of the method of the first aspect of the present invention is at least 50 psi above the initial fracture pressure of the formation, preferably, at least 300 psi above the initial fracture pressure of the formation, for example 300 to 1000 psi above the initial fracture pressure of the formation, with the proviso that the pressure in the wellbore in step (c) is below the breakdown pressure of the strengthened formation. As is well known to the person skilled in the art, formation pressure generally increases with increasing depth of the wellbore. It is therefore generally necessary to continuously increase the pressure of the drilling mud during the drilling operation, for example, by increasing the density of the drilling mud. A problem arises when the increased pressure of the drilling mud exceeds the initial fracture pressure of a previously drilling formation or exceeds the initial fracture pressure of a formation that is yet to be drilled (hereinafter referred to as “weak formation”). The method of the first aspect of the present invention may therefore be used to strengthen such weak formations thereby allowing the pressure of the drilling mud that is employed for completing the drilling operation to be increased to above the initial fracture pressure of the weak formation. The method of the first aspect of the present invention is particularly advantageous where the weak formation is a depleted formation i.e. a formation having a decreased pore pressure owing to production of hydrocarbons therefrom. This decrease in pore pressure weakens the depleted formation while neighbouring or inter-bedded low permeability formations may maintain their pore pressure. Thus, in a specific embodiment of the first aspect present invention there is provided a method of reducing formation breakdown during the drilling of a wellbore through a weak formation with a circulating drilling mud which method comprises: (a) circulating in a wellbore a drilling mud comprising (i) an aqueous or oil based fluid, and (ii) at least one fluid loss additive at a concentration effective to achieve a high temperature high pressure (HTHP) fluid loss from the drilling mud of less than 2 ml/30 minutes and (iii) a solid particulate bridging material having an average particle diameter of 25 to 2000 microns and a concentration of at least 0.5 pounds per barrel; (b) increasing the pressure of the drilling mud to above the initial fracture pressure of the weak formation such that fractures are induced in the weak formation and a substantially fluid impermeable bridge comprising the solid particulate material and the fluid loss additive(s) is formed at or near the mouth of the fractures thereby strengthening the weak formation; (c) thereafter continuing to drill the wellbore with the pressure in the wellbore maintained at above the initial fracture pressure of the weak formation and below the breakdown pressure of the strengthened formation. It is envisaged that the wellbore may be drilled using a conventional drilling mud until the pressure in the wellbore approaches the initial fracture pressure of the weak formation. The conventional drilling mud is then replaced by (or converted into) the drilling mud employed in step (a) before increasing the pressure in the wellbore to above the initial fracture pressure of the weak formation. The conventional drilling mud may be converted into the drilling mud employed in step (a) by adding at least one fluid loss additive (ii) to the mud until the HTHP fluid loss value of the mud is less than 2 ml/30 minutes and adding the solid particulate bridging material (iii) to the mud in an amount of at least 0.5 pound per barrel. Suitably, the solid particulate bridging material (iii) may be added to a drilling mud comprising components (i) and (ii) immediately before increasing the pressure of the drilling mud to above the initial fracture pressure of the weak formation. Thus, the drilling mud that is used to drill the wellbore until the pressure in the wellbore approaches the initial fracture pressure of the weak formation may comprise components (i) and (ii) in the absence of component (iii). The weak formation may lie in a previously drilled section of the wellbore and/or in the rock that is about to be drilled. Where the weak formation is in the rock that is about to be drilled, it is necessary to replace the entire wellbore fluid with the drilling mud employed in step (a). Thus, the weak formation is strengthened as the wellbore is being drilled. Where the weak formation lies in a previously drilled section of the wellbore, it is only necessary to replace the wellbore fluid in the vicinity of the weak formation. Thus, a drilling mud having a high concentration of the particulate solid material may be introduced into the wellbore as a “pill” and may be circulated to the weak formation where the concentrated drilling mud composition is squeezed into the weak formation at a pressure above the initial fracture pressure of the weak formation so that the bridging particulate material bridges the fractures that are induced in the wellbore wall at or near the mouth thereof. Typically, the pill is squeezed into the weak formation by sealing the annulus between a drill string and the wellbore wall, raising the drill string until it lies immediately below the weak formation, and pumping the pill into the wellbore via the drill string until the pressure in the vicinity of the weak formation is greater than the initial fracture pressure. Generally, the well is then shut in for a period of up to 0.5 hour. After strengthening the weak formation, drilling of the wellbore may be continued using a conventional drilling mud with the proviso that the pressure in the wellbore in the vicinity of the strengthened formation is maintained below the breakdown pressure of the strengthened formation. Suitably, the concentration of bridging material in the pill should be at least 50 pounds per barrel, preferably at least 80 lb per barrel. It is also envisaged that the “pill” may be employed as a completion fluid and may be pumped into the wellbore in advance of a cement when casing a wellbore. In a further aspect of the present invention there is provided a drilling mud composition comprising (a) an aqueous or oil based fluid, (b) at least one fluid loss additive at a concentration effective to achieve a high temperature high pressure (HTHP) fluid loss from the drilling mud of less than 2 ml/30 minutes and (c) a solid particulate bridging material having an average particle diameter of 25 to 2000 microns and a concentration of at least 0.5 pounds per barrel. Suitably, the specific gravity of the drilling mud is in the range 0.9 to 2.5, preferably in the range 1.0 to 2.0. Suitably, the solid particulate bridging material that is included in the drilling mud to bridge the fractures (hereinafter “bridging material”) comprises at least one substantially crush resistant particulate solid such that the bridging material props open the fractures (cracks and fissures) that are induced in the wall of the wellbore. By “crush resistant” is meant that the bridging material is physically strong enough to withstand the closure stresses exerted on the fracture bridge. Preferred bridging materials for adding to the drilling mud include graphite, calcium carbonate (preferably, marble), dolomite (MgCO3.CaCO3), celluloses, micas, proppant materials such as sands or ceramic particles and combinations thereof. These materials are very inert and are environmentally acceptable. It is also envisaged that a portion of the bridging material may comprise drill cuttings having the desired average particle diameter in the range of 25 to 2000 microns. The concentration of the bridging material may vary with the drilling mud used and the conditions of use. The concentration must be at least great enough for the bridging material to rapidly bridge the fractures (i.e. cracks and fissures) that are induced in the wall of the wellbore but should not be so high as to make circulation of the drilling mud impractical. Suitably, the bridging material should bridge the fractures that are induced in the wellbore wall within less than 10 seconds, preferably less than 5 seconds from when the fracture opens so that the fracture remains short. Thus, rapid sealing of the fracture mitigates the risk of the fracture propagating. Suitably, the concentration of bridging material in the drilling mud is at least 5 pounds per barrel, preferably at least 10 pounds per barrel, more preferably at least 15 pounds per barrel, for example, at least 30 pounds per barrel. However, as discussed above, where the drilling mud is employed in a “pill” treatment, the concentration of the bridging particulate material is suitably at least 50 pounds per barrel, preferably at least 80 pounds per barrel. Suitably, the bridging material is sized so as not to enter the pores of any permeable rock through which the wellbore is being drilled. Preferably, the bridging material has an average particle diameter in the range 50 to 1500 microns, more preferably 250 to 1000 microns. The bridging material may comprise substantially spherical particles. However, it is also envisaged that the bridging material may comprise elongate particles, for example, rods or fibres. Where the bridging material comprises elongate particles, the average length of the elongate particles should be such that the elongate particles are capable of bridging the induced fractures at or near the mouth thereof. Typically, the elongate particles will have an average length in the range 25 to 2000 microns, preferably 50 to 1500 microns, more preferably 250 to 1000 microns. The bridging material is sized so as to readily form a bridge at or near the mouth of the induced fractures. Typically, the fractures that are induced in the wellbore wall have a fracture width at the mouth in the range 0.1 to 5 mm. The fracture width is dependent, amongst other factors, upon the strength (stiffness) of the formation rock and the extent to which the pressure in the wellbore is increased to above initial fracture pressure of the formation during the fracture induction step (b) of the method of the present invention (in other words, the fracture width is dependent on the pressure difference between the drilling mud and the initial fracture pressure of the formation during the fracture induction step). It is preferred that at least a portion of the bridging material, preferably, a major portion of the bridging material has a particle diameter approaching the width of the fracture mouth. Preferably, the bridging material has a broad (polydisperse) particle size distribution. It is necessary to keep the bridging material in suspension in the drilling mud. Generally, a drilling mud is recycled to the wellbore after removal of substantially all of the drill cuttings. The drill cuttings may be removed using screens as would be well known to the person skilled in the art. Typically the drilling mud is filtered using a 200 mesh size screen (US sieve series) that retains particles having a size of greater than 74 microns. However, in the method of the present invention, it is necessary to filter the mud using a coarser screen so as to avoid separation of substantial amounts of the bridging material from the mud. Suitably, the drilling mud is filtered using a 35 mesh screen (US sieve series) that retains particles having a size of greater than 500 microns. However, if the rheology of the mud deteriorates through the accumulation of fine drill cuttings in the mud, it may be necessary to employ finer mesh screens for a short period of time. It is also envisaged that separation methods may be employed which allow the bridging solids to be retained but a major portion of the cuttings, preferably substantially all of the cuttings, to be separated from the drilling mud. In particular, the cuttings may be separated from the drilling mud by relying on differences in the densities of the cuttings and the bridging particles, for example, using centrifuges or hydrocyclones. In order to maintain the concentration of the bridging material at the desired value in the drilling mud and/or to maintain the fluid loss value of the drilling mud at below 2 ml/30 minutes, it may be necessary to introduce fresh bridging material and/or fresh fluid loss additives respectively into the circulating drilling mud. Alternatively, or in addition, fresh drilling mud may be either continuously or intermittently added to the drilling mud that is being circulated in the wellbore. The drilling mud has an HTHP fluid loss value of less than 2 ml/30 minutes, preferably, less than 1 ml/30 minutes, more preferably less than 0.5 ml/30 minutes, for example 0.1 to 0.3 ml/30 minutes. As would be well known to the person skilled in the art, such ultra-low fluid loss values may be achieved by incorporating at least one fluid loss additive in the drilling mud. Without wishing to be bound by any theory, it is believed that the fluid loss additive(s) will build up on the solid particulate material that bridges the fractures at or near the mouth thereof thereby forming a fluid impermeable immobile mass. Where the solid particulate bridging material is porous, the fluid loss additives may also enter the pores of the bridging material to seal the pores. Suitable fluid loss additives that may be incorporated in the drilling mud of the present invention include organic polymers of natural or synthetic origin. Suitable polymers include starch or chemically modified starches; cellulose derivatives such as carboxymethylcellulose and polyanionic cellulose (PAC); guar gum and xanthan gum; homopolymers and copolymers of monomers selected from the group consisting of acrylic acid, acrylamide, acrylamido-2-methyl propane sulfonic acid (AMPS), styrene sulphonic acid, N-vinyl acetamide, N-vinyl pyrrolidone, and N,N-dimethylacrylamide wherein the copolymer has a number average molecular weight of from 100,000 to 1,000,000, and preferably 200,000 to 500,000; asphalts (for example, sulphonated asphalts); gilsonite; lignite and its derivative, humic acid; lignin and its derivatives such as lignin sulfonates or condensed polymeric lignin sulfonates; and combinations thereof. These polymeric additives are particularly suitable for use in oil based drilling muds. As an alternative or, in addition, to employing such polymeric additives, the fluid loss from the drilling mud of the present invention may be reduced by adding finely dispersed particles such as clays (for example, illite, kaolinite, bentonite, or sepiolite) to the drilling mud. Suitably, the finely dispersed particles have an average particle size of less than 10 microns, preferably, less than 5 microns, for example, about 1 micron. Preferably, the drilling mud contains a smooth/continuous range of particle sizes ranging from about 1 micron for the finely dispersed particulate fluid loss additives to an average particle diameter of the bridging material of up to 2000 microns i.e. has a broad (polydisperse) particle size distribution. It is envisaged that an oil based drilling mud may contain a significant amount of a discontinuous water phase dispersed in a continuous oil phase by means of at least one emulsifier (a water-in-oil emulsion). The fluid loss value of such drilling muds may vary depending upon the oil to water ratio and the nature of the emulsifier(s) employed to form the water-in-oil emulsion (and hence on the size of the dispersed water droplets). Preferably, the water content of the drilling mud is in the range 80:20 to 50:50, more preferably 70:30 to 55:45. Preferred emulsifiers include imidazolines, fatty acids and combinations thereof. Particularly preferred ultra-low fluid loss oil based drilling muds are described in SPE 77446, “Towards Zero Fluid Loss Oil Based Muds”, M Aston, P Mihalik, J Tunbridge and S Clarke, published 2002, which is herein incorporated by reference. The effectiveness of the method of the present invention has been demonstrated in both laboratory and field conditions as shown by the following Examples. EXAMPLE 1 Oil based mud formulations were evaluated in the laboratory by injecting different drilling muds into a model fracture (as described in SPE/IADC 87130, “Drilling Fluids for Wellbore Strengthening, 2-4 Mar. 2004, M S Aston et al). The model fracture was formed from two rectangular-shaped rock pieces (of 0.3 milliDarcy permeability “Ohio” sandstone). Each rock piece had approximate dimensions of 5 cm width×20 cm length×1 cm breadth. The two rock pieces were sandwiched together to create a fracture having a mouth aperture of 1 mm with the aperture of the fracture tapering to 0.5 mm at the far end thereof (fracture tip). A valve was provided at the exit from the fracture tip such that the fracture tip could be open or sealed. The rock sandwich was placed in a purpose-built holder that was supported in a load frame within a test cell. The fracture width was maintained constant using fixed spacers. The fluid pressure within the fracture was measured just inside the mouth of the fracture using a pressure transducer. Initially, the fracture and the pore spaces in the rock were filled with a clear fluid (water) and the system was heated to a temperature of 60° C. A pressure of about 100 psi was applied to compress any air in the system. Drilling mud was then injected at a pressure of 400 psi into the mouth of the fracture with the fracture tip open (to give a differential pressure across the fracture of 300 psi). After 3 minutes, the exit from the fracture tip was closed using the valve so that pressure could build up inside the fracture (n.b. the initial driving force for bridge formation at the fracture mouth was fluid leak-off through the fracture tip). The injection pressure was then increased stepwise to 2000 psi. A low pressure measured on the pressure transducer indicated an effective seal at the mouth of the fracture. The results shown in Table I below compare the pressures measured just inside the fracture mouth for different drilling muds employed in the above test procedure. The pressure just inside the fracture mouth was measured after a steady value was reached at each injection pressure. TABLE 1 Effectiveness of drilling muds in sealing a model fracture Pressure just inside fracture mouth, measured after different mud injection pressures (IP) in psi Mud System IP 400 IP 1000 IP 2000 Mud 1 Base mud plus bridging 300 900 1900 (Comparative) particulate material mix A; API HTHP fluid loss = 3 mls/ 30 minutes at a temperature of 60° C. Mud 2 As mud 1, but containing 0 30 1900 5 lb/bbl Pliolite, API HTHP fluid loss = 0.3 mls/ 30 minutes at a temperature of 60° C. Mud 3 Base mud plus bridging 0 0 0 particulate material mix B plus 5 lb/bbl Pliolite, API HTHP fluid loss = 0.1 mls/ 30 minutes at a temperature of 60° C. Mud 2 forms a more effective seal than Mud 1 (Comparative). This was achieved by reducing the API HTHP fluid loss of the mud system from 3 ml/30 minutes to 0.3 mls/30 minutes. Mud 3 achieved a total seal at the mouth of the fracture by using an improved bridging particulate material mix in a mud having an API HTHP fluid loss of 0.1 mls/30 minutes. The formulation for the base mud employed in the above tests was as follows: Mineral oil: 0.517 bbls Versamul ™ (emulsifier, ex MI) 4.7 lb/bbl Versawet ™ (wetting agent, ex MI) 7 lb/bbl Geltone ™ (organoclay, ex Halliburton) 6 lb/bbl Lime 5.25 lb/bbl Calcium chloride 17.6 lb/bbl Water 0.346 lb/bbl Barite (barium sulfate) 50 lb/bbl Hymod Prima Clay (simulated drill solids) 4.5 lb/bbl Mud 1 is the base mud containing the following bridging particulate materials (mix A): Baracarb™ 150: 46 lb/bbl Baracarb™ 600: 9.3 lb/bbl Mud 2 is as Mud 1 with the addition of 5 lb/bbl Pliolite® DF-01 (fluid loss control additive supplied by Goodyear) Mud 3 is the base mud containing 5 lb/bbl Pliolite® DF-01 and the following bridging particulate materials (mix B): Baracarb™ 150: 18 lb/bbl Baracarb™ 600: 18 lb/bbl Steelseal™: 15 lb/bbl Baracarb™ 150, Baracarb™ 600 and Steelseal™ were obtained from Halliburton. Baracarb™ 150 and Baracarb™ 600 are calcium carbonates with an average particle diameter of 150 microns and 600 microns, respectively. Steelseal™ is a graphitic carbon available from Halliburton, with an average size range of approximately 400 microns. EXAMPLE 2 A field test was conducted onshore in the Arkoma basin, USA, to determine whether the method of the present invention could raise fracture resistance in a shale formation. The well was a vertical well having a 9⅝″ casing. An extended leak off test (pill squeeze treatment) was performed in 10 feet of exposed shale formation (open hole) just below the 9⅝″ casing shoe. In this test, standard “leak-off” procedures were used whereby the annulus was closed whilst mud was pumped into the wellbore. Initially, a standard diesel based mud was present in the well bore and this mud was pumped into the wellbore at a rate of 0.25 bbls/minute until breakdown of the exposed shale formation occurred. FIG. 1 illustrates the extended leak-off pressure curve for the standard diesel based mud (curve 1). The shale formation fractured at about 1200 psi, at which point pumping of the standard diesel based drilling mud was stopped to minimize fracture growth. The pressure stabilized at 800 psi, which is the propagation pressure of the fractures determined by the far-field stress state. The excess pressure in the wellbore was bled off (back to hydrostatic pressure) so that the fractures closed and the leak-off procedure was then repeated by pumping a pill of a mud according to the present invention (hereinafter “Designer mud”) into the wellbore also at a rate of 0.25 bbls/minute. FIG. 1 additionally illustrates the extended leak off curve for the Designer mud (curve 2). The fractures induced in the wall of the open hole wellbore are bridged and sealed by the bridging particles and fluid loss additives of the Designer mud and the breakdown pressure of the strengthened formation climbs to above 2000 psi before the seal breaks down. This is an increase of about 850 psi formation breakdown pressure compared to the original state of the shale formation, equivalent to 5.4 pounds per gallon (ppg) mud weight. The API HTHP fluid loss value for the Designer mud employed in the field trial was 0.45 mls at a temperature of 115° F. (bottom hole temperature), while the standard diesel based mud had an API HTHP fluid loss of 10 mls at a temperature of 250° F. The Designer Mud was made by adding calcium carbonate bridging solids, graphitic material bridging solids, and fluid loss additives to the standard diesel based mud in accordance with the present invention. The bridging solids ranged in size from 10 to 800 microns and were added in an amount of 80 pounds per barrel. The original standard diesel based mud had a mud weight of 9.0 ppg and was free of added bridging solids.

20060124

20081007

20061116

67634.0

E21B2100

BATES, ZAKIYA W

DRILLING METHOD

UNDISCOUNTED

ACCEPTED

E21B

ACCEPTED

Method of evaluating chromsome state and evaluation system

A method of evaluating a cell state based on information of an image taken of a cell containing a chromosome territory is provided. This method includes extracting the chromosome territory from the image (S20), standardizing a positioning state of the chromosome territory and then quantifying the positioning state (S22), and evaluating the cell state based on the quantified positioning state of the chromosome territory (S26).

1. A method of measuring a chromosome territory, the method detecting a difference in state between a plurality of cells containing a chromosome territory by measuring a desired area of said cells in information of a plurality of images formed from a plurality of pixels having an attribute value, the images being taken of said plurality of cells, the method comprising: extracting said chromosome territory from said image; standardizing a positioning state of said chromosome territory and then quantifying said positioning state; and detecting a difference in state between said cells based on the quantified positioning state of said chromosome territory, said extracting including: classifying said image into a plurality of classes; and extracting any of said classes from said image as a region representing said chromosome territory, and said classifying including: setting an initial value for an attribute parameter indicating an attribute value of each of said classes and for a mixture ratio of each of said classes; calculating based on said attribute parameter and said mixture ratio a class membership probability of each of said plurality of pixels being classified into each of said classes; calculating an evaluation function representing a goodness of estimation based on said membership probability and a mixture probability distribution defined by said attribute parameter and said mixture ratio and determining whether or not said evaluation function satisfies predetermined conditions; updating said attribute parameter and said mixture ratio when said evaluation function does not satisfy said predetermined conditions; and classifying said plurality of pixels into any of said plurality of classes based on said attribute parameter and said mixture ratio when said evaluation function satisfies said predetermined conditions. 2. The measurement method as set forth in claim 1, wherein in said chromosome territory extraction, in addition to extracting a nucleus of said cell said chromosome territory contained in said nucleus is extracted, and said positioning state quantification comprises standardizing a form of said nucleus and transforming coordinates of said chromosome territory based on a change in form between said nucleus before standardization and said nucleus after standardization. 3. The measurement method as set forth in claim 1 or claim 2, the method further comprising: statistically processing quantification results of said positioning state of a plurality of cells, wherein in said detection of difference in state between cells, a difference in state of a single cell is detected based on a result of quantifying said positioning state of said single cell and a result of said statistical processing. 4. The detection method as set forth in claim 3, wherein said statistical processing comprises calculating a standard value of a quantification result of said positioning state based on a result of quantifying said positioning state of a plurality of cells, and in said detection of difference in state between cells, a difference in state of a single cell is detected based on a result of quantifying said positioning state of said single cell and said standard value. 5. A method of measuring a chromosome territory, the method detecting a difference in state between a plurality of cells containing a chromosome territory by measuring a desired area of said cells in information of a plurality of images formed from a plurality of pixels having an attribute value, the images being taken of said plurality of cells, the method comprising: extracting a plurality of chromosome territories from said image; quantifying a positioning state of said plurality of chromosome territories; statistically processing results of quantifying said positioning state of a plurality of cells; and detecting a difference in state of a single cell based on a result of quantifying said positioning state of said single cell and a result of said statistical processing, said extracting including: classifying said image into a plurality of classes; and extracting any of said classes from said image as a region representing said chromosome territory, and said classifying including: setting an initial value for an attribute parameter indicating an attribute value of each of said classes and for a mixture ratio of each of said classes; calculating based on said attribute parameter and said mixture ratio a class membership probability of each of said plurality of pixels being classified into each of said classes; calculating an evaluation function representing a goodness of estimation based on said membership probability and a mixture probability distribution defined by said attribute parameter and said mixture ratio and determining whether or not said evaluation function satisfies predetermined conditions; updating said attribute parameter and said mixture ratio when said evaluation function does not satisfy said predetermined conditions; and classifying said plurality of pixels into any of said plurality of classes based on said attribute parameter and said mixture ratio when said evaluation function satisfies said predetermined conditions. 6. The measurement method as set forth in claim 5, wherein said positioning state comprises at least one of a distance between said plurality of chromosome territories and a positioning direction of said plurality of chromosome territories. 7. The measurement method as set forth in claim 5 or 6, wherein said quantifying comprises calculating a distance between said plurality of chromosome territories. 8. The measurement method as set forth in claim 7, wherein said distance calculation comprises: calculating a center of gravity of each of said plurality of chromosome territories; and calculating a distance between said centers of gravity. 9. The measurement method as set forth in any one of claims 5, 6 or 8, wherein said quantifying comprises quantifying a positioning direction of said plurality of chromosome territories. 10. The measurement method as set forth in claim 9, wherein said positioning direction quantification comprises: detecting a principal axis of each of said plurality of chromosome territories; and calculating an angle of said principal axis. 11. A method of measuring a chromosome territory, the method detecting a difference in state between a plurality of cells containing a chromosome territory by measuring a desired area of said cells in information of a plurality of images formed from a plurality of pixels having an attribute value, the images being taken of said plurality of cells, the method comprising: extracting each of a nucleus of said cell and said chromosome territory from said image; quantifying a positioning state of said nucleus and said chromosome territory; statistically processing a result of quantifying said positioning state of a plurality of cells; and detecting a difference in state of a single cell based on a result of quantifying said positioning state of said single cell and a result of said statistical processing, said extracting including: classifying said image into a plurality of classes; and extracting any of said classes from said image as a region representing said chromosome territory, and said classifying including: setting an initial value for an attribute parameter indicating an attribute value of each of said classes and for a mixture ratio of each of said classes; calculating based on said attribute parameter and said mixture ratio a class membership probability of each of said plurality of pixels being classified into each of said classes; calculating an evaluation function representing a goodness of estimation based on said membership probability and a mixture probability distribution defined by said attribute parameter and said mixture ratio and determining whether or not said evaluation function satisfies predetermined conditions; updating said attribute parameter and said mixture ratio when said evaluation function does not satisfy said predetermined conditions; and classifying said plurality of pixels into any of said plurality of classes based on said attribute parameter and said mixture ratio when said evaluation function satisfies said predetermined conditions. 12. The measurement method as set forth in claim 11, wherein said quantifying comprises calculating a distance between a reference point within said nucleus and said chromosome territory. 13. The measurement method as set forth in any one of claims 5, 6, 8, 10, 11 or 12, wherein said chromosome territory positioning state quantification further comprises standardizing a positioning state of said chromosome territory, and after standardizing the positioning state of said chromosome territory, quantifying said positioning state. 14. The measurement method as set forth in claim 13, wherein said statistical processing comprises calculating a standard value of a quantification result of said positioning state based on a result of quantifying said positioning state of a plurality of cells; and in said detection of difference in state of a single cell, a difference in state of a single cell is detected based on a result of quantifying said positioning state of said single cell and said standard value. 15. The measurement method as set forth in any one of claims 1, 2, 4, 5, 6, 8, 10, 11, 12 or 14, wherein said positioning state comprises at least one of a relative position of said chromosome territory within a nucleus of said cell, a direction of a principal axis of said chromosome territory, and a spread of said chromosome territory. 16. (canceled) 17. The measurement method as set forth in claim 1, wherein said class membership probability calculation comprises: decomposing said plurality of pixels into a plurality of partial spaces according to an attribute value of said pixels; calculating a coarse-grained empirical probability distribution representing a proportion of pixels contained in said partial space; and calculating based on said attribute parameter and said mixture ratio a coarse-grained class membership probability of each of said partial spaces being classified into each of said classes; and said evaluation function calculation comprises calculating a coarse-grained mixture probability distribution by averaging, within said partial space, mixture probability distributions defined by said attribute parameter and said mixture ratio, said evaluation function being calculated based on said coarse-grained empirical probability distribution, said coarse-grained mixture probability distribution, and said coarse-grained class membership probability. 18. (canceled) 19. (canceled) 20. (canceled) 21. (canceled) 22. (canceled)

TECHNICAL FIELD The present invention relates to a method and a system for evaluating a state of a cell and of a chromosome contained in a cell based on a positioning state of a chromosome territory in an interphase of a cell cycle. BACKGROUND ART Conventionally, chromosome morphology can only be observed in a condensed state of a mitotic phase of a cell cycle. However, owing to recent developments in visualization techniques (3D-FISH, confocal laser microscopy), it has become possible to observe the positioning and morphology of chromosomes in an interphase of a cell cycle. In accordance with such visualization techniques it has become clear that, within the nucleus of a cell in an interphase, individual chromosomes are present separately in regions that are not intermingled with each other (Non-patent Publication 1, Non-patent Publication 2). Hereinafter, the region occupied by an individual chromosome within the nucleus is called a chromosome territory. [Non-patent Publication 1] T. Cremer, C. Cremer, CHROMOSOME TERRITORIES NUCLEAR ARCHITECTURE AND VENE REGULATION IN MAMMALIAN CELLS, NATURE REVIEWS/GENETICS, vol. 2, pp. 292-301, 2001 [Non-patent Publication 2] Hideyuki Tanabe, ‘Chromosome territory: recent advancement of studies on interphase chromosome intranuclear positioning in relation to nuclear architecture’, Environ. Mutagen Res., 25, pp. 11 to 22, 2003 [Patent Publication 1] Japanese Laid-open Patent Publication No. 2001-92980 DISCLOSURE OF THE INVENTION It is thought that a change from a normal cell to a tumor cell and a change from a benign tumor cell to a malignant tumor cell are caused by gene mutation or gene translocation. In Non-patent Publication 2, the concept of the probability of spatially adjacent chromosome territories undergoing translocation being higher than that of those positioned far from each other is described. From the above, it can be expected that changes in a cell could be evaluated by examining the spatial positioning of chromosome territories. However, there has conventionally been no technique provided for quantitatively analyzing the spatial positioning of chromosome territories and evaluating changes in a cell. The inventors of the present application have devised the invention below for the purpose of evaluating a cell state by examining the positioning state of a chromosome territory in an interphase of a cell cycle, and using, based on the evaluation result, the cell state as an index for diagnosis of a disease such as cancer. According to the present invention, there is provided a method of evaluating a cell state based on information of an image taken of a cell containing a chromosome territory, the method including extracting the chromosome territory from the image, standardizing a positioning state of the chromosome territory and then quantifying the positioning state, and evaluating a cell state based on the quantified positioning state of the chromosome territory. Here, the positioning state may include at least one of the relative position of the chromosome territory in the cell nucleus, the direction of the principal axis of the chromosome territory, and the spread of the chromosome territory. Furthermore, the standardization referred to is processing in order to quantify the forms of chromosome regions in a plurality of cells using a unified index. By carrying out such processing, quantification can be carried out for a plurality of cells using a unified index. The cell state evaluation referred to here means evaluating the state of a chromosome contained in the cell, and evaluating changes occurring in the cell, the expectancy of an abnormality in the morphology of the cell, chromosome translocation, and the possibility of being affected by a disease such as cancer based on changes occurring in the cell. In accordance with the evaluation method of the present invention, since the form of a chromosome territory can be quantified, it can be expected that, based on the quantification result, an abnormality in the morphology of the cell or the existence of a disease will be detected at an early stage. The image taken of a cell may contain a plurality of images obtained by imaging the cell nucleus at nuclear cross sections, and the chromosome territory extraction may include extracting a chromosome territory image in three dimensions by extracting a chromosome territory from each of the plurality of images and combining these images. In the evaluation method of the present invention, in the chromosome territory extraction, in addition to extracting a cell nucleus a chromosome territory contained in the nucleus may be extracted, and the positioning state quantification may include standardizing the form of a nucleus and transforming the coordinates of a chromosome territory based on a change in form between the nucleus before standardization and the nucleus after standardization. The change in form of the nucleus referred to here may include a change in the shape and a change in the size. The chromosome territory coordinate transformation may be carried out by coordinate transformation based on a relative relationship between the nucleus before standardization and the chromosome territory and a relative relationship between the nucleus after standardization and the chromosome territory. The evaluation method of the present invention may further include statistically processing the quantification results of a positioning state of a plurality of cells, and in the cell state evaluation, a state of a single cell may be evaluated based on a result of quantifying a positioning state of the single cell and a result of statistical processing. In the evaluation method of the present invention, the statistical processing may include calculating a standard value of the quantification result of the positioning state based on the result of quantifying a positioning state of a plurality of cells, and in evaluating a cell state, a state of a single cell may be evaluated based on a result of quantifying a positioning state of the single cell and the standard value. In the evaluation method of the present invention, the standard value calculation may include calculating an average value of the result of quantifying the positioning of chromosomes of a plurality of cells. According to the present invention, there is provided a method of evaluating a cell state based on information of an image taken of a cell containing a chromosome territory, the method including extracting a plurality of chromosome territories from the image, quantifying a positioning state of the plurality of chromosome territories, statistically processing the result of quantifying the positioning state of a plurality of cells, and evaluating a state of a single cell based on a result of quantifying a positioning state of the single cell and a result of statistical processing. In this way, by comparing the result of quantifying the positioning state of a chromosome territory of a single cell with the result of statistical processing, the degree of abnormality of the single cell can be evaluated. Furthermore, in accordance with the evaluation method of the present invention, since the form of a chromosome territory can be quantified, it can be expected that, based on the quantification result, an abnormality in the morphology of the cell or the existence of a disease will be detected at an early stage. In the evaluation method of the present invention, the positioning state may include at least one of a distance between the plurality of chromosome territories and a positioning direction of the plurality of chromosome territories. In the evaluation method of the present invention, the quantification may include calculating a distance between the plurality of chromosome territories. In the evaluation method of the present invention, the distance calculation may include calculating a center of gravity of each of the plurality of chromosome territories and calculating a distance between the centers of gravity. Furthermore, in the evaluation method of the present invention, the distance calculation may be carried out as follows. In the evaluation method of the present invention, the distance calculation may include calculating a distance between chromosome territories using the Mahalanobis distance. In the evaluation method of the present invention, the distance calculation may include calculating a distance between boundaries of chromosome territories. Here, as the distance between boundaries of chromosome territories, the shortest distance between the boundaries may be used. In the evaluation method of the present invention, the distance calculation may include approximating the forms of the plurality of chromosome territories using a normal distribution, calculating an average value of the normal distribution of each of the chromosome territories, and calculating a distance between the average values. In the evaluation method of the present invention, the distance calculation may include detecting a skeleton line of each of the plurality of chromosome territories, calculating a center of gravity of the skeleton line, and calculating a distance between the centers of gravity. In the evaluation method of the present invention, the quantification may include quantifying the positioning direction of the plurality of chromosome territories. In the evaluation method of the present invention, the quantification of the positioning direction may include detecting a principal axis of each of the plurality of chromosome territories and calculating an angle of the principal axis. In the evaluation method of the present invention, the detection of a principal axis may include approximating the forms of the plurality of chromosome territories using a normal distribution, calculating an average value of the normal variance and a covariance matrix of each of the chromosome territories based on the approximated forms of the chromosome territories, and subjecting the covariance matrix to eigenvalue decomposition. According to the present invention, there is provided a method of evaluating a cell state based on information of an image taken of a cell containing a chromosome territory, the method including extracting each of a cell nucleus and a chromosome territory from the image, quantifying a positioning state of the nucleus and the chromosome territory, statistically processing the result of quantifying the positioning state of a plurality of cells, and evaluating a state of a single cell based on a result of quantifying a positioning state of the single cell and a result of statistical processing. In the evaluation method of the present invention, the quantification may include calculating a distance between a reference point within the nucleus and the chromosome territory. The reference point within the nucleus referred to here may be, for example, a nuclear wall or a center of gravity. In the evaluation method of the present invention, the quantification of a positioning state of the chromosome territory may further include standardizing a positioning state of the chromosome territory, and the positioning state quantification may be carried out after standardizing a positioning state of the chromosome territory. In the evaluation method of the present invention, the statistical processing may include calculating a standard value of a quantification result of a positioning state based on a result of quantifying a positioning state of the plurality of cells, and in the cell state evaluation, a state of a single cell may be evaluated based on a result of quantifying the positioning state of the single cell and the standard value. In the evaluation method of the present invention, the calculation of a standard value may include calculating an average value of results of quantifying a positioning state of a plurality of cells. According to the present invention, there is provided a method of evaluating a cell state based on information of an image taken of a cell containing a chromosome territory, the method including extracting each of a cell nucleus and a plurality of chromosome territories from the image, standardizing the form of the nucleus, transforming the coordinates of the chromosome territories based on a fixed criterion determined according to a change in form between the nucleus before standardization and the nucleus after standardization, calculating a center of gravity of each of the transformed chromosome territories, calculating a distance between the centers of gravity of the plurality of chromosome territories, statistically processing the obtained distance between the centers of gravity with respect to a plurality of cells, and evaluating a state of a single cell based on the distance between the centers of gravity of the single cell and a result of statistical processing. In the evaluation method of the present invention, the evaluation of a cell state may include quantifying, using the t-test, a difference between a result of quantifying a positioning state of the single cell and a result of statistical processing. In the evaluation method of the present invention, the evaluation of a cell state includes quantifying, using the chi-square test, a difference between a result of quantifying a positioning state of the single cell and a result of statistical processing. According to the present invention, there is provided a system for evaluating a cell state based on information of an image taken of a cell containing a chromosome territory, the system including an extraction processing unit which extracts a chromosome territory from the image, a quantification processing unit which quantifies a positioning state of the extracted chromosome territory, a memory unit which stores a result of quantifying the positioning state, a statistical processing unit which statistically processes results of quantifying a positioning state of a plurality of cells, and an evaluating unit which evaluates a state of a single cell based on a result of quantifying a positioning state of the single cell and a result of statistical processing. In the evaluation system of the present invention, the quantification processing unit may standardize the positioning state of the chromosome territory extracted from the image, and quantify said positioning state after standardizing the positioning state of the chromosome territory. In the evaluation system of the present invention, the extraction processing unit may extract a cell nucleus as well as extract a chromosome territory contained in said nucleus, and the quantification processing unit may standardize the form of the nucleus and transform the coordinates of the chromosome territory based on a change in form between the nucleus before standardization and the nucleus after standardization. According to the present invention, there is provided a program which, in a computer, evaluates a cell state based on information of an image taken of a cell containing a chromosome territory, the program making the computer function as a unit which extracts a chromosome territory from the image, a unit which standardizes a positioning state of the chromosome territory and then quantifies the positioning state, and a unit which evaluates a cell state based on the quantified positioning state of the chromosome territory. According to the present invention, there is provided a program which, in a computer, evaluates a cell state based on information of an image taken of a cell containing a chromosome territory, the program making the computer function as an extracting unit which extracts a chromosome territory from the image, a quantifying unit which quantifies a positioning state of the extracted chromosome territory, a memory unit which stores a result of quantifying the positioning state, a statistical processing unit which statistically processes a result of quantifying a positioning state of a plurality of cells, and an evaluating unit which evaluates a state of a single cell based on a result of quantifying a positioning state of the single cell and a result of statistical processing. In the evaluation method of the present invention, the image may be formed from a plurality of pixels each having an attribute value, and the chromosome territory extraction may include classifying an image into a plurality of classes, and extracting any of the classes from the image as a region representing a chromosome territory. The classifying here includes setting an initial value for an attribute parameter indicating an attribute value of each class and for a mixture ratio of the classes, calculating based on the attribute parameter and the mixture ratio a class membership probability of each of the plurality of pixels being classified into each of the classes, calculating an evaluation function which represents a goodness of estimation based on the membership probability and a mixture probability distribution defined by the attribute parameter and the mixture ratio and determining whether or not the evaluation function satisfies predetermined conditions, updating the attribute parameter and the mixture ratio when the evaluation function does not satisfy the predetermined conditions, and classifying the plurality of pixels into any of the plurality of classes based on the attribute parameter and the mixture ratio when the evaluation function satisfies the predetermined conditions. By use of this method, a chromosome territory can be extracted from an image with high accuracy. By extracting a chromosome territory with high accuracy, variation in the quantification result for the chromosome territory can be reduced, and evaluation of a cell state can be improved. In the evaluation method of the present invention, the class membership probability calculation may include decomposing the plurality of pixels into a plurality of partial spaces according to the attribute value of the pixels, calculating a coarse-grained empirical probability distribution representing the proportion of pixels contained in a partial space, and calculating based on the attribute parameter and the mixture ratio a coarse-grained class membership probability of each of the partial spaces being classified into each of the classes; the evaluation function calculation may include calculating a coarse-grained mixture probability distribution by averaging, within a partial space, mixture probability distributions defined by the attribute parameter and the mixture ratio; and an evaluation function may be calculated based on the coarse-grained empirical probability distribution, the coarse-grained mixture probability distribution, and the coarse-grained class membership probability. By carrying out such coarse-graining, the processing time can be greatly shortened. The coarse-graining is explained in detail below. As the method of extracting a chromosome territory of the present invention, the following methods are also effective. (1) An extraction method involving, with respect to an image containing an extraction target image, classifying pixels in the image into a plurality of classes and extracting a desired region, the method including: a first step of decomposing a data space formed from all the attribute values that each pixel of the image can take into partial spaces at a given resolution, and forming a coarse-grained data space that holds sets of pixels taking attribute values in each of said partial spaces, the average of attribute values of said pixels, and the number of said pixels, a second step of calculating a coarse-grained empirical probability distribution in the coarse-grained data space by dividing the number of pixels of each partial space by the total number of pixels contained in the image, a third step of initializing a class mixture ratio and a class parameter that defines the attribute of each class, a fourth step of calculating a conditional probability distribution under a class designated by the class parameter, and calculating a coarse-grained conditional probability distribution by averaging the conditional probability distributions within each partial space, a fifth step of calculating a class membership probability, which is a probability of each pixel belonging to each class, by multiplying the class mixture ratio by the coarse-grained conditional probability distribution, a sixth step of updating the class parameter and the class mixture ratio, a seventh step of calculating an evaluation function using the coarse-grained conditional probability distribution, an eighth step of examining whether or not the evaluation function satisfies given completion conditions, and a ninth step of determining a class to which each pixel belongs based on the class parameter, the class mixture ratio, and the class membership probability when the evaluation function satisfies the given completion conditions, and extracting a desired region. Here, as the evaluation function, a coarse-grained log likelihood may be used. In this process, in the sixth step, the class parameter and the class mixture ratio may be updated so as to increase the evaluation function. Furthermore, in the third step, a number of classes may be initialized. A number of classes may also be set at a given value beforehand. Moreover, in the extraction method of the present invention, the fourth, fifth, sixth, seventh, and eighth steps may be repeated until the evaluation function satisfies the given conditions in the eighth step. (2) The extraction method as set forth in (1) above, wherein when calculating a coarse-grained conditional probability distribution in the fourth step, an average value of attribute values of pixels contained in each partial space is calculated, and a coarse-grained conditional probability distribution in each partial space is calculated using the average value. (3) The extraction method as set forth in (1) or (2) above, wherein the method further includes a tenth step of examining whether the coarse-graining resolution is the original resolution, and an eleventh step of restoring the resolution of a partial space to the original resolution, after the resolution of the partial space is restored to the original resolution, the first step to the eighth step being carried out, and in the third step the class parameter and the class mixture ratio in the ninth step being used as initial values. (4) The extraction method as set forth in any one of (1) to (3) above, wherein in the ninth step a number of pixels belonging to each class is calculated by multiplying a corresponding class mixture ratio when the evaluation function satisfies the given completion conditions by the total number of pixels contained in the image, and a pixel belonging to each class is determined by selecting pixels at the above-mentioned number of pixels in order from the highest class membership probability. (5) The extraction method as set forth in any one of (1) to (4) above, wherein in the seventh step the AIC is used as the evaluation function, and in the sixth step the parameter is changed so as to decrease the evaluation function. (6) The extraction method as set forth in any one of (1) to (4) above, wherein in the seventh step the MDL (Minimum Description Length) is used as the evaluation function, and in the sixth step the parameter is changed so as to decrease the evaluation function. (7) The extraction method as set forth in any one of (1) to (4) above, wherein in the seventh step the Structural Risk is used as the evaluation function, and in the sixth step the parameter is changed so as to decrease the evaluation function. (8) The extraction method as set forth in any one of (1) to (7) above, wherein the third step includes setting a neighbor radius which defines whether or not partial spaces are in the neighborhood of each other, and setting a number of classes (step B1), setting a representative value of each partial space for each of the partial spaces (step B2), setting a set of classification target partial spaces (step B3), selecting, among the set of classification target partial spaces, a partial space having the highest coarse-grained empirical probability (step B4), selecting, as a neighbor set, all partial spaces having a representative value whose distance from the representative value of the partial space having the highest coarse-grained empirical probability is within the neighbor radius (step B5), examining whether or not the shortest distance between the representative value of the partial spaces contained in an already classified class and the representative value of the partial spaces contained in the neighbor set is larger than the neighbor radius (step B6), if in step B6 the shortest distance between the representative value of the partial spaces contained in the already classified class and the representative value of the partial spaces contained in the neighbor set is larger than the neighbor radius, making the neighbor set a new class and deleting the neighbor set from the classification target partial spaces (step B7), if in step B6 the shortest distance between the representative value of the partial spaces contained in the already classified class and the representative value of the partial spaces contained in the neighbor set is smaller than the neighbor radius, adding the neighbor set to the already classified class and deleting the neighbor set from the classification target partial spaces (step B8), examining whether or not the classification target partial spaces are an empty set (step B9), if in step B9 the classification target partial spaces are not an empty set, repeating step B4 and thereafter, if in step B9 the classification target partial spaces are an empty set, examining whether or not the number of classified classes is equal to or greater than a given number (step B10), if in step B10 the number of classified classes is less than the given number, reducing the neighbor radius (step B11), and repeating step B3 and thereafter, and if in step B10 the classification target partial spaces are an empty set and the number of already classified classes is greater than the given number, calculating a class parameter within each class, making this an initial value of the class parameter, and making the ratio of the number of partial spaces contained in each class an initial value of the class mixture ratio (step B12). In steps B7 and B8, if the shortest distance between the representative value of the partial spaces contained in the already classified class and the representative value of the partial spaces contained in the neighbor set is equal to the neighbor radius, either processing may be carried out. (9) An extraction device which, with respect to an image containing an extraction target image, classifies pixels in the image into a plurality of classes and extracts a desired region, the device including, an inputting device which reads in an image, a region coarse-graining device which decomposes a data space formed from all the attribute values that each pixel of the image can take into partial spaces at a given resolution, holds sets of pixels taking attribute values in each of said partial spaces, the average of the attribute values of said pixels, and the number of said pixels, and forms a coarse-grained data space, a coarse-grained empirical probability distribution calculating device which calculates a coarse-grained empirical probability distribution in a coarse-grained data space by dividing the number of pixels of each partial space by the total number of pixels contained in the image, a coarse-grained conditional probability distribution device which calculates a coarse-grained conditional probability distribution by initializing a class parameter defining the attribute of each class and a class mixture ratio, calculating from the class parameter defining the attribute of each class a conditional probability distribution under a designated class, and averaging conditional probability distributions under designated classes for each partial space, a class membership probability calculating device which calculates from the coarse-grained conditional probability distribution a class membership probability of each pixel of the image belonging to each class, a parameter updating device which updates the class parameter and the class mixture ratio, an evaluation function calculating device which calculates an evaluation function using a coarse-grained conditional probability distribution, a region extraction device which extracts a desired region by examining whether or not the evaluation function satisfies given completion conditions, and determining a class to which each pixel belongs based on the class parameter, the class mixture ratio, and the class membership probability when the evaluation function satisfies the given completion conditions, and an outputting device which outputs an extracted region. Here, the evaluation function calculating device may employ as the evaluation function the coarse-grained log likelihood, the AIC, the MDL, or the Structural Risk. When the evaluation function calculating device employs as the evaluation function the coarse-grained log likelihood, the parameter updating device may update the class parameter and the class mixture ratio so as to increase the evaluation function. Furthermore, when the evaluation function calculating device employs as the evaluation function the AIC, the MDL, or the Structural Risk, the parameter updating device may update the class parameter and the class mixture ratio so as to decrease the evaluation function. (10) The extraction device as set forth in (9) above, wherein the device further includes a resolution restoring device which examines whether the coarse graining resolution is the original resolution after it has been confirmed that the evaluation function satisfies the given completion conditions, and restores the resolution of the data space to the original resolution. The operation of the extraction method and the extraction device as set forth in (1) to (10) above are explained below. In the extraction method as set forth in (1) above, the attribute value of each pixel forming an image is considered as a random variable, and a desired region is extracted based on the probability distribution of an estimated pixel value. Here, as the attribute value, for example, a luminance value may be used for a monochrome image, and an intensity, et cetera, of red (R), green (G), and blue (B) color elements may be used for a color image. Here, in order to extract a desired region, the pixels are classified into a plurality of groups having similar attributes, based on the attribute value of each pixel. In the present specification, a set of pixels having similar attributes is called a class. Each class is characterized by an average value, variance, et cetera, of attribute values belonging to the class. Hereinafter, these characteristics of the class are called ‘class parameters’ of the class and are expressed as φi (i=1 , , , k). Here, k is a number of classes. Here, the probability of a jth pixel taking an attribute value of xj can be expressed by the following mixture distribution. [ Eq . ⁢ 1 ] p ⁡ ( x j ) = ∑ i = 1 k ⁢ w i ⁢ f ⁡ ( x j | ϕ i ) ( 1 ) Here, f (xj1|φi) is a conditional probability distribution assuming that data is generated from the ith class, wi is a mixture ratio of each class, and [ Eq . ⁢ 2 ] ∑ i ⁢ = ⁢ 1 ⁢ k ⁢ w ⁢ i = 1 is satisfied. In the case in which the image is a monochrome image, xj is expressed as an integer value of 0 to 255, et cetera. Furthermore, in the case in which the image is a color image, xj is expressed as a three-dimensional vector (xj1, xj2, xj3) whose components are values of RGB color elements. Here, each xj1 (L=1, 2, 3) takes an integer value of, for example, 0 to 255. The mixture ratio wi represents an area ratio (in the case of a two-dimensional region) or a volume ratio (in the case of a three-dimensional region) of regions belonging to different classes. It is assumed that, for example, there is a monochrome image formed from two regions, that is, a bright image region (called Class 1) characterized by having an average luminance of 200 and a luminance standard deviation of 20, and a dark region (called Class 2) characterized by having an average luminance of 50 and a luminance standard deviation of 10. It is also assumed that the bright region occupies 70% of the image area and the dark region occupies 30% thereof. In this case, the number of classes is k=2, the class parameters are φ1=(200, 20) and φ2=(50, 10), and the mixture distribution of this image can be expressed as follows. [Eq. 3] p(xj)=0.7(xj|200, 20)+0.3(xj|50, 10) (2) Hereinafter, the class mixture ratio wi and the class parameter φi are together expressed by θi. Hereinafter, when simply using ‘parameter’, it means θi. In the extraction method as set forth in (1) above, a parameter that maximizes an average log likelihood defined as below is estimated, [ Eq . ⁢ 4 ] L = 1 n ⁢ ∑ j = 1 n ⁢ log ⁢ ⁢ p ⁡ ( x j ) = 1 n ⁢ ∑ j = 1 n ⁢ log ⁡ [ ∑ i = 1 k ⁢ w i ⁢ f ⁡ ( x j | ϕ i ) ] ( 3 ) and region extraction is carried out using the estimated parameter information. Here, n denotes a number of pixels contained in the image. Such a statistical method is called the maximum likelihood method. However, it is in general difficult to estimate a parameter that maximizes the average log likelihood. Therefore, instead of the average log likelihood, an expectation value Q of a complete log likelihood represented by the following amount may be used for estimation of the parameter. [ Eq . ⁢ 5 ] Q = 1 n ⁢ ∑ j = 1 n ⁢ ∑ i = 1 k ⁢ π ij ⁢ log ⁡ [ w i ⁢ f ⁡ ( x j | ϕ i ) ] ⁢ ⁢ H ⁢ ere , ( 4 ) [ Eq . ⁢ 6 ] ⁢ π ij = w if ⁡ ( x j | ϕ i ) ∑ l = 1 k ⁢ w l ⁢ f ⁡ ( x j | ϕ l ) ( 5 ) is a probability of the jth pixel belonging to the ith class. In the present invention, this is called the class membership probability. It has been mathematically proven that if the parameter is updated so as to increase Q, the above-mentioned average log likelihood L is also certain to increase (for example, A. P. Dempster, N. M. Laird, and D. B. Rubin, Maximum Likelihood From Incomplete Data via The EM Algorithm, J. Roy. Stat. Soc., vol. 30, pp. 205-248, 1977 (hereinafter, called Non-patent Publication 3)). A procedure which estimates a parameter and actually extracts a region using the estimated parameter in the present invention is now explained. First, a class membership probability represented by Equation (5) is determined by starting with appropriate initial parameters. Subsequently, the parameters w and φ are updated so as to increase Q, and Q is calculated anew. This procedure is repeated until Q finally stops increasing. A region is extracted using the parameters w and φ when Q finally stops increasing. Among k classes, for example, in order to extract a pixel belonging to the ith class, a value of the membership probability of each pixel belonging to the ith class is first examined. Subsequently, pixels having a probability value of equal to or greater than a certain value are classified as belonging to that class. When all the pixels are classified into corresponding classes, a class having a desired attribute is selected from the k classes, and by extracting the pixels belonging to that class from the image a desired region can automatically be extracted. In the present invention, in order to carry out the maximization of Q at high speed, the coarse-grained probability distribution is introduced. The coarse-grained probability distribution is formed by decomposing a space containing all the values that the data can take (hereinafter, called a data space) into N partial spaces that do not intersect each other, and assigning a probability to each partial space. Specifically, a coarse-grained conditional probability distribution in the jth partial space is defined by [ Eq . ⁢ 7 ] ⁢ f ~ j ⁡ ( ϕ i ) = 1 m ⁡ ( A j ) ⁢ ∫ A j ⁢ f ⁡ ( x | ϕ i ) ⁢ ⅆ z ( 6 ) and the coarse-grained conditional probability distribution is defined as below. [ Eq . ⁢ 8 ] ⁢ f ~ ⁡ ( x | ϕ i ) = ∑ j = 1 N ⁢ f ~ j ⁡ ( ϕ i ) ⁢ I A j ⁡ ( x ) ( 7 ) Here, Aj denotes the jth partial space. When D is the entire data space, [Eq. 9] D=∪jAj,Ai∩Aj=θ(i≠j) (8) are satisfied. Furthermore, IA (x) is an indicator function that is 1 when the data value is contained in the partial space A and otherwise is 0, and [Eq. 10] m(A)=∫Adx is a measure of A (the area of A when the data space is two-dimensional and the volume when it is three-dimensional). By use of the coarse-grained conditional probability distribution thus defined, Q shown in Equation (4) above can be rewritten as follows. [ Eq . ⁢ 11 ] Q ~ = ∑ i = 1 k ⁢ q ~ j ⁢ π ~ ij ⁢ log ⁡ [ w i ⁢ f ~ j ⁡ ( ϕ i ) ] ⁢ ⁢ Here , ( 9 ) [ Eq . ⁢ 12 ] q ~ j = 1 n ⁢ ∑ l = 1 n ⁢ I A j ⁡ ( x l ) ( 10 ) is a coarse-grained empirical probability distribution, and [ Eq . ⁢ 13 ] π ~ ij = w i ⁢ f ~ j ⁡ ( ϕ i ) ∑ i = 1 k ⁢ w i ⁢ f ~ j ⁡ ( ϕ i ) ( 11 ) is a coarse-grained class membership probability. By maximizing the coarse-grained complete log likelihood given by Equation (9), the coarse-grained average log likelihood below can be maximized. [ Eq . ⁢ 14 ] L ~ = ∑ j = 1 N ⁢ q ~ j ⁢ log ⁡ [ ∑ i = 1 k ⁢ w i ⁢ f ~ j ⁡ ( ϕ i ) ] ( 12 ) Compared with the original Q, the Q given by Equation (4) is the sum with respect to the entire data, but the coarse-grained complete log likelihood given by Equation (9) is the sum only with respect to the partial spaces. As hereinafter described, by carrying out such coarse-graining, the amount of calculation can be greatly reduced. For example, in the case of a 512×512 pixel image, if Equation (4) is used, it is necessary to take a sum of more than 260,000 data, but if the coarse-grained distribution of the present invention is used, it can be reduced down to a sum of about 1,000 with respect to the partial spaces, and a high speed estimation can be carried out. Furthermore, in the extraction method as set forth in (2) above, the coarse-grained probability value of each partial space is approximated by a probability value at an average value of the data contained in the partial space. [Eq. 15] {tilde over (f)}j(φi)=f({tilde over (T)}j|φi) (13) Here, [ Eq . ⁢ 16 ] x ~ j = 1 ∑ l = 1 n ⁢ I A j ⁡ ( x l ) ⁢ ∑ l = 1 n ⁢ x l ⁢ I A j ⁡ ( x l ) ( 14 ) is an average value of the data contained in the jth partial space Aj. By this approximation, integration (or summation) within a partial space can be omitted, and the amount of calculation can be further reduced. Furthermore, it is also possible to carry out estimation again at the original resolution using, as an initial value, a parameter estimated using the coarse-grained probability distribution. In this case, since substantially the most appropriate parameter has been obtained by use of the coarse-grained probability distribution, compared with a case in which estimation is carried out from the beginning at the original resolution, the number of times of sequential updating of the parameter can be greatly reduced, and a highly accurate estimation can therefore be carried out at high speed. Furthermore, when a region is extracted, it is also possible to carry out estimation of the number of pixels belonging to the ith region by multiplying the estimated mixture ratio wi by the total number of pixels. The top ni pixels having the highest region membership probability are extracted as the pixels belonging to this region. By this method, a threshold value, which is the value of the probability value up to which it is considered to belong to the region, can automatically be determined. In the present invention, in order to quantify the form of the chromosome territory and evaluate a cell state based on the quantification result, it is necessary to extract a chromosome territory from an image with good accuracy. By automatically determining a threshold value as described above, a chromosome territory can be extracted with good accuracy. Moreover, as the evaluation function, it is also possible to use each of the AIC, the MDL, and the Structural Risk and select a model that gives the smallest value. When the AIC, the MDL, or the Structural Risk is used as the evaluation function, if an excessive number of parameters are used, since the value of the evaluation function increases, it is possible to estimate an optimum number of parameters. This enables an appropriate number of regions, that is, how many types of regions an image is formed from, to be estimated. As hereinbefore described, when a chromosome territory is extracted from an image, if coarse-graining is carried out, compared with a case in which no coarse-graining is carried out, since the amount of calculation of the conditional probability distribution or the class membership probability can be greatly reduced, the time taken for extracting a chromosome territory can be greatly shortened. Although the class parameter estimated as a result of such processing has poorer accuracy compared with a case in which no coarse-graining is carried out, since extraction of a region is carried out based on the class membership probability calculated from the class parameter in the extraction method of the present invention, it is possible to extract a region with good accuracy without being influenced by errors from coarse-graining. Constitutions of the present invention are explained above, and any combination of these constitutions is also effective as an embodiment of the present invention. Furthermore, conversion of expression of the present invention into another category is also effective as an embodiment of the present invention. In accordance with the evaluation method of the present invention, a positioning state of a chromosome territory in an interphase of a cell cycle can be quantified. This enables a cell state to be evaluated statistically. BRIEF DESCRIPTION OF THE DRAWINGS The above-mentioned object, other objects, features, and advantages will become more apparent from a preferred embodiment described below and the following drawings attached thereto. [FIG. 1] A flowchart showing a processing procedure of a cell state evaluation method in an embodiment of the present invention. [FIG. 2] A block diagram showing an evaluation device of the present embodiment carrying out the processing procedure shown in FIG. 1. [FIG. 3] A block diagram showing an extraction processing unit shown in FIG. 2. [FIG. 4] A flowchart showing a processing procedure of the extraction processing unit. [FIG. 5] A diagram showing a coarse-grained data space and a partial space when coarse-graining has been carried out. [FIG. 6] A flowchart showing a processing procedure of initial value determination for a parameter based on a coarse-grained empirical distribution. [FIG. 7] A diagram specifically explaining the procedure explained with reference to FIG. 6. [FIG. 8] A block diagram showing another example of the extraction processing unit. [FIG. 9] A flowchart showing a processing procedure of the extraction processing unit shown in FIG. 8. [FIG. 10] A flowchart showing a processing procedure for quantifying a positioning state of a chromosome territory. [FIG. 11] A schematic diagram showing a manner in which coordinates of a chromosome territory are transformed. [FIG. 12] A diagram showing a plurality of chromosome territories whose coordinates have been transformed into the interior of a reference sphere. [FIG. 13] A block diagram showing another example of the evaluation device. [FIG. 14] A diagram showing a chromosome territory extracted by the extraction processing unit of the present embodiment. [FIG. 15] A diagram in which, in groups of cells before cytodifferentiation and after cytodifferentiation, distances between the centers of gravity of territories of chromosome 12 and chromosome 16 at the closest position are compared as a relative value to a standardized nuclear radius. [FIG. 16] A diagram showing radial distributions of chromosome 12, prior to standardization of nuclear form, before cytodifferentiation and after cytodifferentiation. [FIG. 17] A diagram showing radial distributions of chromosome 12, subsequent to standardization of nuclear form, before cytodifferentiation and after cytodifferentiation. BEST MODE FOR CARRYING OUT THE INVENTION FIG. 1 is a flowchart showing a processing procedure of the method of evaluating a cell state in an embodiment of the present invention. First, from an image taken of a cell containing a chromosome territory, a chromosome territory image is extracted (S20). In the present embodiment, images of the cell nucleus and a plurality of chromosome territories are each extracted from a three-dimensional image. Subsequently, a positioning state of the chromosome territory is quantified (S22). The result of quantifying the positioning state of the chromosome territory is stored. For a plurality of samples, processing of step 20 and processing of step 22 are carried out, and quantification results for the plurality of samples are accumulated (S24). Furthermore, a particular sample is subjected to processing of step 20 and processing of step 22, the quantification result is compared with the quantification results of the plurality of samples accumulated in step 24, and a cell state of the particular sample is thus evaluated (S26). FIG. 2 is a block diagram showing an evaluation device of the present embodiment carrying out the processing procedure shown in FIG. 1. An evaluation device 100 includes an image acquiring unit 102, an extraction processing unit 104, a quantification processing unit 106, an evaluating unit 110, an outputting unit 112, and a quantification result memory unit 114. The image acquiring unit 102 acquires a three-dimensional image taken of a cell containing a chromosome territory. The extraction processing unit 104 extracts a chromosome territory image from the three-dimensional image. The quantification processing unit 106 quantifies a positioning state of the chromosome territory. The quantification processing unit 106 stores the quantification result in the quantification result memory unit 114. The evaluating unit 110 compares the quantification result of a particular sample with the quantification results of a plurality of samples stored in the quantification result memory unit 114, and evaluates a cell state of the particular sample. The outputting unit 112 outputs the result of extraction of a chromosome region image by the extraction processing unit 104, or the result of evaluation of a cell state by the evaluating unit 110. The outputting unit 112 may be formed from, for example, a display device or a printer. Each procedure shown in FIG. 1 is explained below. (Extraction of Chromosome Territory (S20)) A three-dimensional image of a cell containing a chromosome territory may be obtained using the 3D-FISH (Fluorescent in situ hybridization) method. The image acquiring unit 102 may be formed from an image scanner, a digital camera, et cetera, and an image obtained using the 3D-FISH method may be read in. Furthermore, the image acquiring unit 102 may be formed from a computer connected to a biological microscope, and it is possible to directly input an image via a network. The procedure of the 3D-FISH method is explained below. Cells are cultured on a cover glass, and PFA (Paraformaldehyde) is used for fixing cells. Subsequently, a treatment with a TritonX100 solution is carried out. Freezing and thawing is then repeated several times using liquid nitrogen. Following this, a hydrochloric acid treatment and a pepsin treatment are carried out. This allows cell membrane and nuclear membrane to be partially destroyed, thus enhancing the penetrability for a probe. Furthermore, the above-mentioned treatments enable parts other than the nucleus to be removed to some extent. Subsequently, cells are fixed again, and DNA is denatured at about 75° C. As a result, double strand DNA is converted into single strands. Labeled probes (DNA fragments that are complementary to a target chromosome territory and the nucleus) are added thereto, and by carrying out a reaction at about 37° C., the probes are complementarily bonded to the target chromosome territory and the nucleus. The probes are provided with dyes that generate colors at different wavelengths according to the type of target chromosome territory and the nucleus. By irradiating with a wavelength at which a particular dye generates a color, it is possible to make only that dye generate a color distinctively. By irradiating a sample prepared as above with a particular wavelength using a confocal laser microscope, an image containing a target chromosome territory is obtained. By superimposing images containing chromosome territories and an image containing the nucleus, an image containing a plurality of chromosome territories may be obtained. Processing to which the image thus obtained is subjected is explained below. Hereinafter, when simply ‘chromosome territory’ and ‘nucleus’ are referred to, they do not mean the chromosome territory or the nucleus themselves, but mean a chromosome territory image and a nucleus image on an image. The extraction processing unit 104 shown in FIG. 2 carries out image processing involving extracting a chromosome territory from an image obtained as above. In the present embodiment, the extraction processing unit 104 extracts images of the chromosome territory and the nucleus from the image by classifying an image containing a plurality of pixels into a plurality of classes, and assigning each of the plurality of classes to the chromosome territory and the nucleus. In this process, the extraction processing unit 104 assumes that there are a plurality of luminance sources having different luminances in each pixel, and carries out a classification based on the probability of each luminance source belonging to that pixel and the mixture ratio of the luminance sources in the image. Such a technique is described in, for example, Japanese Laid-open Patent Publication No. 2001-92980 (hereinafter called Patent Publication 1). Patent Publication 1 describes a technique in which, from image data, an expectation value of a region membership probability of each pixel on an image belonging to each of the regions is calculated, an evaluation function is calculated based on a mixture probability distribution determined from the region membership probability and a region parameter, each of the regions is separated based on the region membership probability in the above process, and a contour is extracted based on the separated regions. In the present embodiment, the concept of coarse-graining is further introduced to this technique, and an optimum parameter is obtained at high speed. FIG. 3 is a block diagram showing the extraction processing unit 104 shown in FIG. 2. FIG. 4 is a flowchart showing a processing procedure of the extraction processing unit 104. The extraction processing unit 104 in an embodiment of the present invention includes an inputting device 1 which reads in image data, a data space coarse-graining device 2, a parameter updating device 6, a coarse-grained empirical probability distribution calculating device 3, a coarse-grained conditional probability distribution calculating device 4, a class membership probability calculating device 5, an evaluation function calculating device 7, a region extraction device 8, and an outputting device 9. The inputting device 1 inputs, from the image acquiring unit 102, a color image of a cell obtained by the 3D-FISH method as described above (step A1). The inputting device 1 sends the data thus read in to the data space coarse-graining device 2. The data space coarse-graining device 2 decomposes the data space into N partial spaces that do not intersect each other so as to form a coarse-grained data space (step A2). The data space referred to here means a set of all the attribute values that the pixels of an image can take. For example, in a standard gray scale image, the attribute of each pixel may be expressed as a luminance, and the luminance is usually a one-dimensional space expressed by an integer of 0 to 255. Furthermore, in the case of a standard color image, it is usually a three-dimensional space expressed by an integer of 0 to 255 for each color element of R, G, and B. The data space coarse-graining device 2 sections each of the RGB values into, for example, eights if the resolution is 8, and a 8×8×8 cube may be defined as one partial space. The resolution need not be identical in the axes of three dimensions. For example, coarse-graining may be carried out by sectioning the R axis into h1, the G axis into h2, and the B axis into h3 as long as the partial spaces do not overlap each other and the entire data space is covered without fail. Hereinafter, when expressed as coarse-graining with a resolution of h, it means that the RGB values are sectioned into h×h×h. Furthermore, the data space coarse-graining device 2 contains sets of pixels (the numbers of the pixels) that take values in each partial space, the average attribute values of these pixels, and the number of pixels. FIG. 5 shows a coarse-grained data space 11 and a partial space 12 when coarse-graining is carried out at a resolution of h1×h2×h3. For example, when an attribute value xj of a jth pixel is such that R=128, G=255, and B=18, if coarse-graining is carried out at a resolution of 8, this pixel takes a value in a partial space designated by an index (16, 31, 2). This is expressed below by xj being contained in this partial space. Referring back to FIG. 3, after forming a coarse-grained data space, the data space coarse-graining device 2 sends the numbers of the pixels contained in each partial space and the number of pixels to the coarse-grained empirical probability distribution calculating device 3. The coarse-grained empirical probability distribution calculating device 3 calculates a coarse-grained empirical probability distribution (step A3). The coarse-grained empirical probability distribution referred to here indicates a probability distribution calculated from a value obtained by dividing observation data contained in each partial space of the coarse-grained data space by the total number of pixels. The coarse-grained empirical probability distribution calculating device 3 sends the coarse-grained empirical probability distribution to the coarse-grained conditional probability distribution calculating device 4. The coarse-grained conditional probability distribution calculating device 4 initializes a class parameter (step A4). The procedure of determining an initial value for the parameter is described later. The coarse-grained conditional probability distribution calculating device 4 also calculates a coarse-grained conditional probability distribution (step A5). Specifically, the coarse-grained conditional probability distribution is calculated as follows. Here, it is assumed that a conditional probability under the condition that the jth pixel value is generated from an ith class is given by the multidimensional normal distribution shown below. [ Eq . ⁢ 17 ] f ⁢ ( ⁢ x ⁢  ϕ i ) = 1 ( 2 ⁢ ⁢ π ) 3 ⁢  ∑ i  ⁢ exp [ - 1 2 ⁢ ( x - μ i ) T ⁢ ∑ i - 1 ⁢ ( x - μ i ) ] ( 15 ) Here, x denotes a three-dimensional vector formed from each color of RGB, μi denotes a three-dimensional vector showing an average color of the ith class, Σi denotes a covariance matrix of the ith class, and |Σi| and Σi−1 denote the determinant and the inverse matrix respectively of the matrix Σi. Furthermore, (x−μi)T denotes transposition. In the case in which the image is a gray scale, a conditional probability under the condition that the jth pixel value is generated from the ith class is given by a one-dimensional normal distribution shown below. [ Eq . ⁢ 18 ] f ⁢ ( ⁢ x ⁢  ϕ i ) = 1 σ i ⁢ 2 ⁢ ⁢ π ⁢ exp ⁡ [ - ( x - μ i ) 2 / 2 ⁢ ⁢ σ i 2 ] Here, x denotes a scalar value expressing a luminance value, μi denotes a scalar value expressing an average luminance of the ith class, and σi denotes a standard deviation of the luminance of the ith class. The coarse-grained conditional probability distribution calculating device 4 calculates this conditional probability using an equation given by Equation (6). In this process, a measure m (Aj) of each partial space is the volume of each partial space. For example, when coarse-graining is carried out uniformly at a resolution of 8, it is 8×8×8=512. The coarse-grained conditional probability distribution calculating device 4 may approximate the coarse-grained conditional probability distribution using Equation (13). In accordance with this method, it becomes unnecessary to carry out the operation given by Equation (6) each time the parameter is updated, thereby greatly reducing the amount of calculation. The coarse-grained conditional probability distribution calculating device 4 is capable of determining an initial value for the parameter based on the coarse-grained empirical probability distribution. It roughly classifies each partial space, determines an average value or a variance value within each class obtained as a result of the classification, and determines these values as initial values for parameter estimation. FIG. 6 is a flowchart showing a processing procedure of determining an initial value for a parameter based on the coarse-grained empirical distribution. The procedure of setting an initial value for the parameter is explained below with reference to FIG. 6. Firstly, in step B1, a neighbor radius and a number of classes that are to be classified are set. The neighbor radius referred to here is a reference value for carrying out a rough classification by considering all of the partial spaces within the range to belong to the same class. For example, in the case of a color image, pixels having similar colors have RGB values that are close to each other, and they can therefore be naturally considered to be classified into the same class. When the neighbor radius is too large, classification might be completed before a desired number of classes is attained. In such a case, as described later, the neighbor radius is reduced, and classification is carried out again. It is thereby possible to finally carry out classification into a necessary number of classes. An initial value for this neighbor radius is therefore set at a sufficiently large value, for example, 50. As the number of classes to be classified into, a given value is used as it is. Subsequently, in step B2, a representative value for each partial space is set for each partial space. As the representative value for each partial space, for example, a median value, et cetera, of the partial space can be used. Hereinafter, a distance between these representative values is defined as a distance between partial spaces. Subsequently, a set of partial spaces, which become a classification target, is set (step B3). Hereinafter, this set is expressed as Ω. An initial value for Ω is a set formed from all the partial spaces containing data. Furthermore, the number i of already classified classes is 1, and an initial value for an already classified class Ci is an empty set. Subsequently, among the partial spaces belonging to Ω, a partial space that has the highest coarse-grained empirical probability is selected (step B4). This partial space is expressed as As. Subsequently, a distance between a partial space belonging to Ω and As is examined, all the partial spaces that are within a neighbor radius rare selected, and this is determined to be a neighbor set (step B5). Hereinafter, the neighbor set is expressed as Bs. Subsequently, the shortest distance between a partial space contained in the already classified class Ci and a partial space contained in the neighbor set Bs is determined, and it is examined whether or not this is larger than the neighbor radius r (step B6). If this shortest distance is larger than r, since the neighbor set Bs has an attribute that is sufficiently different from that of the already classified class and appears with high probability, it may be considered to be a new class. Therefore, the neighbor set is employed as a new class as it is. Since classification of Bs has been completed, it is deleted from the classification target set Ω. In FIG. 6, this deletion is expressed using the code ‘Ω←Ω\Bs’. After Ω is updated, the flowchart returns to step B4 (step B7). If the shortest distance between a partial space contained in the already classified class Ci and a partial space contained in the neighbor set Bs is smaller than the neighbor radius r, since the neighbor set Bs and the Ci can be considered to have close attributes, Bs is integrated with Ci. Since classification of Bs has been completed, it is deleted from the classification target set Ω (step B8). Subsequently, whether or not Ω is an empty set is examined (step B9); if it is not an empty set, the flowchart goes to step B4, if Ω is an empty set, whether or not the number of classified classes is equal to or greater than k is examined (step B10), and if it is equal to or less than k, the neighbor radius is reduced by multiplying the neighbor radius by a constant that is smaller than 1. With regard to this constant, for example, a value of 0.9, et cetera, may be used. Following this, step B3 and thereafter are repeated. In step B9, if Ω is an empty set and the number of already classified classes is larger than a given number, then since classification into a desired number of classes is completed, a class parameter of each class is calculated, this is defined as an initial value for the class parameter, and the ratio of the number of partial spaces contained in each class is defined as an initial value for the class mixture ratio (step B12). FIG. 7 is a diagram specifically explaining the procedure explained with reference to FIG. 6. It is assumed here that the data space is one-dimensional, and a total of 10 partial spaces are set (FIG. 7(a)). In FIG. 7(a), the abscissa denotes the numbers of the partial spaces, and the ordinate denotes a coarse-grained empirical probability distribution. Hereinafter, the principal object is to explain the flow of processing intuitively, and specific values are therefore not used for the coarse-grained empirical probability value, the representative value of the partial space, and the neighbor radius. In step B1, the number of classes is for example 2, and the neighbor radius is r. In step B2, a representative value for each partial space is set. In step B3, initial values for the classification target set Q are all the partial spaces containing data, as follows. Ω={A3,A4,A5, A6,A7,A8} Since A1, A2, A9, and A10 have a coarse-grained probability of 0, that is, no data are observed to be contained in these partial spaces, they are not included in the classification target set. In step B4, among the partial spaces included in the classification target set, A7, which has the highest coarse-grained empirical probability, is selected and defined as As (FIG. 7(a)). In step B5, a partial space that is present within the neighbor radius r from A7 is selected and defined as Bs. Since the partial spaces that are present within the neighbor radius shown in FIG. 7(a) are A5,A6,A7,and A8, then Bs={A5,A6,A7,A8} (FIG. 7(b)). In step B6, since there are not yet classified classes, Bs is employed as an initial class C1 as it is, B1 is deleted from the classification target set, and the flowchart returns to step B4. In FIG. 7(b), blank white bars of the bar graph showing the extent of the coarse-grained empirical probability mean that the partial spaces have been deleted from the classification target set. In step B4, since A4 has the highest coarse-grained empirical probability among the remainder of the classification target set, this is defined anew as As (FIG. 7(c)). In step B5, a partial space that is present within the neighbor radius r from A4 is selected and defined as Bs. Here, it is expressed as follows. Bs={A3,A4} In step B6, by examining the already classified classes, that is, C1={A5,A6,A7,A8} they are found to include A5 and A6, which are within the neighbor radius r from A4. Therefore, the current Bs is integrated with the already classified class C1 (FIG. 7(d)). The classification target set thereby becomes empty, and classification of all the partial spaces is completed, but the number of classified classes is 1 and has not attained a desired number of classes of 2 (step B10). Therefore, the neighbor radius is reduced (step B11), and step B3 and thereafter are repeated. Hereinafter, the reduced radius is expressed as r′ (FIG. 7 (e)), and the same procedure as in the above-mentioned explanation is repeated. However, since the neighbor radius is reduced this time, the following difference occurs. That is, this time a partial space that is present within the neighbor radius r′ of A7 is as follows. Bs={A6,A7,A8} This Bs is employed as a first class C1 as it is, and A4, which has the highest coarse-grained empirical probability among the remainder of the classification target set, is selected (FIG. 7 (g)) Partial spaces that are present within the neighbor radius r′ from A4 are as follows. Bs={A3,A4,A5} Since this time the already classified class C1 contains no partial space that is within the neighbor radius r′ from A4, the current Bs is employed as anew class C2 (FIG. 7 (h)). This results incompletion of classification of all the partial spaces into two classes as desired. When rough classification is completed, an average and a variance are determined within the classified class, and they may be used as initial parameters for estimation carried out thereafter. By setting an initial value for a parameter by such a method, the amount of calculation following this may be reduced and region extraction may be carried out at high speed. Furthermore, appropriately setting an initial parameter is effective in preventing falling into a local optimum solution during maximization of the coarse-grained log likelihood. Referring back to FIG. 3, the coarse-grained conditional probability distribution calculating device 4 may determine a coarse-grained conditional probability distribution using the parameter determined above as an initial value. The coarse-grained conditional probability distribution calculating device 4 sends the determined coarse-grained conditional probability distribution to the class membership probability calculating device 5. The class membership probability calculating device 5 calculates a class membership probability using Equation (11) (step A6). This class membership probability indicates the probability of a pixel contained in a jth partial space belonging to an ith class. Therefore, by calculating a class membership probability for each image pixel, and classifying each pixel into a class for which the probability is high, region extraction can be carried out easily. The class membership probability calculating device 5 sends the calculated class membership probability to the parameter updating device 6. The parameter updating device 6 updates the parameter so as to maximize Equation (9). Specifically, the parameter is updated as follows. [ Eq . ⁢ 19 ] w i = ∑ j = 1 N ⁢ q ~ j ⁢ π ~ ij ( 16 ) μ i = ∑ j = 1 N ⁢ q ~ j ⁢ π ~ ij ⁢ x ~ j ∑ j = 1 N ⁢ q ~ j ⁢ π ~ ij ( 17 ) ∑ i ⁢ = ∑ j = 1 N ⁢ q ~ j ⁢ π ~ ij ⁡ ( x ~ j - μ i ) ⊗ ( x ~ j - μ i ) T ∑ j = 1 N ⁢ q ~ j ⁢ π ~ ij ( 18 ) Here, [Eq. 20] μ{circumflex over (×)}νT represents a matrix having a product uivj of an i component and a j component of vectors u and v as an ij element. [Eq. 21] {tilde over (x)}j is the average value of data contained in the jth partial space Aj, which is defined by Equation (14). In the case where the image is a gray scale, updating of wi and μi may be carried out in the same manner as above using a luminance value as x, and updating of the standard deviation σ is as follows. [ Eq . ⁢ 22 ] σ i 2 = ∑ j = 1 N ⁢ q ~ j ⁢ π ~ ij ⁡ ( x ~ j - μ i ) 2 ∑ j = 1 N ⁢ q ~ j ⁢ π ~ ij As described above, by updating the parameter in this way, the coarse-grained complete log likelihood given by Equation (9) increases, and the coarse-grained average log likelihood given by Equation (12) also increases (Non-patent Publication 3). The parameter updating device 6 updates the parameter and then sends the updated parameter to the evaluation function calculating device 7. The evaluation function calculating device 7 calculates a coarse-grained log likelihood using Equation (12) (step A8). Furthermore, as the evaluation function, other than the coarse-grained log likelihood shown by Equation (12), the Akaike Information Criterion (AIC: Akaike Information Criterion), the MDL, or the Structural Risk, which will be explained below, may be used. Firstly, the AIC is explained. [Eq. 23] LAIC=−2n{tilde over (L)}+2m (19) Here, it is possible to use an evaluation function for which the smaller the AIC, the better the estimation result. Here, m denotes the total number of parameters. Since the AIC is proportional to an amount obtained by multiplying the coarse-grained log likelihood by a negative, the AIC changes in a direction such that it decreases when updating using the parameter changing device 6. Furthermore, since a term that is proportional to the parameter is added, an estimation result obtained using a model having fewer parameters is considered to be better for identical coarse-grained log likelihoods. In accordance with use of this evaluation function, it is possible to suppress excessive fitting to data and carry out an estimation that is resistant to noise. Furthermore, the same effect may be obtained using the MDL below. [ Eq . ⁢ 24 ] L MDL = - n ⁢ L ~ + m 2 ⁢ log ⁢ ⁢ n ( 20 ) Moreover, the same effect may be obtained using the Structural Risk below. [ Eq . ⁢ 25 ] L SRM = L ~ 1 - c ⁢ a 1 ⁢ h (  na 2 ⁢ n / h + 1 ) - ln ⁡ ( η / 4 ) n ( 21 ) Here, η denotes that Equation (21) holds true with a probability of η and usually takes a value of 0.01, et cetera. c, a1, and a2 are constants that are determined by properties of the probability distribution, and usually take values such that c=1, a1=1, and a2=1, et cetera. h is called a VC dimension and is an amount proportional to the number of parameters. The evaluation function calculating device 7 examines whether or not a change in the evaluation function satisfies given completion conditions; if the completion conditions are satisfied, it sends a current parameter to the region extraction device 8, and if the completion conditions are not satisfied, it sends the current parameter to the coarse-grained conditional probability distribution calculating device 4 (step A9). With regard to the completion conditions, for example, a difference between the current evaluation function value and the evaluation function value calculated the previous time is divided by the current evaluation function value, and whether or not the absolute value of the value thus obtained is equal to or less than 0.0001 is examined. The region extraction device 8 receives a parameter from the evaluation function calculating device 7, and extracts a region using parameter information (step A10). For example, in order to extract a region belonging to the ith class, the value of the class membership probability is examined for j=1 to j=N, and a partial space that has a probability of not less than a certain value (threshold value) is defined as a partial class belonging to the ith class. Subsequently, pixels contained in that partial space are examined, and these pixels are extracted as being in the ith region. By using, for example, 0.5 as the threshold value for the class membership probability, a desired result may be obtained. It is also possible for the region extraction device 8 to automatically set the threshold value. The following processing is carried out for this. In order to extract the ith region, the estimated class mixture ratio wi is firstly multiplied by the total number of pixels, and an estimated number of pixels belonging to each class is determined. This figure is expressed as ni. Subsequently, the class membership probability is examined for j=1 to j=N, pixels contained in the partial spaces are extracted, in order from the highest value of the partial space, and this is continued until the extracted pixels reach ni. When the number of pixels extracted the nith time is denoted by 1, the value of the coarse-grained class membership probability of Equation (11) becomes a threshold value for the probability of belonging to the ith region. By use of the threshold value thus automatically set, a chromosome territory can be, extracted from an image with good accuracy. Furthermore, the same effect may be obtained by the following. Firstly, a membership probability represented by Equation (11) is calculated for all the pixels. By so doing, the membership probability for each of the k classes can be obtained for each pixel. Subsequently, only the pixel for which the membership probability for the ith class is the highest is extracted. The number of the pixels thus extracted should substantially coincide with the above-mentioned ni. By examining, among these pixels, the pixel having the largest luminance and the pixel having the smallest luminance, an upper limit value and a lower limit value for the luminance belonging to the ith class can automatically be obtained. Since a region of the chromosome territory should be displayed as a region having high luminance on an image, if the above-mentioned procedure is carried out for a class having the maximum average luminance as a subject, it is possible to automatically extract a chromosome territory region. After extraction of a region is completed, the region extraction device 8 sends data of the extracted region to the outputting device 9. The data space coarse-graining device 2, the coarse-grained empirical distribution calculating device 3, the coarse-grained conditional probability distribution 4, the class membership probability calculating device 5, the parameter updating device 6, the evaluation function calculating device 7, and the region extraction device 8, which are described above, may be constructed, for example, using a computer such as a personal computer, a work station, or a supercomputer. The outputting device 9 receives region data from the region extraction device 8 and outputs it to the quantification processing unit 106 of FIG. 2 (step A11). Moreover, output from the outputting device 9 may be displayed by the outputting unit 112. FIG. 8 is a block diagram showing another example of the extraction processing unit 104. FIG. 9 is a flowchart showing the processing procedure of the extraction processing unit 104 shown in FIG. 8. The same constituent elements as those explained with reference to FIG. 3 and FIG. 4 are hereinafter denoted by the same reference numerals and symbols, and their explanation is not represented where appropriate. Here, a region restoring device 10 examines, after parameter estimation using the coarse-grained probability distribution is completed, whether the coarse-graining resolution is equal to the original resolution (step A12), and returns the data to the original resolution if it has been coarse-grained (step A13). If it has not been coarse-grained, since this means that estimation at the original resolution is completed, the parameter estimated at the original resolution is sent to a region extraction device 8. For returning data to the original resolution, the coarse-graining resolution may be set at the minimum unit of the data attribute value (for example, 1), and exactly the same method as the method described in the first embodiment may be repeated. In this case, estimation takes a longer time compared with the method explained with reference to FIG. 3 and FIG. 4, but a parameter can be estimated with higher accuracy, and as a result it becomes possible to extract a region with high accuracy. Furthermore, since a parameter estimated using the coarse-grained probability distribution has already been estimated in the neighborhood of an optimum parameter, the optimum parameter can be estimated with a smaller number of times of updating the parameter compared with a case in which estimation is carried out at high resolution from the beginning, and region extraction can be carried out at a much higher speed. (Positioning State Quantification (S22)) Referring back to FIG. 2, the quantification processing unit 106 carries out standardization processing, prior to quantification of a positioning state of a chromosome territory, by transforming the coordinates of the chromosome territory extracted by the extraction processing unit 104 in accordance with certain criteria. By carrying out this processing, a positioning state of a chromosome territory may be quantified in accordance with unified criteria for a plurality of samples. By so doing, the results of the quantification of a positioning state of a chromosome territory for a plurality of samples may be statistically processed, et cetera. FIG. 10 is a flowchart showing a processing procedure of quantifying a positioning state of a chromosome territory. FIG. 11 is a schematic diagram showing the manner in which the coordinates of a chromosome territory are transformed. The coordinate transformation processing procedure is explained below with reference to FIG. 10 and FIG. 11. The quantification processing unit 106 standardizes a cell nucleus 120 shown in FIG. 11(a) (FIG. 10, S100). Here, first of all, a center of gravity P0 and a volume V of the cell nucleus 120 are calculated. Subsequently, as shown in FIG. 11(b), a reference sphere 124 is calculated so as to have the center of gravity P0 as the center and the volume V. Here, the cell nucleus 120 includes a chromosome territory 122. Although not illustrated in the figure, the cell nucleus 120 may include a plurality of chromosome territories. Following this, the coordinates of the chromosome territory 122 are transformed according to the form and size of the cell nucleus 120 and the reference sphere 124 (FIG. 10, S102). Specifically, as shown in FIG. 11(c), a straight line 1 is envisioned that passes through the center of the reference sphere 124 (the same as the center of gravity P0) and a certain point p within the chromosome territory 122, and a distance R between the center P0 and the surface of the cell nucleus 120 on the straight line 1 is calculated. At the same time, a distance r0 between the center P0 and the surface of the reference sphere 124 on the straight line 1 is calculated. Here, as shown in FIG. 11(d), when the point p within the chromosome territory 122 is transformed to a point within the reference sphere 120, the coordinates p′ within the reference sphere 120 are expressed as follows. p′=r0/R×(p−P0)+P0 By transforming in the same manner all the points within the chromosome territory 122, a chromosome territory 126 that has been coordinate-transformed within the reference sphere 124 can be obtained. In the present embodiment, after the quantification processing unit 106 carries out the above-mentioned coordinate transformation of the chromosome territory, it quantifies a positioning state of the chromosome territory (FIG. 10, S104). FIG. 12 is a diagram showing a plurality of chromosome territories, that is, chromosome territory 126a and chromosome territory 126b, which are coordinate-transformed within the reference sphere 124. Here, an example in which a distance between a plurality of chromosome territories is used as the quantification result of the positioning state is shown. The quantification processing unit 106 calculates the distance between the chromosome territory 126a and the chromosome territory 126b thus coordinate-transformed. By carrying out the above-mentioned coordinate transformation of the chromosome territory, the quantification result of a positioning state of the chromosome territory in a plurality of various forms of samples can be processed using a unified index. Furthermore, in the same cell, the cell nucleus can take various forms depending on the stage. In the present embodiment, by carrying out such a coordinate transformation, it is possible to appropriately quantify a positioning state of a chromosome territory while eliminating the influence of such changes in the form of the cell nucleus according to the stage. Furthermore, when the distance between chromosome territories is used as the quantification result of a positioning state, the quantification processing unit 106 may use as a quantification result a value obtained by dividing the distance between chromosome territories by the radius of the reference sphere 124. This enables the quantification results of the positioning state of the chromosome territories in a plurality of samples having different nucleus sizes to be processed with a unified index. A method of quantifying the positioning state of a chromosome territory is now explained. The positioning state of the chromosome territory may be quantified using a distance between a plurality of chromosome territories, the spread of the chromosome territory, the distribution direction, a distance between the chromosome territory and a reference point within a cell, et cetera. In the case in which quantification is carried out using the distance between a plurality of chromosome territories, the distance between the plurality of chromosome territories may be calculated by various methods. For example, the quantification processing unit 106 may calculate a center of gravity of each of the chromosome territories, and calculate a distance between the centers of gravity. The center of gravity referred to here is the center of gravity of an area when it is assumed that each pixel forming the chromosome territory has equal specific gravity. As the position of the center of gravity of each of the chromosome territories, for example, a center of gravity weighted by the luminance value described below may be used. XG=ΣjIjXj/ΣjIj Here, Ij is a luminance value of a pixel at a position xj. The position of the pixel having the highest luminance value may be used instead of the center of gravity. Hereinafter, a case of a simple center of gravity is explained, but a distance between chromosomes may be defined by the same method when a weighted center of gravity or the position of a pixel having the highest luminance is used. Furthermore, the quantification processing unit 106 may also calculate a distance between boundaries of a plurality of chromosome territories. The distance between the boundaries of the chromosome territories referred to here is for example the shortest distance between the surfaces of the plurality of chromosome territories. Moreover, the quantification processing unit 106 may approximate the form of each of the plurality of chromosome territories by a normal distribution, calculate an average value of the normal distribution of each of these chromosome territories, and calculate a distance between the average values. Furthermore, after the form of each of the plurality of chromosome territories is approximated by the normal distribution, the center of gravity of each of the chromosome territories may be calculated as described above to thus calculate the distance between the centers of gravity, or the distance between the boundaries may be calculated. Furthermore, the quantification processing unit 106 may detect a framework line of each of the plurality of chromosome territories, calculate the center of gravity of each skeleton line, and calculate a distance between the centers of gravity. Moreover, the quantification processing unit 106 may calculate a distance between a plurality of chromosome territories by calculating the Mahalanobis distance, the Bhattacharyya distance, the Kullback-Leibler distance, the symmetrical Kullback-Leibler distance, or the absolute distance. The Mahalanobis distance may be calculated in accordance with the equation below. [Eq. 26] D=(μ1−μ2)TΣ−1(μ1μ2) Here, μi (i=1, 2) denotes an average vector, Σ denotes a covariance matrix within a class defined by [Eq. 27] Σ=w1Σ1+w2Σ2 and w1 and w2 denote class mixture ratios. The Bhattacharyya distance may be calculated in accordance with the equation below. [ Eq . ⁢ 28 ] D = 1 8 ⁢ ( μ 1 - μ 2 ) T [ ∑ 1 ⁢ + ∑ 2 2 ] - 1 ⁢ ( μ 1 - μ 2 ) + 1 2 ⁢ ln ⁢  ∑ 1 ⁢ + ∑ 2 2   ∑ 1  ⁢  ∑ 2  The Kullback-Leibler distance may be calculated in accordance with the equation below. [ Eq . ⁢ 29 ] D = ∫ p 1 ⁡ ( x ) ⁢ ln ⁡ [ p 1 ⁡ ( x ) p 2 ⁡ ( x ) ] ⁢ ⅆ x Here, Pi (i=1, 2) denotes an average vector μi, a multidimensional normal distribution of the covariance matrix Σi. The symmetrical Kullback-Leibler distance may be calculated in accordance with the equation below. [ Eq . ⁢ 30 ] D = 1 2 ⁢ ∫ p 1 ⁡ ( x ) ⁢ ln ⁡ [ p 1 ⁡ ( x ) p 2 ⁡ ( x ) ] ⁢ ⅆ x + 1 2 ⁢ ∫ p 2 ⁡ ( x ) ⁢ ln ⁡ [ p 2 ⁢ ( x ) p 1 ⁢ ( x ) ] ⁢ ⅆ x The absolute distance may be calculated in accordance with the equation below. [Eq. 31] D=·|p1(x)−p2(x)|dx When quantification is carried out using the spread of a chromosome territory, for example, a method in which the form of the chromosome territory is approximated using the normal distribution may be used. The direction and the size of the spread of the chromosome territory may thereby be quantified. Specifically, with regard to an original image, a luminance value is considered to be the extent of the probability of a chromosome territory being present, and approximation is carried out by a mixed normal distribution. This processing may be carried out with the same procedure as that of the above-mentioned chromosome territory extraction method by the extraction processing unit 104. In this process, the coordinates of each pixel on an image are considered to be a 2-dimensional probability vector, and a luminance value at that position is considered to be a probability value. In order to treat the luminance as a probability value, the sum of luminance values of all the pixels in the image is determined, and the luminance value of each pixel is divided by the sum so as to carry out normalization. In this way, the form of the chromosome territory is quantified. The chromosome territory is present in the cell nucleus with a certain degree of spread, and it is thought that the form of this spread is related to ease of interaction between chromosomes or with the exterior through the nuclear membrane. Therefore, when quantifying the positioning state of the chromosome territory, it is expected that by taking into consideration the spread of the chromosome territory, the cell state can be evaluated with good accuracy. When quantification is carried out using the positioning direction between chromosome territories, a principal axis of each chromosome territory may be detected, and a result of quantifying an angle formed by these principal axes may be used. The principal axis of the chromosome territory may be calculated by, for example, a normal distribution as described above. In this way, by approximating the form of the chromosome territory using the normal distribution, the principal axis of the spread of each chromosome territory may be identified clearly. In this process, estimated parameters are as follows. p(w1, μ1, Σ1, w2, μ2, Σ2)=w1×φ(μ1, Σ1)+w2×φ(μ2, Σ2) Here, φ((μ, Σ) denotes a two-dimensional normal distribution, μ denotes an average value, and Σ denotes a covariance matrix. The parameter w obtained as a result of the above denotes the ratio of the size of the spread, μ denotes the position of the center of the spread, and Σ denotes the principal axis of the spread. Furthermore, by decomposing the covariance matrix into eigenvalues, the principal axis of the spread is specifically obtained. By quantifying the form as described above, the positioning state of the chromosome territories can be expressed numerically. When the positioning state of two chromosome territories is considered, it is thought that in a case in which the principal axes of the spread of the two chromosome territories are parallel to each other, an area of interaction is larger and they have more influence on each other compared with a case in which they are perpendicular to each other. Therefore, when the positioning state of a chromosome territory is quantified, by taking into consideration the form of the spread or the positioning direction of the chromosome territory, it can be expected that a cell state may be evaluated with good accuracy. In a case in which the distance between a chromosome territory and a reference point within a cell is quantified, the reference point within a cell may be on the nuclear membrane or at the center of gravity. Furthermore, the nuclear membrane referred to in this case may be the surface of a reference sphere calculated by the above-mentioned method. In general, it is known that, when a chromosome is present in an outer edge part of the cell nucleus, it is in a more genetically active state than when it is present in a central part. Therefore, it can be expected that, by quantifying the distance between the chromosome territory and the cell nucleus membrane or the distance between the chromosome territory and the cell nucleus membrane, the genetic activity of the cell may be evaluated. The quantification processing unit 106 may quantify a positioning state of the chromosome territory using the above-mentioned methods singly or in a combination of a plurality thereof. By use of the results of quantification by the plurality of methods, a cell state can be evaluated in further detail. (Evaluation (S26)) Evaluation of a cell state may be carried out by various methods, but by subjecting the quantification results obtained for a plurality of samples to statistical processing and comparing the results of the statistical processing, the cell state of a particular sample may be evaluated. Statistical processing may employ various methods; for example, the statistical processing unit 108 may calculate a standard value of the results of quantification of the positioning state of the chromosome territory of a plurality of samples. In this case, as the standard value, an average value of the results of quantification of the positioning state may be used. When a standard value is calculated in this way, by comparing a result of quantification of a positioning state of the chromosome territory of a particular sample with the standard value, the cell state of the particular sample may be evaluated. In this case, the evaluation device 100 may include, as shown in FIG. 13, the statistical processing unit 108 and a statistical result memory unit 116 in addition to the constitution shown in FIG. 2. The statistical processing unit 108, for example, calculates the above-mentioned standard value and stores the standard value in the statistical result memory unit 116. The evaluating unit 110 may evaluate a cell state of a particular sample by comparing a quantification result of the particular sample with the standard value. Furthermore, the statistical processing may store a result of quantification of a positioning state of the chromosome territory of a sample and a corresponding actual diagnosis result of the provider of the sample. For example, quantification data of a positioning state of the chromosome territory of a cell sampled from an individual with a disease such as cancer and quantification data of a positioning state of the chromosome territory of a cell sampled from an individual without such a disease may be prepared. The evaluating unit 110 may evaluate whether or not a tested individual has a disease by determining which of the quantification data is close to the quantification result of a positioning state of the chromosome territory of a cell sampled from the tested individual. In the present embodiment, a cell state is evaluated using the result of quantifying a positioning state of the chromosome territory, and the existence of a disease is determined based on the result. Since a change in the positioning state of a chromosome territory occurs in an earlier stage than the stage at which a cell undergoes morphological change, early identification of a disease may be expected. Furthermore, the statistical processing unit 108 may construct a neural network based on quantification results obtained from a plurality of samples. Here, for example, a plurality of results obtained by quantification by various methods, such as the distance between a plurality of chromosome territories, the spread of the chromosome territory, the positioning direction, or the distance between a chromosome territory and a reference point within a cell may be inputted as input parameters. The evaluating unit 110 may evaluate a cell state by the output of the neural network. Moreover, the evaluating unit 110 may quantify, using the t-test or the chi-square test, a difference between the result of quantifying a positioning state of a single sample and the result of statistical processing. EXAMPLE Using an adipocyte (25th cell and 13th cell), a three-dimensional color image (554×576) was obtained. The color image here was obtained by the 3D-FISH method using probes that complementarily bonded to chromosome 16, chromosome 12, and the nucleus. Such a color image was inputted by the image acquiring unit 102. The extraction processing unit 104 extracted chromosome territories and the nucleus from the image using the above-mentioned coarse-grained region extraction method with a coarse graining resolution of 8 and a number of classes of 3. The classes were assigned respectively to the chromosome territory of chromosome 12, the chromosome territory of chromosome 16, and the nucleus. As a result, as shown in FIG. 14, the chromosome territory (class 1) of chromosome 12, the chromosome territory (class 2) of chromosome 16, and the cell nucleus (class 3) were extracted. FIG. 14 shows the extracted image. Subsequently, the distance between the center of gravity of the chromosome territory of chromosome 16 and that of the chromosome territory of chromosome 12 was calculated by the quantification processing unit 106. Chromosome 16 and chromosome 12 contain homologous chromosomes, and among these, the shortest distance between chromosome 16 and chromosome 12 was employed. This is because it is surmised that interaction such as translocation occurs at a position where the distance between the chromosome territories is the shortest. A reference sphere of the cell nucleus extracted from the image data was first calculated, and the chromosome territory of chromosome 12 and the chromosome territory of chromosome 16 were normalized. Here, since the chromosome territory had a substantially flat form, transformation in the z direction was not carried out, and two-dimensional transformation was carried out. When three-dimensional transformation is carried out, the same processing procedure may be carried out. After transformation was carried out in this way, the distance between the center of gravity of chromosome 12 and that of chromosome 16 was calculated for each of the 25th cell and the 13th cell. It was found that the distance between the centers of gravity in the 25th cell was 3.38 μm, and the distance between the centers of gravity in the 13th cell was 4.12 μm. An example in which the distance between centers of gravity of chromosome territories was statistically compared among a group of cells is next shown in FIG. 15. The ordinate of FIG. 15 is a relative value obtained by normalizing the distance between the centers of gravity of territories of chromosome 12 and chromosome 16 in the closest position, using a standardized nuclear radius. a denotes the relative distance (0.41) between chromosome 12-16 territories among a group of cells prior to cytodifferentiation (prior to cell maturing), and b denotes the relative distance (0.33) between chromosome 12-16 territories among a group of cells subsequent to the cytodifferentiation (subsequent to cell maturing). It was clear from this that the chromosome territories in the closest position moved significantly (p<0.05) closer to each other subsequent to cytodifferentiation. This result was first obtained by applying the standardization method described in the embodiment to a group of cells having different sizes and forms. An example in which a change in chromosome positioning, which is difficult to identify by a normal measurement method, has been clarified by standardization of the cell nucleus form in accordance with the embodiment is now illustrated. FIG. 16 is a radial distribution within a nucleus of the chromosome 12 position. FIG. 16(a) is a diagram showing a radial distribution prior to cytodifferentiation (prior to cell maturing), and FIG. 16(b) is a diagram showing a radial distribution subsequent to cytodifferentiation (subsequent to cell maturing). The abscissa denotes the distance (μm) from the center of gravity of the nucleus, and the ordinate denotes the relative frequency. Since the nuclear shape differs in normal measurement, the distance from the center of gravity is expressed here using an actual measurement. A change in chromosome positioning prior to and subsequent to cytodifferentiation is not clear from this figure. In contrast, a radial distribution of chromosome 12 after carrying out the standardization explained in the present embodiment is shown in FIG. 17. FIG. 17(a) shows a radial distribution prior to cytodifferentiation, and FIG. 17(b) shows a radial distribution subsequent to cytodifferentiation. Furthermore, the abscissa denotes relative positional distance (%) from the center of gravity of the nucleus, and the ordinate denotes relative frequency. By the standardization of nucleus form described in the present embodiment, the chromosome radial position can be compared for all cells using the same criteria, and it has been found that the distribution is significantly (p<0.05) displaced toward the interior of the nucleus subsequent to cytodifferentiation. As hereinbefore described, in accordance with the method of the present embodiment, a change of a cell state, which could not originally be detected, could be identified. The present invention is explained by way of an embodiment and an example. The embodiment and example are illustrative only and it can be understood by a person skilled in the art that various modification examples are possible and such modification examples are included in the scope of the present invention.

<SOH> BACKGROUND ART <EOH>Conventionally, chromosome morphology can only be observed in a condensed state of a mitotic phase of a cell cycle. However, owing to recent developments in visualization techniques (3D-FISH, confocal laser microscopy), it has become possible to observe the positioning and morphology of chromosomes in an interphase of a cell cycle. In accordance with such visualization techniques it has become clear that, within the nucleus of a cell in an interphase, individual chromosomes are present separately in regions that are not intermingled with each other (Non-patent Publication 1, Non-patent Publication 2). Hereinafter, the region occupied by an individual chromosome within the nucleus is called a chromosome territory. [Non-patent Publication 1] T. Cremer, C. Cremer, CHROMOSOME TERRITORIES NUCLEAR ARCHITECTURE AND VENE REGULATION IN MAMMALIAN CELLS, NATURE REVIEWS/GENETICS, vol. 2, pp. 292-301, 2001 [Non-patent Publication 2] Hideyuki Tanabe, ‘Chromosome territory: recent advancement of studies on interphase chromosome intranuclear positioning in relation to nuclear architecture’, Environ. Mutagen Res., 25, pp. 11 to 22, 2003 [Patent Publication 1] Japanese Laid-open Patent Publication No. 2001-92980

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The above-mentioned object, other objects, features, and advantages will become more apparent from a preferred embodiment described below and the following drawings attached thereto. [ FIG. 1 ] A flowchart showing a processing procedure of a cell state evaluation method in an embodiment of the present invention. [ FIG. 2 ] A block diagram showing an evaluation device of the present embodiment carrying out the processing procedure shown in FIG. 1 . [ FIG. 3 ] A block diagram showing an extraction processing unit shown in FIG. 2 . [ FIG. 4 ] A flowchart showing a processing procedure of the extraction processing unit. [ FIG. 5 ] A diagram showing a coarse-grained data space and a partial space when coarse-graining has been carried out. [ FIG. 6 ] A flowchart showing a processing procedure of initial value determination for a parameter based on a coarse-grained empirical distribution. [ FIG. 7 ] A diagram specifically explaining the procedure explained with reference to FIG. 6 . [ FIG. 8 ] A block diagram showing another example of the extraction processing unit. [ FIG. 9 ] A flowchart showing a processing procedure of the extraction processing unit shown in FIG. 8 . [ FIG. 10 ] A flowchart showing a processing procedure for quantifying a positioning state of a chromosome territory. [ FIG. 11 ] A schematic diagram showing a manner in which coordinates of a chromosome territory are transformed. [ FIG. 12 ] A diagram showing a plurality of chromosome territories whose coordinates have been transformed into the interior of a reference sphere. [ FIG. 13 ] A block diagram showing another example of the evaluation device. [ FIG. 14 ] A diagram showing a chromosome territory extracted by the extraction processing unit of the present embodiment. [ FIG. 15 ] A diagram in which, in groups of cells before cytodifferentiation and after cytodifferentiation, distances between the centers of gravity of territories of chromosome 12 and chromosome 16 at the closest position are compared as a relative value to a standardized nuclear radius. [ FIG. 16 ] A diagram showing radial distributions of chromosome 12 , prior to standardization of nuclear form, before cytodifferentiation and after cytodifferentiation. [ FIG. 17 ] A diagram showing radial distributions of chromosome 12 , subsequent to standardization of nuclear form, before cytodifferentiation and after cytodifferentiation. detailed-description description="Detailed Description" end="lead"?

20060124

20101123

20061102

73733.0

C12Q168

CLOW, LORI A

METHOD OF EVALUATING CHROMOSOME STATE AND EVALUATION SYSTEM

UNDISCOUNTED

ACCEPTED

C12Q

ACCEPTED

Dual polarised antenna device for an antenna array and method for manufacturing the same

An antenna device (1, 1′, 1″) comprising: a sheet-shaped support (2) which is folded along a fold-line (3-8, 80-83). The support (2) includes a first support (10-13) plane adjacent to said fold-lines (3-8, 80-83) and a second support plane (10-13) adjacent to a of said fold-lines (3-8, 80-83). The first support plane (10-13) has a first antenna structure (100) arranged for receiving or emitting electro-magnetic radiation and the second support plane (10-13) has a second antenna structure (100) arranged for receiving or emitting electro-magnetic radiation. The second support plane is (10-13) positioned at an angle with respect to the first support plane (10-13). The second antenna structure (100) is sensitive to electro-magnetic radiation which differs in a property to the electro-magnetic radiation to which said first antenna structure (100) is sensitive.

1. An antenna device (1, 1′, 1″), comprising: at least one sheet-shaped support (2) which is folded along at least one fold-line (3-8, 80-83), said support (2) including: at least one first support plane (10-13) adjacent to at least one of said fold-lines (3-8, 80-83), which first support plane (10-13) has at least one first antenna structure (100) arranged for receiving or emitting electro-magnetic radiation; and at least one second support plane (10-13) adjacent to at least one of said fold-lines (3-8, 80-83), which second support plane (10-13) is positioned at an angle with respect to the first support plane (10-13) and which second support plane (10-13) has at least one second antenna structure (100) arranged for receiving or emitting electro-magnetic radiation. 2. An antenna device (1, 1′, 1″) as claimed in claim 1, wherein at least one of the first antenna structures (100) is arranged for receiving or emitting electro-magnetic radiation of a first polarization; and wherein at least one of the second antenna structures (100) is arranged for receiving or emitting electro-magnetic radiation of a second polarization different from said first polarization. 3. An antenna device (1, 1′, 1″) as claimed in claim 1, wherein the support (2) is folded along at least two fold-lines (3-8, 80-83), and further comprises a base plane (15, 15a, 15b) adjacent to a side of a fold-line (3-8, 80-83), at least one of the first and second support plane (10-13) being adjacent to another side of that fold-line (3-8,80-83); and said base plane (15,15a, 15b) being positioned at an angle with respect to the first and second support plane (10-13). 4. An antenna device (1, 1′, 1″) as claimed in claim 1, wherein the support (2) comprises an electrically isolating layer (20,21). 5. An antenna device (1, 1′, 1″) as claimed in claim 4, wherein the electrically isolating-layer (20,21) is made of a flexible material. 6. An antenna device (1, 1′, 1″) as claimed in claim 4 or 5, further comprising: a first electrically conducting layer (22) at a first side of the electrically isolating layer (20, 21); and and an electrically conducting layer (23) at a second side of the electrically isolating layer (20,21) shaped into a feed (102). 7. An antenna device (1, 1′, 1″) as claimed in claim 4, further comprising a second electrically conductive layer (24) at the second side of the electrically isolating layer (20,21) shaped into connecting lines (105) for transmitting signals from or to the antenna structure (100). 8. An antenna device (1, 1′, 1″) as claimed in claim 7, wherein the feed (102) lies between a first electrically isolating layer (20) and a second electrically isolating layer (21); and wherein the connecting lines (105) are present at a side of the second electrically isolating layer (21) facing away from the first electrically isolating layer (20). 9. An antenna device (1, 1′, 1″) as claimed in claims 3 and 6, wherein the first conducting layer (22) extends at least partially over at least a part of the base plane (15, 15a, 15b). 10. An antenna device (1, 1′, 1″) as claimed in claim 6, further comprising an amplifier element (103) positioned at the second side, which amplifier element (103) is electrically connected with a signal input to the feed (102) and is connected with a reference input to a ground (104). 11. An antenna device (1, 1′, 1″) as claimed in claim 6, wherein the first conducting layer (22) is used as ground (104). 12. An antenna device (1, 1′, 1″) as claimed in claim 1, wherein the antenna structures (100) include flat antennas. 13. An antenna device (1, 1′, 1″) as claimed in claim 12, wherein the antenna structures (100) include vertical antennas. 14. An antenna device (1, 1′, 1″) as claimed in claim 13, wherein the antenna structures (100) include tapered slot antennas. 15. An antenna device (1, 1′, 1″) as claimed in claim 1, wherein the support (2) is folded along at least one of said fold-lines (3-8, 80-83) such that at least one of the first support plane (10-13), the second support plane (10-13), and the base plane (15, 15a, 15b) is positioned substantially perpendicular to at least one of the other planes. 16. An antenna device (1, 1′, 1″) as claimed in claim 3, wherein the base plane (15, 15a, 15b) is substantially rectangular, said first support plane (10-13) is positioned at a first side of the rectangular base plane (15, 15a, 15b) and said second support plane (10-13) is positioned at a second side of the rectangular base plane (15, 15a, 15b) transverse to the first side. 17. An antenna device as claimed in claim 1, wherein the support plane is folded to a sleeve-like shape. 18. An antenna device as claimed in claim 1, wherein at least one of the antenna structures is connectable to further signal processing devices outside the antenna device via a non-contact connection, such as a capacitive or an inductive connection. 19. An antenna array (30) comprising at least two antenna devices (1′, 1″) as claimed in claim 1. 20. An antenna array (30) as claimed in claim 19, comprising at least one sheet shaped support member (200, 201) which is folded along at least two fold-lines (3-8, 80-83) to obtain at least two antenna devices (1, 1′, 1″) as claimed in claim 1. 21. An antenna array as claimed in claim 20, wherein the sheet shaped supports (200, 201) are connected to each other at or close to at least one of the fold-lines (3-8, 80-83). 22. An intermediate product (40) for an antenna device (1, 1′, 1″) and/or an antenna array (30) as claimed in claim 1, comprising: a sheet shaped support (2, 200, 201) with a first structure and a second structure, which sheet shaped support (2, 200, 201) is foldable along a fold-line, by means of which folding a first support plane (10-13) with said first structure and a second support plane (10-13) with said second structure can be obtained, which first structure and second structure after folding the support (2, 200, 201) form at least a part of the first and second antenna structures (100). 23. A method for manufacturing an antenna device (1, 1′, 1″) or an antenna array as claimed in claim 1, comprising: folding at least one sheet shaped support (2, 200, 201) provided with at least two antenna structures (100) along at least one fold-line, such that at least one first support plane (10-13) adjacent to at least one of said fold-lines (3-8, 80-83), which first support plane (10-13) has at least one first antenna structure (100) arranged for receiving or emitting electro-magnetic radiation; at least one second support plane (10-13) adjacent to at least one of said fold-lines (3-8, 80-83), which second support plane (10-13) is positioned at an angle with respect to the first support plane (10-13) and which second support plane (10-13) has at least one second antenna structure (100) arranged for receiving or emitting electro-magnetic radiation which differs in at least one property from the electro-magnetic radiation which can be received or emitted by said first antenna structure (100).

The invention relates to an antenna device. The invention further relates to an antenna array, an intermediate product for an antenna device and a method for manufacturing an antenna device. Antenna devices are generally known and used for receiving and emitting electro-magnetic radiation and may, for example, be employed in radar and other direction finding systems, astronomical observatories and satellite receiving equipment, for example. Often, an antenna device has to receive or emit electro-magnetic radiation with differing spatial properties, for example electro-magnetic radiation with different directions of polarisation or electro-magnetic radiation stemming from different sources (and, accordingly, emitted from different positions). For instance, for receiving electro-magnetic radiation with different polarisations dual polarised antenna device are known. A dual polarised phased array antenna is known, for example, from the European patent publication 0 349 069 A1. This prior art document describes a phased array antenna having a plurality of antenna elements positioned in a matrix-shaped arrangement. The matrix comprises an assembly of two orthogonal sets of parallel insulating planar supports. Each of the insulating planar supports is provided with a conductive surface layer patterned to form a succession of tapered notch antenna elements. The tapered notch antenna elements are distributed along an outward facing edge of the planar support. Each of the tapered notch antenna elements has a polarisation parallel to the planar supports. The phased array antenna thus comprises two orthogonal sets of line-shaped arrangements of tapered notch antenna elements, of which sets each has a respective, orthogonal polarisation. In the phased array antenna described in the above mentioned patent publication, the insulating planar supports of each set intersect and engage on the supports of the other set. To that end, the supports are provided with a slot extending from the edge of a planar support to half way across the support. The sets are positioned such that the supports of one set extend in the slots of supports of the other sets. The supports of one set thus intersect and engage with the supports of the other set to form a matrix-shaped support structure. However, a draw-back of the antenna device described in said patent publication is that each planar support has to be provided with a multitude of slots, in which thereafter the supports of the other sets have be positioned. Accordingly, manufacturing of the dual polarised phased array antenna is complex. Furthermore, the planar supports have to be made of a rigid material in order to obtain a support construction with sufficiently high stiffness, which limits the choice of materials which can be used in the antenna device. It is an object of the invention to provide an antenna device which can receive or emit electro-magnetic radiation with different spatial properties and which can be manufactured in a less complex manner. Therefore, according to the invention an antenna device is provided according to claim 1. Such an antenna device can be manufactured by folding a suitable intermediate product, e.g. blank. Compared to cutting slots into rigid supports and positioning sets of slotted rigid supports in a matrix arrangement, folding is a simple operation with few steps. The antenna device can receive or emit electro-magnetic radiation with different spatial properties because the first support plane has a first antenna structure and the second support plane is positioned at an angle with respect to the first support plane and has a second antenna structure. Furthermore, the at least one sheet-shaped support is folded along at least one fold-line, which has the additional advantage that the mechanical stiffness of the antenna device is increased. A wider variety of material can thus be used for the supports, since less rigid, even flexible, materials can be used, such as for instance a foldable plastic sheet material such as kapton. Furthermore, an antenna array according to claim 19 is provided. Such an antenna array can be manufactured in a simple manner, by suitable folding of one or more intermediate products. An intermediate product according to claim 22 is also provided. An antenna device can be manufactured in a simple operation from such intermediate product by suitable folding of the support along one or more fold-lines. A method according to claim 23 is provided as well. In such a method, an antenna device or antenna array is manufactured in a simple manner. Specific embodiments of the invention are set forth in the dependent claims. Further-details, aspects and embodiments of the invention will be described, by way of example only, with reference to the figures in the attached drawings. FIG. 1 schematically shows a perspective view of an example of an embodiment of an antenna device according to the invention. FIG. 2 schematically shows a top view of an example of an embodiment of a semi-finished product suitable for manufacturing an antenna device according to the invention. FIG. 3 schematically shows a perspective, partially exploded view of a part of the semi-finished product of FIG. 2. FIG. 4 schematically shows a perspective view of an example of an embodiment of an antenna array according to the invention. FIG. 5-8 schematically show examples of folded sheets shaped supports suitable for in an example of an embodiment of an antenna array according to the invention FIG. 9-12 schematically show some examples of sheet shaped intermediate product suitable for manufacturing an example of an embodiment of an antenna device according to the invention. FIG. 13 schematically shows a block diagram of an example of an embodiment of a phased array antenna. FIG. 1 shows an example of an embodiment of an antenna device 1. The antenna device 1 comprises a sheet-shaped support 2 which is folded along one or more, in this example four, fold-lines 3-6. Support planes 10-13 are present between the fold-lines 3-6, which support planes are obtained by means of the folding. Each of the support planes 10-13 is provided with an antenna structure 100. In this example, the antenna structures 100 each have an electro-magnetic polarisation direction which is coplanar with the plane of the support plane on which the antenna structure 100 is formed. Thus, by folding the sheet shaped support 2 along the respective fold-lines 3-7, an antenna device with antenna structures 100 is obtained in a simple manner, which can receive or emit spatially different electro-magnetic radiation, e.g. differently polarised radiation. However, the antenna structures may likewise be sensitive to radiation which differs in another spatial aspect. For example, the antenna structures may be sensitive to electromagnetic radiation from different directions and/or for example comprise so called horizontal antennas. Horizontal antennas are flat antennas sensitive to incident radiation with at least a radiation component orthogonal with respect to the plane in which the antennas lie whereas vertical antennas are sensitive to incident radiation with at least a radiation component parallel to the plane of the antennas. Thus, if a sheet-shaped support comprising two or more horizontal antenna structures is folded along fold-lines, such that two or more support planes each with one or more horizontal antenna structures are obtained, the antenna structures on the respective planes are sensitive to radiation from different directions. The sheet shaped support 2 may be made of any foldable material suitable for the specific implementation. The antenna device 1 has an increased mechanical stiffness because of the fold-lines, which allows the support 2 to be made of a flexible material, which can be folded with a small amount of bending force. The flexible material may for example be a thin plastic foil, kapton, Mylar, Teflon, poly propylene, Poly ethylene or otherwise. In the example of FIG. 1, the antenna structures 100 include a vertical antenna, but the antenna structures may include other types of antennas. In the example, the antenna structure 100 comprises a patterned conductive surface layer 10 which extends over at least a part of the respective support planes 10-13. The conductive layer 101 is provided with a slot 106. The slot 106 has a tapered shape which narrows from an open, wide end 1061 at an edge of the support plane 10-13 towards a narrow end 1062 at a distance from the edge. At the narrow end, the slot 106 mounds in a circular space 1063. The antenna structure 100 in the example of FIG. 1, is of a type which is sometimes called a Vivaldi antenna. Such antennas are generally known in the art, for example from the European patent publication 0 349 069 A1 and United Kingdom Patent Number GB 1 601 441. The description of a Vivaldi antenna is hereby assumed to be incorporated herein by way of reference and for this reason the antenna structure will not be further described in detail herein. The Vivaldi antenna element provides an electrical polarisation direction which is coplanar with the plane of the dielectric plate on which it is formed. In the example of FIG. 1, a feed 102 extends across the tapered slot 106 at the narrow end 1062. The feed 102 is connected to an signal input of an amplifier 103, in this example a low noise amplifier, while a reference input of the amplifier 103 is connected to a ground 104. The amplifiers of the antenna structures 100 are further connected to a suitable control circuit and/or signal processing circuit 108 via contact lines 105 and connectors 107. A signal from the feed 102 can for example be transmitted to a signal processing circuit via the amplifier 103, the contact lines 105 and the connectors 107, while a suitable power supply can be provided to the amplifier 103 via the contact lines 105 and the connectors 107. The connection between the antenna device and additional electronic circuitry may be implemented in any manner suitable for the specific implementation. For instance, a capacitive, inductive or other connection without physical contact can be used. In the example of FIG. 1, the fold-lines 3-6 are parallel to each other and positioned at equal distances from each other. However, the fold-lines may be positioned in a non-parallel arrangement with respect to each other and/or a different spacing maybe present between the fold-lines. The sheet-shaped support 2 is folded along the fold-lines 3-6 into support planes which are perpendicular to each other. Accordingly, the folded sheet-shaped support 2 encloses a square shaped area. However, the sheet shaped support 2 may likewise be folded in a different manner. For example, the support planes 10-13 may be positioned at another angle with respect to each other, more or less support planes may be present. For instance, three support planes may be provided positioned at an angle of more or less 60 degrees with respect to each other. In FIG. 1, the sheet-shaped support 2 is folded into a sleeve-like shape, with an open top and bottom. However, the sheet-shaped support 2 may be folded into another shape and/or with more or less open sides. The blank 40 shown in FIG. 2, for example, has, when folded into an antenna device, a closed bottom side which forms a base plane 15 of the antenna device. FIG. 2 shows a top view of an example of an intermediate product, e.g. a blank 40, which can be folded to obtain an antenna device. The blank 40 comprises an elongated sheet-shaped support 2 provided with two or more, in this example four, flat antenna structures 100 arranged along the longitudinal direction of the sheet shaped support 2. The sheet-shaped support 2 is foldable along fold-lines 4-6 which extend across the sheet-shaped support 2 from one of the longitudinal edges 210,211 to the other longitudinal edge 211. The fold-lines divide the sheet-shaped support 2 into support planes 10-13, each of which has an antenna structure 100. An antenna device according to the invention can be manufactured from the blank 40 by folding the sheet-shaped support 2 along the fold-lines 4-6, such that the short edges 212,213 of the elongated support 2 are in contact with each other. By folding the blank 40 in this manner, a sleeve-shaped antenna device can be obtained. In the example of FIG. 2, the support 2 further has at the longitudinal edge 210 an extension 220 adjacent to the support plane 11. The extension 220 is foldable along fold-line 7 with respect to the rest of the sheet-shaped support 2. The fold-line 7 extends in a direction transverse to the fold-lines 4-6 and parallel to the longitudinal edge 210. The extension 220 further has a fold-line 8 at a distance from and parallel to the fold-line 7. The fold-line 8 divides the extension into a plane 14 and a base plane 15. By suitable folding of the extension 220 along fold-lines 7 and 8, the base plane 15 of the extension 220 can be used as a bottom closure of the sleeve. Thus, a box-shaped antenna device can be obtained. For instance, the plane 14 can be folded along fold-line 7 such that the plane 14 lies parallel to and against the support plane 11. The base plane 18 can then be folded along the fold-line 8 which divides the extension 20, to extend transverse to the support plane 11 and form the base plane of an antenna device. In the example of FIG. 2, the base plane 15 is covered at one side with a conducting layer, such as for example a metallic layer or otherwise. By suitable folding the extension 220, the base plane 15 can be positioned with its conductive layer in contact with the conductive layer 101 on the support planes 10-13. In such case, the base plane 15 forms the bottom of the box-shaped folded support as well as an electrical base plane for the antennas device. For instance in the example of FIG. 2, the conductive layer 101 of the antenna structures 100 extends over a part of the width of the sheet-shaped support 2 only, as indicated with the dashed line parallel to and between the longitudinal edges 210,211. The fold-line 8 lies as far from the fold-line 7 as the edge of the conductive layer 101, indicated with the dashed line, lies from the longitudinal edge 210 of the sheet-shaped support 2. Thus, after folding, the fold-line 8 then lies against the edge of the conductive layer 101, indicated with the dashed line. The invention is not limited to the arrangement of fold-lines and support planes shown in FIG. 2 and other arrangements are likewise possible. For instance FIGS. 9-12 show, by way of example only, blanks 40 with alternative arrangements of the fold-lines and support planes. In the example of FIG. 9 the support planes 10-13 are positioned in a line shaped arrangement and foldable along fold-lines 4-7 such that the lines 3,3′ at the short ends of the blank 4 are positioned in contact with each other. A base plane extension 15 is positioned at the lowerside of support plane 10 to form the base plane after folding along the fold-line 8. The example of FIG. 10 comprises two base-plane extensions 15a, 15b which extend over half the length of the base plane after folding. Such an extension arrangement allows to manufacture the support plane from a band of support plane material with negligible loss of material, because two support planes blanks 40,40′ can be cut from the band, as is indicated in FIG. 10 with the dashed lines. In the example of FIGS. 11 and 12, the support planes 11,13 resp. 10-13 are connected to each other via the base plane which can be formed by folding along fold-lines 80,81 resp. 80-83. Thereby the respective support planes 13,11 resp. 10-13 adjacent to the base plane 15 are in contact with the base plane, and when the base plane has to be an electrical base plane, electrical contact between the base plane 15 and the adjacent support planes is ensured. Furthermore, the examples of FIGS. 11 and 12 can be modified easily to obtain an antenna device with a frustrated pyramid-like shape by providing the support planes 11,13 resp, 10-13 with a trapezoid shape. The antenna structure 100 and the sheet-shaped support 2 may be implemented in any manner suitable for the specific implementation. As shown in FIG. 3, the sheet-shaped support 2 and/or the antenna structures 100 may for instance be a multilayer structure. A multilayer structure can for instance be used to integrate two or more functions of the antenna device. In the example of FIG. 3, the tapered notch antenna, the feed and the connection of the antenna device are integrated. In FIG. 3, the sheet-shaped support 2 comprises a first electrically isolating layer 20, which may for instance be made out of a plastic material, such as polyethylene, polypropylene, cartboard, kapton or otherwise. The first electrically isolating layer 20 is provided at a backside with a first electrically conductive layer 22. The first electrically conductive layer 22, for example, may be provided in a relatively simple manner, by adhering a conductive foil, such as aluminium foil, to the backside of the electrically isolating layer 20. Techniques for fixating aluminium foil onto a plastic layer; such as polypropylene or polyethylene, are generally known, for example in the field of packaging food products and are for the sake of brevity not described in further detail. However, the electrically conductive layer 22 may be obtained in any other manner suitable for the specific implementation. A second electrically conducting layer 23 is present at a front side, opposite to the backside, of the first electrically isolating layer 20. The second electrically conducting layer 23 can, for instance, be strip-shaped and be formed into the feed 102 of an antenna structure 100 suitable for the example of FIG. 1. The strip-shaped electrically conducting layer 23 lies between the first electrically isolating layer 20 and a second electrically isolating layer 21. A third electrically conducting layer 24 lies on top of the second electrically isolating layer 21, which is shaped into a ground connection of an amplifier 103 or other electronic circuitry present in the antenna structure 100. The ground connection in the third electrically conducting layer 24 is connectable to the first electrically conducting layer 22 by means of a passage 25 in which an electrically conducting pin can be positioned which then connects the first and third electrically conducting layers 22,24 electrically. The third electrically conducting layer is further shaped into connecting lines 105 for transmitting signals from or to the antenna. Thus, the connecting lines 105 are integrated in the flat design of the antenna structures 100. Thereby, the antenna structures 100 can be connected to further circuitry in a simple manner and there is no necessity to connect cables directly to the amplifier 103 of the feed 102. FIG. 4 shows an example of an antenna array 30 which includes two or more examples of antenna devices 1′, 1″ according to the invention. As indicated in FIG. 4 by way of example with reference numbers 200,201, the antenna array comprises one or more step shaped folded supports provided with antenna structures. The step-shaped folded supports 200,201 are folded into a number of antenna devices 1′,1″ according to the invention. The antenna devices 1′, 1″ are provided with antenna structures 100 each have an electro-magnetic polarisation direction which is coplanar with the plane of the support plane on which the antenna structure 100 is formed. The antenna array 30 therefore comprises sets of antenna device 1′ resp. 1″ with different orthogonal orientations, as indicated with the arrows A and B, and the antenna array 30 is a dual polarised antenna array which can be used to receive or emit electro-magnetic radiation with different polarisations. Additionally, each set of antenna devices 1′ resp. 1″ comprises arrangements of antenna device 1′ resp. 1″ in the direction of arrow A and arrangements in the direction of arrow B. Accordingly, each set forms a matrix-shaped arrangement with a certain polarisation and the antenna array 30 shown in FIG. 4 comprises two, intermingled matrix-shaped arrangements each of which has a different polarisation. In FIG. 4, the antenna devices 1′1,″ are positioned in a two-dimensional matrix shaped arrangement. It should be noted that in general any number of antenna elements may be used and the invention is not limited to the shown number of antenna elements. Furthermore, the antenna elements may likewise be positioned in an arrangement different from the line-shaped arrangement in FIG. 4 such as, depending on the specific implementation, a line-shaped arrangement, a random distribution, a three dimensional arrangement or otherwise. In the example of FIG. 4, the support 200 is folded along more than one fold-line. The support 200 is repeatedly folded along a fold-line in a first direction and in a following fold-line in a second direction opposite to the first direction, such that a stair-shaped support is obtained, as is for instance shown in FIG. 6. A number of supports folded in a similar fashion is positioned parallel to the support 200. However, the invention is not limited to the specific manner in which the support 200 is folded. The supports may likewise be folded in another manner. FIG. 5, for example, shows a support 200 which is folded along a first pair of fold-lines in a first direction and a following pair of fold-lines in a second direction, such that the support is locally U-shaped. FIG. 7 shows a support which is first folded along a first set of three equally spaced fold-lines in a first direction and then again along a second set of three equally spaced fold-lines at that same direction, to obtain two sleeve shaped antenna devices 1a and 1b. In the antenna array 30 shown in FIG. 4, the supports are attached near the fold-lines to each other by means of clamps 202. A fixation by means of clamps is low-cost and non-complex. However, the supports may likewise be attached in another manner. For instance of different sheets may be glued to each other in the support planes or otherwise. The antenna array system shown in FIG. 4 may be implemented as a phased array antenna. For instance, by connecting the different sets of antenna devices 1′ resp. 1″ to suitable beam forming and control circuitry. Phased array antennas are generally known, for instance from the American patent publication U.S. Pat. No. 6,232,919 and the European patent publication EP 805 509. In FIG. 13, the operation of such an antenna system is illustrated. The antenna system shown comprises, by way of example, four antenna units 401-404 which are arranged next to each other in one line. The antenna units 401-404 are each connected with an amplifier device 511-514. The amplifier devices 511-514 are each connected with a time- or phase-shifting circuit 521-524. The time- or phase-shifting circuits 521-524 are connected with each other through combining circuits 611-613 in an electronic circuit 600. The antenna system shown in FIG. 4 could be designed as a phased array antenna system, for instance by adding time- or phase-shifting circuits, for instance via different lengths of the contact lines 105, implementing the amplifier devices 103 in the signal processing circuit 500 and connecting the contact lines 105 to a suitable electronic circuit. The antenna units 401-404 can receive electromagnetic radiation which reaches the antenna at an angle which is within the viewing range. In FIG. 7 a bundle of electromagnetic radiation is shown which is built up from four parallel rays s1-s4. In the example shown, the ray s1 incident on the antenna unit 401 has a phase phi1. The ray s2 incident on the antenna unit 402, however, must cover an additional distance Δ11, which is equal to the distance between the antenna units multiplied by the cosine of the angle α which the rays make with the plane X in which the antenna units are situated. As a result, the ray s2 has a phase shift relative to the ray s1 at the moment when the antenna is reached. The phases of the rays s3 and s4 differ similarly. In the antenna system, this phase shift can be compensated by setting the phase- or time-shift of the phase- or time-shifting circuits 521-524, such that the mutual differences thereof correspond to the phase differences in the incoming rays. In this way, because the phase- or time-shift depends on the angle of the incoming radiation, the direction in which the antenna system receives can be adjusted. By designing an antenna system according to the invention as a phased array antenna, an inexpensive antenna unit is obtained which can be simply directed electronically at a source by setting the time- or phase-shifting circuits. Moreover, several sources can be received simultaneously, by connecting each of the antenna units with several time- or phase-shifting circuits and setting a separate shift for each source to be received. Further, with a phased array antenna, a rotation of the antenna system relative to the source can be automatically compensated electronically. For instance satellite receivers mounted on ships and trucks, and in general on moving carriers, are subject to such rotation, so that the known receiver, at least the antennas thereof, must be held in position mechanically. With a phased array antenna system as proposed, this mechanical compensation can be replaced with an electronic compensation, which is cheaper and more wear-resistant. It should be noted that the above-mentioned embodiments illustrate rather than limit the invention, and that those skilled in the art will be able to design alternatives without departing from the scope of the appended claims. For instance, a line of weakness may be provided to the sheet shaped support to facilitate the folding. Also, the fold-lines may, for example, be provided at other positions of the support than shown and/or the support planes may be oriented differently with respect to each other. Furthermore, the antenna device may for example comprise more or less support planes. Also, the antenna device may be positioned in recesses of a cover shielding the antenna device from environmental influences, such as water, temperature or otherwise. Such a cover may for example be made of a foam material and, for instance, be provided with one or more slots corresponding to the shape of the support. Other variations and modifications are likewise possible and features from different embodiments may be combined. In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim. The word ‘comprising’ does not exclude the presence of other elements or steps than those listed in a claim. Unless explicitly specified otherwise, the word ‘a’ is used as including one, two, three, or more of the specified elements. The mere fact that certain measures are recited in mutually different claims does not indicate that a combination of these measures cannot be used to advantage.

20060605

20080819

20061207

95759.0

H01Q1310

DUONG, DIEU HIEN

DUAL POLARISED ANTENNA DEVICE FOR AN ANTENNA ARRAY AND METHOD FOR MANUFACTURING THE SAME

UNDISCOUNTED

ACCEPTED

H01Q

ACCEPTED

Communication device for establishing a data connection between intelligent appliances

The invention relates to a communication apparatus for automatically setting up a data connection between two intelligent devices (10, 20, 30). The apparatus comprises a coil (13, 23, 33) for carrying out a contactless data exchange which is part of a transmission oscillator (50), a communication element (12, 22) which is connected to the coil (13, 23, 33) and the data processing component (11, 21) of an intelligent device (10, 20, 30) and emits search signals via the coil (13, 23, 33) to receive a response from another intelligent device (10, 20, 30), a measuring device (14, 24) for monitoring a property of the transmission oscillator (50), which outputs a control signal when ascertaining a change in the monitored property, and a switching apparatus (15, 25) which is connected to the measuring device (14, 24) and the communication element (12, 22) and which switches on the communication element (12, 22) when it has received a control signal from the measuring device (14, 24).

1. A communication apparatus for setting up a data connection between intelligent devices, comprising: a transmission oscillator for carrying out a contactless data exchange, said oscillator including a coil; a communication element which is connected to the coil and the data processing component of an intelligent device and which emits search signals via the coil to receive a response from another intelligent device, a measuring device for monitoring a property of the transmission oscillator which outputs a control signal when ascertaining a change of the monitored property, and a switching apparatus which is connected to the measuring device and the communication element and which switches on the communication element when it has received a control signal from the measuring device. 2. The communication apparatus according to claim 1, including an assembly that is switchable to the transmission oscillator via a switch, said assembly causing an increase in the bandwidth of the oscillating circuit. 3. The communication apparatus according to claim 2, wherein the assembly is a resistive element. 4. The communication apparatus according to claim 1, including an assembly switchable to the transmission oscillator via a switch, said assembly causing a change in the resonant frequency of the transmission oscillator. 5. The communication apparatus according to claim 4, wherein the assembly is arranged to enable a reduction in the resonant frequency. 6. The communication apparatus according to claim 4, wherein the assembly comprises a capacitor. 7. The communication apparatus according to claim 1, wherein the measuring frequency of the measuring device is sweepable over a predetermined frequency domain. 8. The communication apparatus according to claim 1, wherein the switching apparatus has a time controller for cyclically switching the measuring device on and off. 9. The communication apparatus according to claim 8, wherein the time controller keeps the on state of the measuring device shorter than the off state. 10. The communication apparatus according to claim 8, wherein the measuring device stores a measuring value obtained during a cyclical on phase. 11. The communication apparatus according to claim 10, wherein the measuring device emits a control signal to the switching apparatus when a measuring value deviates from the average of the measuring values stored with the previous on phases. 12. The communication apparatus according to claim 8, wherein, when the intelligent device is switched on, the communication element is initially on and the measuring device off. 13. The communication apparatus according to claim 1, wherein the measuring device has a first oscillator device coupled at least temporarily with the coil, for producing a first oscillation signal, and a second oscillator device for producing a second oscillation signal. 14. The communication apparatus according to claim 13, wherein the measuring device has circuit components for producing the control signal for the switching apparatus on the basis of a phase relation between the first and second oscillation signals or signals derived therefrom. 15. A method for switching on a communication element configured to use a coil, which is part of a transmission oscillator, for automatically setting up a data connection with an intelligent device likewise having a communication element and a coil, comprising the following steps: monitoring a parameter of the transmission oscillator by means of a measuring device, producing a control signal upon the occurrence of a change in the monitored property, switching on the communication element by a switching apparatus due in response to the control signal. 16. The method according to claim 15, wherein the measuring frequency of the measuring unit is swept over a given frequency domain during the monitoring of the property.

This invention relates to the use of communication elements automatically setting up a data connection in intelligent devices designed for carrying out a data transmission, the data connection set-up being triggered by the approach of two intelligent devices. A concept for automatically setting up a data connection between intelligent devices is known from the specification ECMA/TC32/TG19/2003/12 under the name of “Near Field Communication” (NFC). The purpose of the concept is to make the set-up of a data connection between intelligent devices as simple as possible. The concept provides for two intelligent devices both designed for carrying out an NFC protocol automatically setting up a data connection when they come together at a distance of typically less than 0.2 meters. In a search mode one of the intelligent devices, the initiator, sends a search query which is answered by the second intelligent device, the target. In an immediately following data exchange the two intelligent devices agree on a data transmission mode according to which a data exchange is then effected between the data processing components of the intelligent devices involved. Detection of whether another intelligent device is located within the response range of the NFC protocol is done in the search mode by cyclically emitting search queries. The parameters provided for the search queries are a transmitting frequency of 13.56 MHz and a magnetic field strength of at least 1.5 A/m up to a maximum of 7.5 A/m. The provided minimum field strength causes a relatively high constant power consumption in intelligent devices ready to carry out an NFC protocol. For devices with limited energy resources, especially for battery-operated devices, this results in a reduction of the possible service life. To reduce this undesirable effect, it can be provided to equip the intelligent devices with a switching device to be actuated by the user for activating the search mode of an NFC unit. However, this possibility at least partly cancels out the goal of particular ease of operation aimed at by the NFC concept, since at least the switching function must be actuated separately. The standards ISO/IEC 14443 and ISO/IEC 15693 describe a method in which a reading device tries to produce a data connection with another intelligent device (contactless chip card/RFID transponder). For this purpose, the reading device emits a search signal—REQUEST—periodically with high field strength (e.g. 1.5-7.5 A/m according to ISO/IEC 14443) until an intelligent device comes into the response range of the reading device. German patent application DE 102 06 676 discloses a switching apparatus to be actuated with a transponder, which can be operated almost non-dissipatively as long as no switching process is triggered. The device to be switched has for this purpose a coil which is part of an oscillating circuit which is operated as a substantially unloaded pure oscillating circuit in the detection mode. The resonant frequency tuned in the oscillating circuit is monitored by a frequency observer. When a transponder with a transponder coil is brought close to the detection coil, the resonant frequency of the oscillating circuit changes. This is detected by the frequency observer, which thereupon produces a switching signal which switches on the device to be switched. The proposed solution focuses on the direct change from detection mode to data transmission mode, i.e. on the direct, single-stage switch-on of an intelligent device by means of a coil support which serves primarily as a switching component. The problem of the invention is to specify a communication apparatus for intelligent devices designed for automatic data connection set-up, which has minimal energy consumption without restricting the ease of use. This problem is solved by an apparatus having the features of the main claim. The inventive communication apparatus has a communication element with a coil for emitting search signals, whereby the search signal mode is only commenced when a property change in a transmission oscillator set up by means of the same coil has been detected by means of a measuring device. Since transmission oscillator and measuring device can be operated almost non-dissipatively, the output of search signals for detecting the presence of corresponding intelligent devices must only be effected when a further intelligent device is possibly located within the response range of the coil. The energy requirement of the communication apparatus can thus be considerably reduced. The inventive solution is therefore in particular also suitable for intelligent devices with limited energy resources, e.g. for battery-operated devices. It is particularly advantageous that an intelligent device equipped with an inventive communication apparatus can be handled just the same as if the device permanently emitted search queries. No special actions by a user are required. Advantageously, the use of an inventive communication apparatus also does not require any intervention in the execution of the data connection set-up after detection of a further intelligent device present. In an advantageous development, it is provided that for carrying out a data transmission after the communication element is switched on an ohmic resistor is switched to the oscillating circuit to thereby increase the bandwidth of the transmission oscillator while reducing the quality factor. In a further advantageous development of the communication apparatus, it is provided to influence the oscillating circuit in such a way that the resonant frequency changes by connecting suitable components after the communication element is switched on. This additionally ensures that other intelligent devices designed for automatic data connection set-up in the same way are not disturbed by a search mode. In a further advantageous embodiment of the inventive communication apparatus, it is provided that the measuring device is put into operation only periodically. This permits the energy consumption of the communication apparatus to be reduced further. For realizing the periodic putting into operation, the communication apparatus expediently has a time controller, and a measurement result is evaluated by comparison with an average value obtained from preceding measurements. The measuring device preferably has two oscillator devices for producing oscillation signals, one such oscillator device being coupled with the coil. Further, the measuring device can have circuit components for producing the control signal for the switching apparatus on the basis of a phase relation between said oscillation signals or signals derived therefrom. This permits very precise monitoring of the transmission oscillator to be obtained with comparatively little effort, and the presence of a further device within the response range of the coil to be reliably ascertained in this way. An embodiment of the invention will hereinafter be explained in more detail with reference to the drawing, in which: FIG. 1 shows the structure and arrangement of intelligent devices designed for automatic data connection set-up, FIG. 2 shows a simplified equivalent circuit diagram of a communication apparatus, FIG. 3 shows a flow chart of the operation of a communication apparatus, FIG. 4 shows a flow chart of the operation of a communication apparatus provided with a time controller, FIG. 5 shows a first embodiment of a circuit implementation of the measuring unit by means of a PLL circuit, FIG. 6 shows a plurality of signal patterns within the measuring unit upon the approach of another device, FIG. 7 shows a second embodiment of a circuit implementation of the measuring unit by means of a PLL circuit, and FIG. 8 shows a circuit implementation of the functional blocks, voltage differentiator and threshold switch, from FIG. 5 or 7. FIG. 1 shows intelligent devices 10, 20, 30 in different embodiments. All are designed to conduct a data exchange with one of the other intelligent devices 10, 20, 30 via a coil 13, 23, 33. All intelligent devices 10, 20, 30 referred hereinafter simply as devices have fundamentally the same kind of structure and consist of a data processing component 11, 21, 31 and a communication apparatus 1, 2, 3. The data processing component 11, 21, 31 substantially brings about the intelligence of the devices 10, 20, 30 and comprises a central processor unit for executing data processing operations. The data processing component 11, 21, 31 moreover substantially determines the outer form of the devices 10, 20, 30. As indicated in FIG. 1, the device 10, 20, 30 can have e.g. the form of a portable computer 11 or a mobile telephone 21 or be realized in an RFID transponder with a chip 31, formed e.g. in a contactless chip card 30. The enumeration of possible forms of design is not final here. Besides those shown, the device 10, 20, 30 can likewise be realized e.g. in an article of daily use, such as a wrist watch, or a garment, such as a jacket, provided with electronic components, but also constitute a firmly installed reading device in a ticketing or access system. The communication apparatus 1, 2, 3 comprises in each case a communication element 12, 22, a coil 13, 23, 33 connected to the communication element 12, 22, a measuring device 14, 24, connected to the coil 13, 23, 33, and a switching apparatus 15, 25 connected to the data processing component 11, 21, the communication element 12, 22 and the measuring device 14, 24. In practical implementation, the communication apparatus 1, 2, 3 is formed as a rule as one structural unit with the data processing component 11, 21 and is thus located e.g. in the housing of a portable computer 11, a mobile telephone 21 or is integrated in the chip 31 of a chip card 30. The function of the communication element 12, 22 is to ascertain the presence of another device 10, 20, 30 within the response range of the coil 13, 23, 33. The communication element 12, 22 has means for executing software program routines and can be formed as an independent assembly. When another device 10, 20, 30 has been detected, the communication element 12, 22 further automatically sets up a data connection thereto and produces the data transmission mode for a subsequent data exchange between the particular data-processing components 11, 21, 31. In a particularly expedient embodiment, the communication element 12, 22 is designed to execute an NFC protocol as described in the stated publication ECMA/TC32-TG19/2003/12, or a contactless transmission protocol as described e.g. in the standards ISO/IEC 14443, ISO/IEC 15699 and ISO/IEC 18000-3. The coil 13, 23, 33 is of the usual design and serves in the way known in the art to carry out a contactless data exchange with a corresponding device 10, 20, 30. As a rule, it is an integrated part of the device 10, 20, 30, as indicated in the execution as a chip card 30. Within the communication apparatus 1, 2, 3 the coil 13, 23, 33 is part of a transmission oscillator 50 with a defined, characteristic resonant frequency which can depend on the operating state of the device 10, 20, 30. The measuring device 14, 24 is connected to the coil 13, 23, 33 and detects a property of the transmission oscillator 50 formed with the coil 13, 23, 33. It can in particular be of the type as described in the stated German patent application DE 102 06 676. The switching apparatus 15, 25 serves to switch on and off the communication element 12, 22 and the measuring device 14, 24. The switching on and off of one or both components 12, 22 or 14, 24 can be done indirectly via the data processing component 11, 21. The switching apparatus 15, 25 serves further to connect and disconnect single elements of the measuring device 14, 24. Furthermore, the switching apparatus 15, 25 can be used to switch other components (not shown) of a device 10, 20, 30. FIG. 2 shows a simplified equivalent circuit diagram of a device 10, 20, 30. The data processing component 11, 22, and therefore the external appearance of the device 10, 20, is represented therein by an on/off switch 40 operable by a user for switching on and off the main energy supply 41 of the device 10, 20. The main energy supply 41 can be in particular a battery or an accumulator. Particularly a firmly installed reading device can also use a mains voltage as the main energy supply 41. The presence of the switch 40 depends on the form of the device; in certain embodiments, e.g. upon execution as a chip card 30, the switch 40 can be omitted. The device 30 is then either constantly on or is switched on by an equally acting mechanism adapted to the design. The switching apparatus 15, 25 comprises two switches 42, 44 which are drivable by means of an actuator 43, as well as optionally a time controller 45. Actuator 43 and time controller 45 are connected to the main energy supply 41. The first switch 42 is placed between the main energy supply 41 and the communication element 12, 22, the second switch 44 between main energy supply 41 and measuring device 14, 25. The second switch 44 is actuated via the time controller 45 which is connected for this purpose to the actuator 43 and receives a switching signal therefrom. The first switch 42 can be used to switch on and off not only the communication element 12, 22 but also further components (not shown) of the particular device 10, 20,30, as indicated by the connection 146. All components of the switching apparatus 15, 25 can be realized discretely, as circuits or also in the form of software programs. Actuator 43 and time controller 45 moreover expediently have a certain intelligence and are designed to execute software program routines. The essential element of the measuring device 14, 24 is a measuring unit 46 which is switchable on and off by means of the switch 44 of the switching apparatus 15, 25. The measuring unit 46 is further connected to the actuator 43 of the switching apparatus 15, 25 as well as via a switch 47 to the coil 13, 23. The switch 47 is actuated by the actuator 43. It thereby connects the coil 13, 23 either to the measuring unit 46 or to the communication element 12, 22. The coil 13, 23 is furthermore connected to the communication element 12, 22. Like the switching apparatus 15, 25, the components of the measuring device 14, 24 can be realized discretely, as circuits or in the form of software programs. The measuring unit 46 is expediently likewise equipped with a certain intelligence and designed to execute software program routines. In embodiments of the device that are particularly restricted with regard to energy resources, e.g. upon execution in the form of a chip card 30, the measuring device can be omitted. The device 30 can then be detected by other devices 10, 20 but not detect other devices 10, 20, 30 itself. Disposed in parallel with the coil 13, 23 is a capacitor 48 which forms together with the coil 13, 23 a transmission oscillator 50. The transmission oscillator 50 is connectable via the switch 47 to the communication element 12 or the measuring unit 46. In parallel with the transmission oscillator 50 but behind the switch 47 with respect to the transmission oscillator 50, a further capacitor 51 as well as a resistor 52 can be disposed. Both elements 51, 52 can be switched to the transmission oscillator 50 via the switch 47. The capacitor 51 causes a change in the resonant frequency of the transmission oscillator 50, the resistor 52 an increase in the bandwidth while simultaneously reducing the oscillating circuit quality factor. The mentioned passive components 47, 49, 51, 52 can be executed as discrete components but also in the form of assemblies with a corresponding external effect. In an advantageous variant particularly suitable for devices 10, 20 with sufficient energy resources, the measuring unit 46 is formed as a frequency sweeper which sweeps the measuring frequency continuously over a predetermined frequency domain. The predetermined frequency domain comprises at least one frequency to which another device 10, 20, 30 is tuned. FIG. 3 illustrates a first possible operating mode of a device 10, 20, 30. In accordance with the equivalent circuit diagram rendered in FIG. 2, it optionally has a capacitor 51 as well as a resistor 52 to influence the transmission oscillator 50. Operation starts by the device 10, 20, 30 being switched on, step 100, e.g. by means of a switch 40 which actuates the main energy supply 41. Said switching-on also switches on the actuator 43. The latter then sets the switch 47 so that the coil 13, 23, 33 is connected to the communication element 12, 22 via the switch 47. At the same time, the setting of the switch 47 causes the resistor 52, step 102, and the capacitor 51, if present, to be switched to the transmission oscillator 50, step 104. Connection of the resistor 52 results in a worsening of the quality factor Q of the transmission oscillator 50, but at the same time causes an increase in the bandwidth B available for a data transmission in the transmission oscillator 50, since it applies to the relation between quality factor Q and bandwidth B that B≈1/Q. Connection of the capacitor 51 reduces the resonant frequency of the transmission oscillator 50 and sets it to a transmission frequency suitable for a data transmission, e.g. 13.56 MHz. The change makes the subsequent data transmission and the operation of the communication apparatus 1, 2, 3 insensitive to interference by magnetic fields of devices 10, 20, 30 of the same kind located in the vicinity and working in the detection mode, i.e. at a higher resonant frequency. Furthermore, the actuator 43 switches on the communication element 12, 22, step 106. The communication element 12, 22 thereby goes into the search mode and cyclically emits a search signal via the coil 13, 23, 33 to receive a response from another device 10, 20, 30 possibly located within the response range of the coil 13, 23, 33. If another device 10, 20, 30 is located within the response range of the coil 13, 23, 33 it reacts to the search signal by returning a response, whereupon the communication element 12, 22 puts the communication apparatus 1, 2, 3 in the data transmission mode. For this purpose, it sets up a data connection with the data processing component 11, 21, 31 of the answering device 10, 20, 30 using a suitable protocol, e.g. the above-mentioned protocols (NFC, 14443, . . . ), step 108. After the data connection is set up, the data processing component 11, 21, 31 conducts a data exchange via the coil 13, 23, 33 in the known way with the corresponding data processing component 11, 21, 31 of the device 10, 20, 30 present, step 110. The actuator 43 waits until the data exchange between the data processing components 11, 21, 31 of the devices 10, 20, 30 involved is completed, step 114. Detection that the data exchange is finished can be effected by reception of a corresponding signal from the data processing component 11 or the communication element 12 or also by cyclical execution of a check step in the actuator 43 itself. The communication element 12, 22 can be connected to the time controller 45 and the actuator 43 independently of the switch 42. When the data exchange is finished, the actuator 42 puts the communication device 1, 2, 3 in the detection mode. For this purpose, the actuator 43 separates the communication element 12, 22 from the main energy supply 41 by shifting the switch 42, step 116. Further, the actuator 43 actuates the switch 47 and connects the measuring unit 46 to the transmission oscillator 50. The switch actuation further causes the resistor 52 and optionally the capacitor 51 to be switched out of the transmission oscillator 50 again, step 120, 122. Removal of the resistor 52 brings about in the transmission oscillator 50 an unloaded quality factor Q0 which is determined in the ideal case only by the inductance of the coil 13, 23, 33, the oscillating circuit capacitor 48 and the input resistance of the coil 13, 23, 33. In accordance with the improved quality factor Qo the detection range increases in which other devices 10, 20, 30 present are detected in the detection mode. The possible switching off of a capacitor 51 permits the frequency of the oscillating circuit 50 and thus the measuring frequency of the measuring unit 46 to be optionally increased and set e.g. in the range of 13.56 to 17 MHz. This has the consequence that the measuring unit 46 is not, or not as strongly, influenced by other intelligent devices located in the close vicinity and in the communication mode (i.e. transmit mode). Since signals of other reading devices could otherwise be misunderstood as the approach of an intelligent device, the obtained reduction of the detection of signals of other reading devices is advantageous. Likewise, any other devices 10, 20, 30 located in the vicinity which are in the data transmission mode are thus not disturbed during operation in the detection mode. Further, the actuator 43 switches on the measuring unit 46 by actuating the switch 44 for producing the detection mode, step 124. The measuring unit 46 then monitors a property of the transmission oscillator 50. For example, it monitors the frequency tuned in the transmission oscillator 50 while the latter is operated in resonance. If in this state the coil 13, 23, 33 of another device 10, 20, 30 is brought into the detection range of the coil 13, 23, 33, this causes a change of resonant frequency in the transmission oscillator 50, which is detected by the measuring unit 46, step 132. Alternatively, it is also possible to evaluate/measure the impedance of the transmitting oscillator 50 operated in resonance. When the measuring unit 46 has detected a change in the observed oscillating circuit property, it transmits a corresponding control signal to the actuator 43, whereupon the actuator 43 executes the steps 102 ff. again and initiates the search or data transmission mode. If the measuring device 46 allows sweeping of the oscillating circuit frequency, monitoring of the oscillating circuit property is effected over the total frequency domain swept. The frequency domain swept contains at least the resonant frequency of one kind of device with which a data connection can be set up. If the resonant frequency of such a device 30 is e.g. 13.56 MHz, the sweep range can be for example between 13 and 18 MHz. If a change in the oscillating circuit property occurs at any frequency within the frequency domain swept, the measuring unit 46 transmits a control signal to the actuator 43 for executing the steps 102 ff. FIG. 4 shows a variant for operating a communication apparatus built up according to FIG. 2. The operating variant can be designed as an alternative or also in addition to the operating mode illustrated in FIG. 3. The operating variant shown in FIG. 4 presupposes that the device 10, 20, 30 has a time controller 45 as indicated in FIG. 2. Operation again starts by the device 10, 20 being switched on, step 100, e.g. by switching on the main energy supply 41 by means of a switch 40. The communication apparatus 1, 2, 3 thereupon first goes into the search mode. For this purpose, the actuator 43 switches on the communication element 12, 22, step 202, which subsequently checks by cyclically outputting search signals whether another device 10, 20, 30 is located within the response range of the coil 13, 23, 33, step 204. If the outputting of the search signal in step 204 is followed by a response from another device 10, 20, 30 present, the communication apparatus 1, 2, 3 changes to the data transmission mode after set-up of a data connection with the other device 10, 20, 30, and conducts a data exchange with the detected device 10, 20, 30, step 208. If the search signal is not followed by a response, the actuator 43 switches off the communication element 12, 22 again, step 206. Further, the actuator 43 activates the time controller 45 which thereupon switches on the measuring unit 46 in cyclical switch on and off operation for a predetermined time by driving the switch 44 accordingly, step 210. The measuring unit 46 then performs a measurement of the monitored oscillating circuit property and stores the measuring value, step 212. From all hitherto determined and stored measuring values it subsequently forms a measuring value average, step 214. It compares the measuring value obtained in step 212 with the determined measuring value average, step 216. If the measuring value corresponds to the average, no other device 10, 20, 30 is located within the detection range of the transmission oscillator 50. The measuring unit 46 then performs no further function and is switched off by the action of the time controller 45, step 218. The measuring unit 46 subsequently remains off, while the time controller 45 waits for the expiration of a predetermined off time, step 220. The off time is expediently selected to be greater than the on time in which the measuring unit 46 performs the measurement. During the waiting period the device 10, 20 can be switched off as a whole, e.g. by actuating the switch 40, step 222. When this case occurs, the working sequence ends, step 224. If the predetermined off time expires without the device being switched off as a whole, the time controller 45 switches on the measuring unit 46 again by actuating the switch 44 and repeats the steps 210 ff. If the check in step 216 yields that a measuring value found does not correspond to the determined measuring value average, another device 10, 20, 30 is located within the detection range of the oscillating circuit 50, step 226. The measuring unit 46 then transmits a corresponding control signal to the actuator 43, whereupon the actuator 43 puts the communication apparatus 1, 2, 3 in the search mode. For this purpose, it switches off the measuring unit 46 by actuating the switch 44, step 228, and switches on the communication element 12, 22 by actuating the switch 42, step 230. The communication element 12, 22 then produces the data transmission mode, as described, in which the data exchange is then effected between the data processing components 11, 21 of the devices involved, step 208. FIG. 5 shows a first embodiment of a circuit implementation of the measuring unit 46 by means of a PLL circuit. PLL stands for “phase locked loop” and means that a signal with a frequency is set relative to a signal with a reference frequency so exactly that the phase relation between the signals is permanently maintained. The first embodiment of the measuring unit 46 has a first oscillator 60 which produces a signal with a frequency f1 and feeds it to a first frequency divider 61, which can be formed as an integer or binary divider and performs a frequency division with a division factor N. It is indicated by dashed lines that the coil 13, 23 is connected to the first oscillator 60. The connection can be effected in the way shown in FIG. 2 via the switch 47 and a common ground. The exact execution depends on the circuit design of the oscillator circuit used, as well as the circuit design of the communication element 12, 22 (transmitter final stage). Thus, oscillator circuits are known, e.g. Colpitts, in which a connection of the coil 13, 23 can be grounded (on the alternating voltage side). In this case, the switch 47 can be executed so that only one connection of the coil must be switched over to the measuring unit 46, as shown in FIG. 2 for example. In another embodiment of the oscillator circuit 60, it can also be required that a second connection of the coil is connected not to ground but to the supply voltage (e.g. Colpitts circuit variant). In this case, a second switch 47b (not shown) may be necessary. Likewise, oscillator circuits are known in which two connections of the coil must be connected to the oscillator circuit 60. In this case, too, an additional switch 47b (not shown) is required for switching over the coil 13, 23 between the measuring unit 46 and the communication element 12, 22. The connection likewise shown in FIG. 2 of the measuring unit 46 to the switch 44 for switching the measuring unit 46 on and off is not shown in FIG. 5, since the energy supply of the individual components of the measuring unit 46 is omitted in FIG. 5 for reasons of clarity. The measuring unit 46 further has a second oscillator 62 which feeds a signal with a frequency f2 to a second frequency divider 63 which performs a frequency division with a division factor M. The second frequency divider 63 is formed according to the first frequency divider 61 and connected on the output side to an input of a phase comparator 64. A further input of the phase comparator 64 has connected thereto the first frequency divider 61 with its output. The phase comparator 64 is followed by a low-pass filter 65 which feeds a voltage U both to an input of the second oscillator 62 and to an input of a voltage differentiator 66. The voltage differentiator 66 is connected on the output side to an input of a threshold switch 67 which supplies at its output a switching voltage Us for the actuator 43 shown in FIG. 2. The components 60, 61, 62, 63, 64 and 65 of the measuring unit 46 form a modified PLL circuit whose operation will be explained more closely hereinafter in connection with the further components 66 and 67. The first oscillator 60 is formed as an LC oscillator, the coil 13, 23 being used as the frequency-fixing inductor L. By suitable dimensioning of a frequency-fixing capacitor C the first oscillator 60 is so adjusted that it begins oscillating at the transmitting frequency used in the detection mode when another device 10, 20, 30 is absent. Optionally, the capacitor 51 can be used to employ a higher frequency. The first frequency divider 61 divides the frequency f1 of the signal produced by the first oscillator 60 using the division factor N, thereby producing a signal with a frequency f1/N. Since frequency division is advantageous but not compulsory, the first frequency divider 61 can also be omitted or have a division factor N=1. The second oscillator 62 is formed as a voltage-controlled oscillator, so that the frequency f2 of the signal produced by the second oscillator 62 depends on the fed voltage U. The signal with the frequency f2 is converted by the second frequency divider 63 to a signal with a frequency f2/M. Like the first frequency divider 61, the second frequency divider 63 can also be omitted or have a division factor M=1. The signals output by the frequency dividers 61 and 63 are supplied to the phase comparator 64 which compares them with each other and outputs a signal dependent on the phase shift to the low-pass filter 65. The low-pass filter 65 suppresses the high-frequency signal components so that the voltage U output by the low-pass filter 65 is suitable as a control voltage for the second oscillator 62. Through the control properties of the PLL circuit, the frequency f2 of the second oscillator 62 is automatically so adjusted that a value f2=f1*M/N results and the two oscillators 60 and 62 are coupled in phase lock. In an advantageous embodiment, a division factor of N>1 is provided for the first frequency divider 61, and a division factor M=1 for the second frequency divider 63. This results in the second oscillator 62 being operated at a lower frequency than the first oscillator 60 and thus not being able to disturb the operation of the device 10, 20, 30 by its own signal. For example, the second oscillator 62 can be operated at a frequency f2 of 6.78 MHz for N=2. It is also particularly favorable if the division factors N and M of the frequency dividers 61 and 63 have a non-integral relationship to each other, e.g. M/N=5/6. This permits the frequency f2 of the second oscillator 62 to be selected so that no same-frequency interference having an especially negative effect is to be feared through any harmonic waves of the second frequency f2 and a parasitical irradiation of the second oscillator 62 into the coil 13, 23. It is irrelevant here whether the ratio M/N is selected to be smaller or greater than one. When the measuring unit 46 is in the adjusted state, i.e. there is phase-locked agreement between the signals of the two frequency dividers 61 and 63, a constant value comes about for the voltage U output by the low-pass filter 65. When another device 10, 20, 30 approaches the coil 13, 23, the influence of the inductively coupled-in impedance of the other device 10, 20, 30 leads to a change of the phase and optionally the frequency of the first oscillator 60 and thus to a phase shift between the two input signals of the phase comparator 64. This leads to a change of the voltage U output by the low-pass filter 65 and thus to a change of the frequency f2 and the phase of the signal produced by the second oscillator 62 until the signals produced by the two oscillators 60 and 62 are coupled in phase lock again. The readjustment of the frequency f2 of the second oscillator 62 performed in this way and the associated detection of the presence of another device 10, 20, 30 will be explained more closely with reference to FIG. 6. FIG. 6 shows a plurality of signal patterns within the measuring unit 46 upon the approach of another device 10, 20, 30. For all signal patterns the time t is plotted on the abscissa with the same scaling in each case so as to permit a direct comparison of the signal patterns. The upper diagram in FIG. 6 shows the time behavior of the voltage U output by the low-pass filter 65, i.e. the voltage U is plotted on the ordinate. In the middle diagram the temporal change of the voltage dU/dt is plotted on the ordinate, which is determined by the voltage differentiator 66 and output to the threshold switch 67. In the lower diagram the switching voltage Us produced by the threshold switch 67 is plotted on the ordinate. One possibility for designing the functional blocks 66, 67 is shown in FIG. 8. A low-pass filter is formed here by R4, R5, C2, whereby an average of a partial voltage of U comes about with a large time constant (e.g. 1 s) at the (−) input of an amplifier V1. Likewise, a partial voltage of U comes about at the (+) input of the amplifier V1 via R1, R2, R3. When the voltage U e.g. quickly drops upon the approach of a coil 13, 23, 33, the voltage at the (+) input momentarily drops below the voltage at the (−) input, thus producing a switching signal Us until the voltage at the (−) input has adjusted to the new (average) value. The voltage U can rise or also fall upon the approach of a coil 13, 23, 33. The exact behavior depends on the circuit used (FIG. 5, FIG. 7) and the practical execution thereof. The approach of another device as of the time t=t1 results in the above-mentioned change of the hitherto constant voltage U of the low-pass filter 65. This is expressed in the upper diagram of FIG. 6 in an abrupt increase in the voltage U, which subsequently remains at a higher level. Since the value by which the voltage U changes can be relatively small, the voltage U itself is not used for driving the threshold switch 67, but rather the temporal change thereof dU/dt. As indicated by the middle diagram, the temporal change of the voltage dU/dt has a very pronounced maximum immediately after the time t=t1, which is well-suited for further processing. This maximum exceeds the response threshold of the threshold switch 67, which is shown by a dashed horizontal line. This has the consequence that the threshold switch 67 responds and produces the square pulse shown in the lower diagram. Because of the finite gradient with which the voltage U rises and the time for signal processing required by the threshold switch 67, the square pulse of the switching voltage Us starts at a slight time delay after the time t=t1. The square pulse is output by the measuring unit 46 to the actuator 43 for further processing. FIG. 7 shows a second embodiment for a circuit implementation of the measuring unit 46 by means of a PLL circuit. The structure corresponds largely to the first embodiment. However, unlike the first embodiment of the measuring unit 46, the second oscillator 62 is not executed as a voltage-controlled oscillator but as a stable-frequency quartz oscillator. The first oscillator 60 is now executed as a voltage-controlled LC oscillator. Adjustment of the frequency f1 is effected here via a voltage-dependent capacitance which, together with the inductance of the coil 13, 23, determines the frequency f1 of the first oscillator 60. Due to the different formation of the oscillators 60 and 62, the circuitry of the individual components of the measuring unit 46 is changed to the effect that the output of the low-pass filter 65 is connected to an input of the first oscillator 60. The second oscillator 62 does not receive an input signal. The changed structure results for the second embodiment of the measuring unit in the following operation. Using an analogous control mechanism as described for the first embodiment, the frequency f1 of the first oscillator 60 is adjusted to a constant value which is fixed by the frequency f2 of the second oscillator 62 and the division factors N and M of the frequency dividers 61 and 63. By accordingly selecting the frequency f2 and the division factors N and M it is in particular possible to operate the first oscillator 60 constantly at a frequency f1 corresponding to the transmitting frequency used in the detection mode. Upon the approach of another device 10, 20, 30, the frequency f1 of the first oscillator 60 does not change despite the inductively coupled-in impedance. Nevertheless, a detectable change occurs in the voltage U upon the approach of another device 10, 20, 30, since the first oscillator 60 is readjusted with the help of the voltage U, thereby compensating the detuning of the first oscillator 60. On the basis of the voltage U a drive signal for the actuator 43 is produced in the above-described way. According to FIG. 2, the measuring unit 46 and the communication element 12, 22 are executed as independent circuit components. The thus required switch 47 which switches over the coil 13, 23 between the measuring unit 46 and the communication element 12, 22 must be designed for high voltages and performances. Due to the voltage overshoot in resonance, very high RF voltages, occasionally even in the range of a few 100 V, can occur on the coil 13, 23. The required large-signal stable signal switchover can be realized in some cases only with an elaborate and expensive circuit, depending on the transmit power. In a variation of the invention, it is therefore provided that the final stage of the communication element, which is preferably formed as a transistor circuit, is also used as the first oscillator 60 or the second oscillator 62 by a suitable switchover of operating point, amplification and the feedback of the output signal. Such a final stage already tends to oscillate upon a corresponding feedback. The measuring unit 46 has high responsitivity, since even extremely small phase changes can be detected. Upon corresponding dimensioning of the measuring unit 46 and the coil 13, 23, other devices 10, 20, 30 can be detected even over a large distance of up to a few meters. This makes it possible, for example, to use the measuring unit 46 for theft protection of articles of sale. In this case, it is provided to use the switching voltage Us produced by the threshold switch 67 to trigger an alarm signal. The articles of sale can be provided for example with RF labels which have an oscillating circuit without a chip and are typically intended for a frequency domain of 8.2 MHz. Likewise, acoustomagnetic labels can also be used, the typical frequency domain then being below 60 kHz. While retaining the basic idea of switching on a communication element that automatically sets up a data connection with a corresponding communication element of the same kind, only when the presence of such a corresponding communication element has already been ascertained, the above-described concept allows a number of embodiments. Thus, the structure of the intelligent devices 10, 20, 30 can deviate from that described here while having exactly the same functionality. Above all, the stated components can be replaced by other assemblies or circuits that act accordingly. Also, the breakdown of the intelligent devices and communication elements, switching apparatus, measuring device and data processing component selected for the description is arbitrary and can be done differently without affecting the functionality. In particular, the functionalities of actuator 43, time controller 45 and measuring unit 46 can be realized completely or partly in software form in the central processor unit of the device 10, 20, 30. Within limits, a simplified execution of the above-described invention is also conceivable. For example, the changing of the resonant frequency in the transmission oscillator 50 in the search mode and thus the necessity of providing the capacitor 51 can be omitted.

20060630

20120508

20061102

66531.0

H04Q900

TUN, NAY L

COMMUNICATION APPARATUS FOR SETTING UP A DATA CONNECTION BETWEEN INTELLIGENT DEVICES

UNDISCOUNTED

ACCEPTED

H04Q

ACCEPTED

Flame-retardant polyester fibers for artificial hair

There are provided a polyester fiber which maintains fiber properties such as heat resistance and strength and elongation possessed by a common polyester fiber, has excellent flame retardance, setting properties, transparence, devitrification resistance, stickiness reduction, and combing properties required for artificial hair, and has luster controlled according to need, and artificial hair using the same. Specifically, the present invention relates to a flame retardant polyester fiber for artificial hair, which is obtained by melt spinning a composition as a mixture of 100 parts by weight of (A) a polyester made of one or more of polyalkylene terephthalate and a copolymer polyester comprising polyalkylene terephthalate as a main component with 5 to 30 parts by weight of (B) a brominated epoxy flame retardant. The present invention also relates to the polyester fiber for artificial hair which has at least one modified cross-section, is a mixture with a fiber having a modified cross-section, and has a mixing ratio of the fiber having a round cross-section to the fiber having a modified cross-section is 8:2 to 1:9, and to the flame retardant polyester fiber for artificial hair which further comprises a hydrophilic fiber treating agent attached thereto, and thus has excellent smooth feeling, combing properties, and flame retardance.

1. A flame retardant polyester fiber for artificial hair, formed from 100 parts by weight of (A) a polyester made of one or more of polyalkylene terephthalate or copolymer polyester comprising polyalkylene terephthalate as a main component, and 5 to 30 parts by weight of (B) a brominated epoxy flame retardant. 2. The flame retardant polyester fiber for artificial hair according to claim 1, wherein the component (B) is (B1) a brominated epoxy flame retardant having a number average molecular weight of 20,000 or more represented by the following general formula (1), and the fiber surface has minute projections. 3. The flame retardant polyester fiber for artificial hair according to claim 1, wherein the component (A) is a polyester made of at least one polymer selected from the group consisting of polyethylene terephthalate, polypropylene terephthalate, and polybutylene terephthalate. 4. The flame retardant polyester fiber for artificial hair according to claim 1 or 3, wherein the component (B) is at least one flame retardant selected from the group consisting of brominated epoxy flame retardants represented by the general formulas (2) to (4): wherein m represents 0 to 29, wherein R1 represents a C1-10 alkyl group, and n represents 0 to 100, and 5. The flame retardant polyester fiber for artificial hair according to claim 1 or 2, wherein the component (B1) is at least one flame retardant selected from the group consisting of brominated epoxy flame retardants represented by the general formulas (5) to (7): wherein m represents 30 to 150, wherein R1 represents a C1-10 alkyl group, and n represents 30 to 100, and wherein R2 represents a C1-10 alkyl group, p represents 30 to 100, and y represents 0 to 5. 6. The flame retardant polyester fiber for artificial hair according to any of claim 2 and 3, wherein the projections on the fiber surface are amorphous. 7. The flame retardant polyester fiber for artificial hair according to any of claim 2 and 3, wherein the projections on the fiber surface have a major axis length of 0.2 to 20 μm, a minor axis length of 0.1 to 10 μm, and a height of 0.1 to 2 μm each. 8. The flame retardant polyester fiber for artificial hair according to any of claims 1, 2 and 3, which is formed from a composition obtained by further mixing the components (A) and (B) with organic fine particles (C) and/or inorganic fine particles (D), and has minute projections on the fiber surface. 9. The flame retardant polyester fiber for artificial hair according to claim 8, wherein the component (C) is at least one member selected from the group consisting of a polyarylate, polyamide, fluororesin, silicone resin, crosslinked acrylic resin, and crosslinked polystyrene. 10. The flame retardant polyester fiber for artificial hair according to claim 8, wherein the component (D) is at least one member selected from the group consisting of calcium carbonate, silicon oxide, titanium oxide, aluminum oxide, zinc oxide, talc, kaolin, montmorillonite, bentonite, and mica. 11. The flame resistant polyester fiber for artificial hair according to any of claims 1, 2 and 3, which has at least one modified cross-section selected from the group consisting of shapes of an ellipse, crossed circles, a cocoon, a potbelly, a dog bone, a ribbon, three to eight leaves, and a star. 12. The polyester fiber for artificial hair according to claim 11, wherein the fiber cross-section has a shape with two or more circles or flat circles lapped or brought into contact with each other. 13. The polyester fiber for artificial hair according to claim 11, wherein the fiber cross-section has a shape of three to eight leaves, and the fiber is a modified cross-section fiber having a degree of modification represented by the expression (1) of 1.1 to 8. Degree of modification=(Circumscribed circle diameter of monofilament cross-section)/(Inscribed circle diameter of monofilament cross-section) (Expression 1) 14. The polyester fiber for artificial hair according to claim 11, wherein the fiber cross-section has a flatness ratio of 1.2 to 4. 15. The flame retardant polyester fiber for artificial hair according to claim 11, which is a mixture of a fiber having a round cross-section with a fiber having at least one modified cross-section selected from the group consisting of shapes of an ellipse, crossed circles, a cocoon, a potbelly, a dog bone, a ribbon, three to eight leaves, and a star, wherein the mixing ratio of the fiber having a round cross-section to the fiber having a modified cross-section is 8:2 to 1:9. 16. The flame retardant polyester fiber for artificial hair according to any of claims 1, 2 and 3, further comprising (E) a hydrophilic fiber treating agent attached thereto. 17. The flame retardant polyester fiber for artificial hair according to claim 16, wherein the component (E) is at least one member selected from the group consisting of a polyether compound, fatty acid ester compound, organic amine, organic amide, organic fatty acid ester, organic amine salt, organic ammonium salt, organic pyridium salt, organic ammonium salt, organic pyridinium salt, organic picolinium salt, organic fatty acid salt, resinate, organic sulfonate, organic succinate, organic monosuccinate, organic carboxylate, organic sulfate, and organic phosphate. 18. The flame retardant polyester fiber for artificial hair according to claims 1 and 2, wherein the component (E) is at least one member selected from the group consisting of polyoxyalkylene alkyl ether, polyoxyalkylene alkenyl ether, and polyoxyalkylene aryl ether, and their random copolymer polyethers, polyoxyalkylene alkylaryl ether, polyoxyalkylene alkyl ester, polyoxyalkylene alkenyl ester, and polyoxyalkylene alkylaryl ester. 19. The flame retardant polyester fiber for artificial hair according to claim 16, wherein the component (E) is at least one member selected from the group consisting of an ethylene oxide-propylene oxide random copolymer polyether (molecular weight MW: 15,000 to 50,000), polyethylene oxide (molecular weight: 100 to 1,000), and polypropylene oxide (molecular weight: 100 to 1,000). 20. The flame retardant polyester fiber for artificial hair according to claim 19, wherein the component (E) is attached to the fiber at a weight ratio of 0.01% to 1%. 21. The flame retardant polyester fiber according to any of claims 1, 2 and 3, which is in the form of a non-crimped raw silk. 22. The flame retardant polyester fiber for artificial hair according to any of claims 1, 2 and 3, which is spun dyed. 23. The flame retardant polyester fiber according to any of claims 1, 2 and 3, which has a monofilament size of 30 to 80 dtex.

TECHNICAL FIELD The present invention relates to a flame retardant polyester fiber for artificial hair, made of a polyester and a brominated epoxy flame retardant. More particularly, the present invention relates to a fiber for artificial hair which maintains fiber properties such as flame resistance, heat resistance, and strength and elongation, and has excellent curl-setting properties, transparence, devitrification resistance, and combing properties. The present invention also relates to a modified cross-section fiber. More particularly, the present invention relates to a modified cross-section fiber having luster, hue, texture and bulkiness close to human hair, which is used as a fiber for artificial hair for hair goods or the like such as wig, braid, or extension hair, and to a fiber for artificial hair using the modified cross-section fiber. Furthermore, the present invention relates to a fiber for artificial hair which has excellent smooth feeling, combing properties, and antistatic properties. BACKGROUND ART Fibers made of polyethylene terephthalate or a polyester comprising polyethylene terephthalate as a main component has excellent heat resistance, chemical resistance, a high melting point and a high modulus of elasticity, therefore are thus widely used in curtains, carpets, clothes, blankets, sheetings, table clothes, upholstery fabrics, wall coverings, artificial hair, interior materials for automobiles, outdoor reinforcing materials, and safety nets. On the other hand, human hair, artificial hair (modacrylic fibers, polyvinyl chloride fibers), or the like has been conventionally used in hair products such as wigs, hair wigs, extensions, hair bands, and doll hair. However, it has now become difficult to provide human hair for hair products, and thus artificial hair has become more important. Modacrylic fibers have been often used as artificial hair materials due to their flame retardance, but have only insufficient heat resistance. In recent years, there has been proposed artificial hair using, as a main component, a polyester typified by polyethylene terephthalate having excellent heat resistance. However, fibers made of a polyester typified by polyethylene terephthalate are flammable materials, and thus have insufficient flame resistance. Conventionally, various attempts have been made to improve flame resistance of polyester fibers. Known examples of such attempts include a method comprising using a fiber made of a polyester obtained by copolymerizing a flame retardant monomer containing a phosphorus atom, and a method comprising adding a flame retardant to a polyester fiber. As the former method comprising copolymerizing a flame retardant monomer, a method comprising copolymerizing a phosphorus compound with excellent heat stability having a phosphorus atom as a ring member (Japanese Patent Publication No. 55-41610), a method comprising copolymerizing carboxyphosphinic acid (Japanese Patent Publication No. 53-13479), a method comprising copolymerizing a polyester containing a polyallylate with a phosphorus compound (Japanese Patent Laid-open No. 11-124732), or the like has been proposed. As artificial hair to which the above flame retardant technology is applied, a polyester fiber copolymerized with a phosphorus compound has been proposed (Japanese Patent Laid-open No. 03-27105, Japanese Patent Laid-open No. 05-339805, etc.), for example. However, since artificial hair is demanded to be highly flame resistant, such a copolymer polyester fiber must have a high copolymerization amount when used for artificial hair. This results in a significant decrease in flame resistance of the polyester, and causes other problems in which it is difficult to perform melt spinning, or, when flame approaches, the artificial hair does not catch fire and is not burned, but molten and dripped. When the phosphorus flame retardant is added, stickiness is increased because it must be added in a large amount to exhibit flame retardance, and the resulting artificial hair made of a polyester fiber tends to have a heat history and, under high humidity conditions, be devitrified to affect the appearance of the fiber. On the other hand, as the latter method comprising adding a flame retardant, a method comprising adding a halogenated cycloalkane compound as fine particles to a polyester fiber (Japanese Patent Publication No. 03-57990), a method comprising adding a bromine-containing alkylcyclohexane to a polyester fiber (Japanese Patent Publication No. 01-24913), or the like has been proposed. However, in the method comprising adding a flame retardant to a polyester fiber, in order to achieve sufficient flame retardance, the addition treatment temperature must be as high as 150° C. or more, the addition treatment time must be long, or a large amount of a flame retardant must be used, disadvantageously. This causes problems such as deteriorated fiber properties, reduced productivity, and an increased production cost. As described above, artificial hair has not yet been provided which maintains fiber properties possessed by a conventional polyester fiber such as flame resistance, heat resistance, and strength and elongation and has excellent setting properties, devitrification resistance, and stickiness reduction. Synthetic fibers conventionally used for hair include acrylonitrile fibers, vinyl chloride fibers, vinylidene chloride fibers, polyester fibers, nylon fibers, and polyolefin fibers. Conventionally, these fibers have been processed into products for artificial hair such as wigs, braids, and extension hair. However, these fibers do not have properties necessary for a fiber for artificial hair such as heat resistance, curling properties, and good feeling together. Thus, products with various properties satisfied cannot be produced from a single fiber, and products making use of properties of each fiber are produced and used. Fibers having a cross-section suitable to characteristics of each goods have also been studied and improved. Examples of such fibers include a filament for wigs having a cocoon cross-section with a length L of a longest part, a diameter W of round parts on both ends, and a width C of a central constriction, each within a specific range (Japanese Utility Model Laid-open No. 48-13277); a synthetic fiber for artificial hair having a largest diameter (L) passing through the gravity in the fiber cross-section within a specific range (Japanese Patent Publication No. 53-6253); a filament for wigs and braids having a Y-shaped cross-section in which four unit filaments having an almost round shape or an elliptical shape are provided with one unit filament radially adjacent to the other three unit filaments at the same intervals, and the adjacent unit filaments have contact points having a width almost equal to the radius of the unit filaments (Japanese Utility Model Laid-open No. 63-78026); and a filament for wigs having a cross-section with at least two flat circles lapped, in which the ratio L/W of the major axis length L to the minor axis length W, the distance between the centers of two adjacent flat circles, the angle between the straight line linking the centers of two adjacent flat circles and the major axes of the flat circles, and the like are limited (Japanese Patent Laid-open No. 55-51802). However, any of the above-described conventional fibers developed as fibers for artificial hair has a cross-section with a length and an angle extremely limited and with a unique shape, and cannot necessarily easily produced. In addition, such fibers do not necessarily have preferable texture when used for braids or extension hair, and tend to be felt hard because the fibers are intended to keep a hairstyle or make the resulting hair straight. Further, these fibers cannot be sufficiently easily handled manually. Ribbon-section fibers have conventionally widely used for piles, but have been assumed to be inappropriate for use as fibers for artificial hair such as wigs due to their disliked too much softness or the like. On the other hand, in the method comprising adding a flame retardant to a polyester fiber, in order to achieve sufficient flame retardance, the addition treatment temperature must be as high as 150° C. or higher, the addition treatment time must be long, or a large amount of a flame retardant must be used, disadvantageously. This causes problems such as deteriorated fiber properties, decreased productivity, and an increased production cost. In order to provide such synthetic fibers poorly flame retardant or not flame retardant with flexibility, smooth feeling, or the like, various silicone finishing agents have been provided. Examples of the finishing agents for providing the fibers with flexibility, crease resistance, elastic force, and compression recovery properties include dimethylpolysiloxane, methylhydrogenpolysiloxane, dimethylpolysiloxane having hydroxyl groups at both terminals, a vinyl group-containing organopolysiloxane, an epoxy group-containing organopolysiloxane, an amino group-containing organopolysiloxane, an ester group-containing organopolysiloxane, and a polyoxyalkylene-containing organopolysiloxane. A treating agent composed of a combination of alkoxysilanes and/or a polyacrylamide resin or a catalyst or the like has also been known. For example, there is disclosed a method using a treating agent composed of an organopolysiloxane containing at least two epoxy groups in one molecule and an organopolysiloxane containing an amino group, or a treating agent composed of an organopolysiloxane having hydroxyl groups at both terminals, and an organopolysiloxane containing an amino group and an alkoxy group in one molecule and/or its partial hydrolysate and condensate (Japanese Patent Publication No. 53-36079). Further, there are described a treating agent composed of an organopolysiloxane containing an epoxy group and an aminoalkyltrialkoxysilane (Japanese Patent Publication No. 53-197159 and Japanese Patent Publication No. 53-19716), and a diorganopolysiloxane having triorganosiloxy groups at both terminals, which contains two or more amino groups in one molecule (Japanese Patent Publication No. 53-98499). In addition, there is proposed a method using a treating agent composed of an aminopolysiloxane containing two or more amino groups in one molecule and an alkoxysilane containing one or more reactive groups such as amino groups or epoxy groups (Japanese Patent Publication No. 58-17310). Further, there are disclosed a method using a treating agent composed of a diorganosiloxane containing at least two amino groups in one molecule and a diorganopolysiloxane containing at least two ester bonds in one molecule (Japanese Patent Laid-open No. 55-152864), and a method using a polysiloxane containing an amino group, a hydroxyl group-terminated polysiloxane, and an alkylalkoxysilane containing a reactive group (Japanese Patent Laid-open No. 58-214585). In addition, there are disclosed a method using a treating agent composed of an organopolysiloxane containing an epoxy group, an aminosilane compound, and a curing catalyst (Japanese Patent Laid-open No. 59-144683), and a method using an organopolysiloxane containing at least two epoxy groups in one molecule and a polyacrylamide resin (Japanese Patent Laid-open No. 60-94680). However, fibers to which these silicone-containing fiber treating agents are attached exhibit improved smooth feeling, combing properties, and the like, but the silicone-containing fiber treating agents are flammable, and thus provide significantly reduce flame retardance of flame retardant synthetic fibers, disadvantageously. DISCLOSURE OF THE INVENTION The present invention relates to a flame retardant polyester fiber for artificial hair, formed from 100 parts by weight of (A) a polyester made of one or more of polyalkylene terephthalate and a copolymer polyester comprising polyalkylene terephthalate as a main component, and 5 to 30 parts by weight of (B) a brominated epoxy flame retardant represented by the general formula (1): and more preferably the flame retardant polyester fiber for artificial hair, wherein the component (A) is a polyester made of at least one polymer selected from the group consisting of polyethylene terephthalate, polypropylene terephthalate, and polybutylene terephthalate, or the flame retardant polyester fiber for artificial hair, wherein the component (B) is at least one flame retardant selected from the group consisting of brominated epoxy flame retardants represented by the general formulas (α) to (γ): wherein p represents 0 to 150, and y represents 0 to 5. Preferably, the present invention relates to the flame retardant polyester fiber for artificial hair, characterized by comprising the components (A) and (B) further mixed with (C) organic fine particles and/or (D) inorganic fine particles to form minute projections on the fiber surface, wherein the component (C) is at least one member selected from the group consisting of a polyallylate, polyamide, fluororesin, silicone resin, crosslinked acrylic resin, and crosslinked polystyrene, or wherein the component (D) is at least one member selected from the group consisting of calcium carbonate, silicon oxide, titanium oxide, aluminum oxide, zinc oxide, talc, kaolin, montmorillonite, bentonite, mica, and an antimony compound. The present invention also relates to a fiber for artificial hair, comprising the flame retardant polyester fiber to which (E) a hydrophilic fiber treating agent comprising an aliphatic polyether compound as a main component is attached. A flame retardant fiber for artificial hair is thus provided which does not have reduced flame retardance as in the case where a flame retardant polyester fiber, a flame retardant polypropylene fiber, a flame retardant polyamide fiber, or the like is treated with a silicone fiber treating agent in order to improve smooth feeling and texture, for example; has slip feeling, combing properties, and antistatic properties the same as in the case where such a fiber is treated with a silicone oil agent for the same purpose; and has excellent flame retardance. Further, the polyester fiber of the present invention can have a specific modified cross-section. The present invention further relates to the polyester fiber for artificial hair, which has at least one modified cross-section selected from the group consisting of shapes of an ellipse, crossed circles, a cocoon, a potbelly, a dog bone, a ribbon, three to eight leaves, and a star. The present invention also relates to the polyester fiber for artificial hair, wherein the fiber cross-section has a shape with two or more circles or flat circles lapped or brought into contact with each other. The present invention also relates to the polyester fiber for artificial hair, wherein the fiber cross-section has a shape of three to eight leaves, and the fiber is a modified cross-section fiber having a degree of modification represented by the expression (1) of 1.1 to 8. The present invention further relates to the polyester fiber for artificial hair, wherein the fiber cross-section has a flatness ratio of 1.2 to 4. The present invention still further relates to the polyester fiber for artificial hair, which is a mixture of a fiber having a round cross-section with a fiber having at least one modified cross-section selected from the group consisting of shapes of an ellipse, crossed circles, a cocoon, a potbelly, a dog bone, a ribbon, three to eight leaves, and a star, wherein the mixing ratio of the fiber having a round cross-section to the fiber having a modified cross-section is 8:2 to 1:9. Preferably, the flame retardant polyester fiber for artificial hair is in the form of a non-crimped fiber, is spun dyed, and has a monofilament size of 30 to 80 dtex. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1 to 10 are schematic views respectively showing a cross-section of a polyester fiber made of the composition of the present invention, with the figures corresponding to the following: FIG. 1: A view of a cross-section in the shape of crossed circles FIG. 2: A view of a cross-section in the shape of crossed flat circles FIG. 3: A view of a cross-section in the shape of a dog bone FIG. 4: A view of a cross-section in the shape of three leaves FIG. 5: A view of a cross-section in the shape of five leaves FIG. 6: A view of a cross-section in the shape of seven leaves FIG. 7: A view for describing a flatness ratio of a modified cross-section FIG. 8: A modified nozzle 1 FIG. 9: A modified nozzle 2 FIG. 10: A modified nozzle 3 BEST MODE FOR CARRYING OUT THE INVENTION The flame retardant polyester fiber for artificial hair of the present invention is a fiber obtained by melt spinning a composition comprising (A) a polyester made of one or more of polyalkylene terephthalate or a copolymer polyester comprising polyalkylene terephthalate as a main component, and (B) a brominated epoxy flame retardant. Examples of the polyalkylene terephthalate or the copolymer polyester comprising polyalkylene terephthalate as a main component, which is contained in the polyester (A) used in the present invention, include polyalkylene terephthalates such as polyethylene terephthalate, polypropylene terephthalate, and polybutylene terephthalate, and/or a copolymer polyester comprising such polyalkylene terephthalate as a main component and a small amount of a copolymerization component. The phrase “containing as a main component” refers to “containing in an amount of 80 mol % or more”. Examples of the copolymerization component include polycarboxylic acids such as isophthalic acid, orthophthalic acid, naphthalenedicarboxylic acid, paraphenylenedicarboxylic acid, trimellitic acid, pyromellitic acid, succinic acid, glutaric acid, adipic acid, suberic acid, azelaic acid, sebacic acid, and dodecanedioic acid, and their derivatives; 5-sodiumsulfoisophthalic acid; dicarboxylic acids including sulfonic acid salts such as dihydroxyethyl 5-sodiumsulfoisophthalate, and their derivatives; 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, 1,6-hexanediol, neopentyl glycol, 1,4-cyclohexanedimethanol, diethylene glycol, polyethylene glycol, trimethylolpropane, pentaerythritol, 4-hydroxybenzoic acid, and ε-caprolactone. Typically, the copolymer polyester is preferably produced by adding a small amount of a copolymerization component to a main component which is a polymer of terephthalic acid and/or its derivative (for example, methyl terephthalate) and alkylene glycol, and reacting these components, in view of stability and convenience for handling. However, the copolymer polyester may be produced by adding a small amount of a monomer or oligomer component as a copolymerization component to a main component which is a mixture of terephthalic acid and/or its derivative (for example, methyl terephthalate) and alkylene glycol, and polymerizing the components. The copolymer polyester may be any copolymer polyester in which the copolymerization component is polycondensed with the main chain and/or the side chain of polyalkylene terephthalate as a main component. There are no particular limitations to the manner of polymerization and the like. Examples of the copolymer polyester comprising polyalkylene terephthalate as a main component include a polyester obtained by copolymerizing polyethylene terephthalate as a main component with ethylene glycol ether of bisphenol A; a polyester obtained by copolymerizing polyethylene terephthalate as a main component with 1,4-cyclohexanedimethanol; and a polyester obtained by copolymerizing polyethylene terephthalate as a main component with dihydroxyethyl 5-sodiumsulfoisophthalate The polyalkylene terephthate and its copolymer polyester may be used singly or in a combination of two or more. Preferable examples thereof include polyethylene terephthalate, polypropylene terephthalate, polybutylene terephthalate, and a copolymer polyester (a polyester obtained by copolymerizing polyethylene terephthalate as a main component with ethylene glycol ether of bisphenol A; a polyester obtained by copolymerizing polyethylene terephthalate as a main component with 1,4-cyclohexanedimethanol; a polyester obtained by copolymerizing polyethylene terephthalate as a main component with dihydroxyethyl 5-sodiumsulfoisophthalate; or the like). A mixture of two or more of these is also preferable. The component (A) has an intrinsic viscosity of preferably 0.5 to 1.4, and more preferably 0.5 to 1.0. If the intrinsic viscosity is less than 0.5, the resulting fiber tends to have reduced mechanical strength. If more than 1.4, the melt viscosity is increased as the molecular weight is increased, and thus the fiber tends to be melt spinned only with difficulty, and have a non-uniform size. There are no specific limitations to the brominated epoxy flame retardant (B) used in the present invention. A conventional brominated epoxy flame retardant may be used. Specific examples of the component (B) include a terminal non-blocked brominated epoxy flame retardant with, containing a compound represented by the following formula (α): a brominated epoxy flame retardant with one terminal blocked, containing a compound represented by the following formula (β): a brominated epoxy flame retardant with both terminals blocked, containing a compound represented by the following formula (γ): These may be used singly or in a combination of two or more. The component (B) is used in an amount of 5 to 30 parts by weight based on 100 parts by weight of the component (A). In particularly, the amount is preferably 6 to 25 parts by weight, and more preferably 8 to 20 parts by weight. If the component (B) is used in an amount of less than 5 parts by weight, it is difficult to achieve a flame retardant effect. If more than 30 parts by weight, mechanical properties, heat resistance, and drip resistance are impaired. The component (B) has a number average molecular weight of preferably 20,000 or more, and more preferably 30,000 to 80,000. If the number average molecular weight is less than 20,000, a domain in which the flame retardant is dispersed in the polyester is small, projections on the fiber surface are large, and the fiber is highly glossy. If the molecular weight is too high, the dispersion domain is large, and the fiber is less colored. As the component (C), any organic resin component may be used insofar as the component is not compatible or partially not compatible with the component (A) as a main component and/or the component (B). For example, a polyallylate, polyamide, fluororesin, silicone resin, crosslinked acrylic resin, crosslinked polystyrene, and the like are preferably used. These may be used singly or in a combination of two or more. As the component (D), such a component having a refractive index close to those of the component (A) and/or the component (B) is preferable. This is because the component has an influence on transparence and coloration of the fiber. Examples include calcium carbonate, silicon oxide, titanium oxide, aluminum oxide, zinc oxide, talc, kaolin, montmorillonite, bentonite, mica, and an antimony compound. There are no specific limitations to an antimony compound among these used as the component (D). Specific examples include an antimony trioxide compound, an antimony pentoxide compound, and sodium antimonite. Such an antimony compound has a particle size of preferably 0.02 to 5 μm, more preferably 0.02 to 3 μm, and still more preferably 0.02 to 2 μm, but the particle size is not specifically limited thereto. The antimony compound used in the present invention may be surface treated with an epoxy compound, silane compound, isocyanate compound, titanate compound, or the like as required. The antimony compound is used in an amount of preferably 0.1 to 5 parts by weight, more preferably 0.1 to 3 parts by weight, and still more preferably 0.2 to 2 parts by weight based on 100 parts by weight of the component (A), but the amount is not specifically limited thereto. If the compound is used in an amount of more than 5 parts by weight, the fiber has impaired appearance, hue, and coloration. If less than 0.1 part by weight, only a small number of minute projections are formed on the fiber surface, and thus gloss on the fiber surface is inadequately adjusted. The component (D) may be used in combination with another component (D). In this case, the components (D) are used in a total amount of 5 parts by weight. The antimony compound is preferably used as the component (D), since the compound can not only control properties of the fiber surface, but also improve the flame retardant effect of the fiber itself. There are no specific limitations to the hydrophilic fiber treating agent (E) used in the present invention. The fiber treating agent may be a mixture of at least one member selected from the group consisting of polyoxyalkylene alkyl ether, polyoxyalkylene alkenyl ether, polyoxyalkylene aryl ethers, and polyoxyalkylene alkylaryl ether, and their random copolymer polyethers, polyoxyalkylene alkyl ester, polyoxyalkylene alkenyl ester, and polyoxyalkylene alkylaryl ester with a conventionally used ether-containing fiber treating agent such as a polyoxyalkylene alkylamine, N,N-dihydroxyethylalkylamide, polyoxyalkylene alkylamide, glycerol fatty acid ester, polyglycerol fatty acid ester, pentaerythritol fatty acid ester, polyoxyalkylene pentaerythritol alkyl ester, sorbitan fatty acid ester, polyoxyalkylene sorbitan fatty acid ester, sucrose fatty acid ester, polyoxyalkylene sucrose fatty acid ester, polyoxyalkylene, alkylamine salt, alkylammonium salt, alkylaralkylammonium salt, alkylpyridinium salt, alkylpicolinium salt, fatty acid salt, resinate, sulfated fatty acid salt, alkyl sulfonate, alkylbenzene sulfonate, alkylnaphthalene sulfonate, sulfofatty acid alkyl ester salt, dialkyl sulfosuccinate, polyoxyalkylene alkyl ether monosulfosuccinate, polyoxyalkylene alkenyl ether monosulfosuccinate, polyoxyalkylene aryl ether monosulfosuccinate, alkyl diphenyl ether disulfonate, sulfated oil, sulfated fatty acid ester salt, alkyl sulfate, alkenyl sulfate, polyoxyalkylene alkyl ether sulfate, polyoxyalkylene alkyl ether carboxylate, polyoxyalkylene alkenyl ether sulfate, polyoxyalkylene aryl ether sulfate, alkyl phosphate, polyoxyalkylene alkyl ether phosphate, polyoxyalkylene alkenyl ether phosphate, or polyoxyalkylene aryl ether phosphate; or a mixture of a conventionally used ether-containing fiber treating agent with a conventionally used ionic surfactant. However, the fiber treating agent must not contain a compound containing a silicone component, because the treating agent has significantly reduced flame retardance if it contains a constituent having a silicone component as a main component. The hydrophilic fiber treating agent (E) is preferably at least one member selected from the group consisting of a polyether compound, fatty acid ester compound, organic amine, organic amide, organic fatty acid ester, organic amine salt, organic ammonium salt, organic pyridium salt, organic ammonium salt, organic pyridinium salt, organic picolinium salt, organic fatty acid salt, resinate, organic sulfonate, organic succinate, organic monosuccinate, organic carboxylate, and organic sulfate, or a mixture of two or more thereof, and particularly preferably at least one member selected from the group consisting of a polyethylene oxide-polypropylene oxide random copolymer polyether (molecular weight MW: 15,000 to 50,000), polyethylene oxide (molecular weight: 100 to 1,000), and polypropylene oxide (molecular weight: 100 to 1,000). The hydrophilic fiber treating agent (E) is attached to the fiber preferably at a total weight ratio of 0.01% to 1%, in order to provide smooth feeling, combing properties, antistatic properties, and the like. If the hydrophilic fiber treating agent (E) is added in an amount of 0.01% or less, the fiber has insufficient combing properties and smooth feeling. On the other hand, if 1% or more, an oil agent is attached to hands and makes the hands wet when touching a tow filament, and the flame retardance of the fiber may be reduced since the oil agent itself is more or less flammable, unfavorably. In order to make the fiber exhibit excellent smooth feeling and combing properties and sufficient antistatic properties, a 50:50 combination of an ethylene oxide-propylene oxide random copolymer polyether with a cationic surfactant is most preferable. However, the present invention is not limited thereto. The fiber treating agent may be attached to the fiber by treatment continuous from drawing or heat treatment or by batch treatment. The polyester fiber can have a specific modified cross-section. When the fiber of the present invention has a cross-section in which two or more circles or flat circles are lapped or brought into contact with each other (as shown in FIGS. 1 to 3, wherein the ratio of the major axis a to the minor axis b (a/b) is 1.2 to 4), the two or more circles or flat circles lapped or brought into contact with each other are preferably arranged on a straight line and bilaterally symmetric. When the fiber of the present invention has a cross-section with a shape of three to eight leaves (of which examples are shown in FIGS. 4 to 6, wherein the ratio of the circumscribed circle diameter D to the inscribed circle diameter d (D/d) is 1.1 to 8), the fiber has a degree of modification represented by the expression (1) of preferably 1.1 to 8, and more preferably 1.3 to 6. If the degree of modification exceeds 8, the fiber tends to exhibits impaired feeling and combing properties. If less than 1.1, the fiber tends to be felt hard. If the cross-section has a shape of nine or more leaves, its difference from a round cross-section tends to be small, and the effect of the present invention tends to be decreased. Degree of modification=(Circumscribed circle diameter of monofilament cross-section)/(Inscribed circle diameter of monofilament cross-section) (Expression 1) In the present invention, the modified cross-section has a flatness ratio (ratio of the major axis length to the minor axis length in the cross-section) of preferably 1.2 to 4, and more preferably 1.5 to 2.5, as shown in FIG. 7, wherein the ratio of the major axis x to the minor axis y (x/y) is 1.2 to 4. If the flatness ratio exceeds 4, the fiber cannot be provided with luster and feeling close to human hair. If less than 1.2, the fiber tends to have a hard texture. When the polyester fiber of the present invention used is a mixture of a fiber having a round cross-section with a fiber having at least one modified cross-section selected from the group consisting of shapes of an ellipse, crossed circles, a cocoon, a potbelly, a dog bone, a ribbon, three to eight leaves, and a star, the mixing ratio of the fiber having a round cross-section to the fiber having a modified cross-section is preferably 8:2 to 1:9, and more preferably 7:3 to 2:8. The modified cross-section fiber of the present invention as described above preferably has a size of 30 to 80 dtex when used for artificial hair. Further, when the modified cross-section fiber is blended with human hair at any ratio, the resulting hair goods can have any hairstyle freely. If the modified cross-section fiber of the present invention is blended in too high a proportion, the resulting product is felt hard. If the modified cross-section fiber is blended in too low a proportion, the hair goods cannot have any hairstyle freely. For this reason, it is preferable that 80 to 10 wt % of the modified cross-section fiber be blended with 20 to 80 wt % of human hair. The modified cross-section fiber can be blended for use with another fiber for artificial hair conventionally used, for example, an acrylonitrile fiber, vinyl chloride fiber, vinylidene chloride fiber, polyester fiber, nylon fiber, or polyolefin fiber, in addition to the aforementioned human hair. The flame retardant polyester composition used in the present invention can be produced by, for example, dry blending the components (A) and (B) and the optional component (C) or (D) in advance, and then melt kneading the components in various common kneading machines. Examples of the kneading machines include a single-screw extruder, twin-screw extruder, roll, Banbury mixer, and kneader of these, a twin-screw extruder is preferable in terms of adjustment of the kneading degree and convenience for operation. The flame retardant polyester fiber for artificial hair of the present invention can be produced by melt spinning the flame retardant polyester composition by a typical melt spinning process. Specifically, a spun yarn can be obtained by, for example, melt spinning the composition while setting an extruder, gear pump, spinneret, and the like at a temperature of 270 to 310° C.; allowing the spun yarn to pass through a heating tube; then cooling the yarn to a glass transition temperature or lower; and taking off the yarn at a rate of 50 to 5,000 m/min. The size of the spun yarn can also be controlled by cooling the yarn in a tank filled with cooling water. The temperature or length of the heat sleeve, the temperature or spraying amount of cooling air, the temperature of the cooling tank, the cooling time, and the take-off rate can be appropriately adjusted according to the discharge amount and the number of holes in the spinneret. The resulting spun yarn may be hot drawn by either a two-step process comprising winding up the spun yarn once and then drawing the yarn, or a direct spinning and drawing process comprising successively drawing the spun yarn without winding. Hot drawing is carried out by a one-stage drawing process or a multistage drawing process. As heating means in hot drawing, a heat roller, heat plate, steam jet apparatus, hot water tank, or the like can be used. These can be appropriately used in combination. The flame retardant polyester fiber for artificial hair of the present invention may contain various additives such as a flame retardant other than the component (B), a heat resistant agent, a photostabilizer, a fluorescent agent, an antioxidant, an antistatic agent, a pigment, a plasticizer, and a lubricant as required. The fiber containing a pigment can be provided as a spun dyed fiber. When the flame retardant polyester fiber for artificial hair of the present invention thus obtained is a fiber in the form of a non-crimped raw silk, and has a size of usually 30 to 80 dtex, and furthermore 35 to 75 dtex, the fiber is suitable for artificial hair. Preferably, the fiber for artificial hair has heat resistance to allow a thermal appliance for beauty (hair iron) to be used therefor at 160 to 200° C., catches fire only with difficulty, and has self-extinguishing properties. When the flame retardant polyester fiber of the present invention is spun dyed, the fiber can be used as is. When the fiber is not spun dyed, it can be dyed under the same conditions as in a common flame retardant polyester fiber. The pigment, dye, adjuvant, or the like used for dyeing preferably exhibits excellent weather resistance and flame retardance. The flame retardant polyester fiber for artificial hair of the present invention exhibits excellent curl setting properties and curl holding properties when a thermal appliance for beauty (hair iron) is used. When the component (C) or (D) is added to the fiber if necessary, the fiber can have a surface with irregularities, can be appropriately matted, and can be more suitably used for artificial hair. Further, the hydrophilic fiber treating agent (E) or an oil agent such as a softening agent can provide the fiber with feeling and texture and make the fiber closer to human hair. The flame retardant polyester fiber for artificial hair of the present invention may be used in combination with another material for artificial hair such as a modacrylic fiber, polyvinyl chloride fiber, or nylon fiber, or in combination with human hair. Generally, human hair used in hair products such as wigs, hair wigs, or extensions has cuticle treated, is bleached or dyed, and contains a silicone fiber treating agent or softening agent in order to ensure its feeling and combing properties. Thus, the human hair is flammable, unlike untreated human hair. However, when the human hair is blended with the flame retardant polyester fiber for artificial hair of the present invention at a human hair blending ratio of 60% or less, the product exhibits excellent flame retardance. EXAMPLES Next, the present invention will be described in more detail with reference to Examples. However, the present invention should not be limited thereto. Properties values are measured as follows. (Combing Properties) A fiber surface treating agent is attached to a tow filament with a length of 30 cm and a total size of 100,000 dtex. The treated tow filament is combed with a comb (made of Derlin resin) to evaluate ease of combing. Good: Filament is combed with almost no resistance (Light) Fair: Filament is combed with a little resistance (heavy) Bad: Filament is combed with a large resistance, or becomes uncombable in the middle (Strength and Elongation) Tensile strength and elongation of a filament are measured using INTESCO Model 201 manufactured by INTESCO Co., Ltd. Both 10 mm-long ends of one 40 mm-long filament are sandwiched in a board (thin paper) to which a two-sided tape pasted with an adhesive is bonded, and are air-dried overnight to prepare a sample with a length of 20 mm. The sample is mounted on a test machine, and a test is carried out at a temperature of 24° C., at a humidity of 80% or less, at a load of 0.034 cN×size (dtex), and at a tensile rate of 20 mm/min to measure strength and elongation. The test is repeated ten times under the same conditions, and the average values are defined as strength and elongation of the filament. (Flame Retardance) A filament is cut into filaments with a length of 150 mm each. Filaments with a weight of 0.7 g are bundled, with one end of the bundle sandwiched by a clamp, and the bundle is fixed on a stand and hung vertically. The fixed filaments with an effective length of 120 mm are brought into contact with 20 mm-long fire for 3 seconds, and burned. Flammability Very good: Afterflame time is 0 second (Filaments do not catch fire) Good: Afterflame time is less than 3 seconds Fair: Afterflame time is 3 to 10 seconds Bad: Afterflame time is more than 10 seconds Drip Resistance Very good: The number of drips until extinguishment is 0 Good: The number of drips until extinguishment is 5 or less Fair: The number of drips until extinguishment is 6 to 10 Bad: The number of drips until extinguishment is 11 or more (Gloss) A tow filament with a length of 30 cm and a total size of 100,000 dtex is visually evaluated under sunlight. Very good: Gloss is adjusted to be the same as in human hair Good: Gloss is appropriately adjusted Fair: Gloss is a little too high or a little too low Bad: Gloss is too high or too low (Transparence) A tow filament with a length of 30 cm and a total size of 100,000 dtex is visually evaluated under sunlight. Good: Transparent and deep-colored (bright) Fair: A little opaque (cloudy) Bad: Opaque and not deep-colored (Devitrification Resistance) A tow filament with a length of 10 cm and a total size of 100,000 dtex is processed with steam (at 120° C. and at a relative humidity of 100% for 1 hour), and then sufficiently dried at room temperature. The change in gloss and hue between the tow filament before steam processing and the tow filament after steam processing is examined. As the change is more significant, the tow filament exhibits lower devitrification resistance. Very good: Neither gloss nor hue is changed Good: Gloss is not changed, but hue is slightly changed Fair: Both gloss and hue are slightly changed Bad: Both gloss and hue are obviously changed (Feeling) Stickiness A tow filament with a length of 30 cm and a total size of 100,000 dtex is allowed to stand in a room with constant temperature and humidity (at 23° C. and at a relative humidity of 55%) for 3 hours, and then evaluated using a thumb, forefinger, and middle finger on the right hand. Good: Not sticky Fair: A little sticky Bad: Sticky Smooth Feeling A tow filament with a length of 30 cm and a total size of 100,000 dtex is allowed to stand in a thermo-hygrostatic chamber (at 23° C. and at a relative humidity of 55%) for 3 hours, and then evaluated using a thumb, forefinger, and middle finger on the right hand. Very good: Smooth and very slippy Good: Smooth and slippy Fair: Not so slippy Bad: Not slippy (Surface Roughness) Surface roughness was measured using a laser microscope (VK-9S00, manufactured by Keyence Corp.). The sides of 10 fibers in parallel with the fiber axes were measured at a magnification of 3,000 (objective lens magnification: 150×built-in lens magnification: 20) to obtain an image. Surface roughness was calculated from this image based on a calculation formula in accordance with the definition of surface roughness (JIS B0601-1994). (Iron Setting Properties) Iron setting properties are an index of the extent to which a hair iron can perform curl setting easily and hold the curl shape. Filaments are loosely sandwiched in a hair iron heated to 180° C., and pre-heated three times by rubbing. Adhesion and combing among the filaments, and frizz and breakage of the filaments are visually evaluated. Next, the pre-heated filaments are wound around the hair iron and held for 10 seconds, and then the iron is withdrawn. The degree of ease of withdrawing the iron (rod out properties) and curl holding properties when withdrawing the iron are visually evaluated. (Curl Setting Properties) Straw-haired filaments are wound around a pipe with a diameter of 32 mm. Curl setting is performed at 110° C. for 60 minutes, and aging is performed at room temperature for 60 minutes. Then, one ends of the curled filaments are fixed, and the filaments are hung down to visually evaluate the degree of ease of curl setting and stability of the curl. Good: The curl is sufficiently set and is stable Fair, The curl is set, but is not stable Bad: The curl is not sufficiently set Examples 1 to 15 To a composition made of polyethylene terephthalate dried to have a moisture content of 100 ppm or less, a brominated epoxy flame retardant, organic fine particles, and inorganic fine particles at a composition ratio shown in Tables 1 and 2, 2 parts of a coloring polyester pellet PESM6100 BLACK (manufactured by Dainichiseika Color & Chemicals Mfg. Co., Ltd., carbon black content: 30%, polyester contained in the component (A)) was added, and the components were dry blended. The blend was fed into a twin-screw extruder and melt kneaded at 280° C. to form a pellet. Then, the pellet was dried to have a moisture content of 100 ppm or less. Next, the pellet was put into a melt spinning machine, and the molten polymer was spun through a spinneret having round cross-sectional nozzle holes with a nozzle diameter of 0.5 mm each at 280° C., air-cooled, and rolled up at a rate of 100 m/min to obtain a spun yarn. The resulting spun yarn was drawn in a hot water bath at 80° C. to prepare a yarn at a draw ratio of 4. The drawn yarn was wound up around a heat roll heated to 200° C. at a rate of 30 m/min and heat-treated. Fiber treating agents KWC-Q (ethylene oxide-propylene oxide random copolymer polyether, manufactured by Marubishi Oil Chemical Co., Ltd.) and KRE-103 (cationic surfactant, manufactured by Matsumoto Yushi-Seiyaku Co., Ltd.) were attached to the yarn in an amount of 0.20 %omf, respectively, to obtain a polyester fiber (multifilament) having a monofilament size of about 50 dtex. TABLE 1 Example 1 2 3 4 5 6 7 8 9 EFG-85A*1 100 100 100 100 100 100 100 100 100 EP-200*2 10 EC-200*2 10 EPC-15*2 10 15 YDB-412*3 10 15 SR-T2000*4 15 SR-T5000*4 10 SR-T7040*4 10 U Polymer U-100*5 2 Tipaque CR-60*6 0.2 0.2 0.2 PKP-53*7 0.6 0.6 0.6 0.6 0.6 *1Polyethylene terephthalate, manufactured by Kanebo Gohsen, Ltd. *2Terminal blocked/terminal non-blocked brominated epoxy flame retardant, manufactured by Dainippon Ink and Chemicals, Inc. *3Terminal non-blocked brominated epoxy flame retardant, manufactured by Tohto Kasei Co., Ltd. *4Terminal blocked/terminal non-blocked brominated epoxy flame retardant, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd. *5Polyallylate, manufactured by Unitika Ltd. *6Titanium oxide, manufactured by Ishihara Sangyo Kaisha, Ltd. *7Talc, manufactured by Fuji talc Industrial Co., Ltd. TABLE 2 Example 10 11 12 13 14 15 EFG-85A*1 100 100 100 100 100 100 XAC-4965*9 15 SR-T20000*10 12 16 YPB-43M*11 5 10 15 U Polymer U-100*5 2 PKP-53*7 0.6 0.6 *1Polyethylene terephthalate, manufactured by Kanebo Gohsen, Ltd. *9Terminal non-blocked brominated epoxy flame retardant, manufactured by Asahi Kasei Corp. *10Terminal non-blocked brominated epoxy flame retardant, number average molecular weight: 30,000, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd. *11Terminal non-blocked brominated epoxy flame retardant, number average molecular weight: 40,000, manufactured by Tohto Kasei Co., Ltd. *5Polyallylate, manufactured by Unitika Ltd. *7Talc, manufactured by Fuji talc Industrial Co., Ltd. Strength and elongation, flame retardance, gloss, transparence, devitrification resistance, combing properties, feeling, surface roughness, iron setting properties, and curl setting properties of the resulting fiber were evaluated. The results are shown in Tables 3 and 4. TABLE 3 Comparative Example 1 2 3 4 5 Nozzle shape Round Round Round Round Round Size (dtex) 52 48 47 47 50 Amount of KWC-Q 0.2 0.2 0.2 0.2 0.2 fiber treating agents KRE-103 0.2 0.2 0.2 0.2 0.2 attached (% omf) Strength (cN/dtex) 2.2 2.0 1.9 2.9 2.6 Elongation (%) 68 63 42 52 47 Flame Flammability Fair Fair Good Very Very retardance good good Drip Bad Bad Bad Very Very resistance good good Gloss Bad Fair Fair Very Bad good Transparence Fair Fair Fair Bad Fair Devitrification Fair Fair Bad Fair Fair resistance Combing properties Bad Bad Fair Fair Bad Feeling Stickiness Bad Bad Bad Good Bad reduction Smooth Bad Bad Bad Good Bad feeling Surface Arithmetic 0.1 0.6 0.5 1.2 0.1 roughness mean roughness (μm) Ten-point 0.1 0.4 0.4 0.5 0.4 mean roughness (μm) Iron setting properties Adhesion Good Good Good Good Good (180° C.) Crimping/end Good Good Good Good Good breakage Rod out Good Good Good Good Good Holding Good Good Good Good Good properties Curl setting properties Good Good Good Good Good (110° C.) TABLE 4 Comparative Example 1 2 3 4 5 Nozzle shape Round Round Round Round Round Size (dtex) 52 48 47 47 50 Amount of KWC-Q 0.2 0.2 0.2 0.2 0.2 fiber treating agents KRE-103 0.2 0.2 0.2 0.2 0.2 attached (% omf) Strength (cN/dtex) 2.2 2.0 1.9 2.9 2.6 Elongation (%) 68 63 42 52 47 Flame Flammability Fair Fair Good Very Very retardance good good Drip Bad Bad Bad Very Very resistance good good Gloss Bad Fair Fair Very Bad good Transparence Fair Fair Fair Bad Fair Devitrification Fair Fair Bad Fair Fair resistance Combing properties Bad Bad Fair Fair Bad Feeling Stickiness Bad Bad Bad Good Bad reduction Smooth Bad Bad Bad Good Bad feeling Surface Arithmetic 0.1 0.6 0.5 1.2 0.1 roughness mean roughness (μm) Ten-point 0.1 0.4 0.4 0.5 0.4 mean roughness (μm) Iron setting properties Adhesion Good Good Good Good Good (180° C.) Crimping/end Good Good Good Good Good breakage Rod out Good Good Good Good Good Holding Good Good Good Good Good properties Curl setting properties Good Good Good Good Good (110° C.) Comparative Examples 1 to 5 To a composition made of polyethylene terephthalate dried to have a moisture content of 100 ppm or less, a brominated epoxy flame retardant, and inorganic fine particles at a composition ratio shown in Table 5, 2 parts of a coloring polyester pellet PESM6100 BLACK (manufactured by Dainichiseika Color & Chemicals Mfg. Co., Ltd., carbon black content: 30%, polyester contained in the component (A)) was added, and the components were dry blended. The blend was fed into a twin-screw extruder and melt kneaded at 280° C. to form a pellet. Then, the pellet was dried to have a moisture content of 100 ppm or less. Next, the pellet was put into a melt spinning machine, and the molten polymer was discharged from a spinneret having round cross-sectional nozzle holes with a nozzle diameter of 0.5 mm each at 280° C., air-cooled, and wound up at a rate of 100 m/min to obtain a spun yarn. The resulting spun yarn was drawn in a hot water bath at 80° C. to prepare a yarn at a draw ratio of 4. The drawn yarn was wound up around a heat roll heated to 200° C. at a rate of 30 m/min and heat-treated. Fiber treating agents KWC-Q (ethylene oxide-propylene oxide random copolymer polyether, manufactured by Marubishi Oil Chemical Co., Ltd.) and KRE-103 (cationic surfactant, manufactured by Matsumoto Yushi-Seiyaku Co., Ltd.) were attached to the yarn in an amount of 0.20% omf, respectively, to obtain a polyester fiber (multifilament) having a monofilament size of about 50 dtex. Strength and elongation, flame retardance, gloss, transparence, devitrification resistance, combing properties, feeling, surface roughness, iron setting properties, and curl setting properties of the resulting fiber were evaluated. The results are shown in Table 6. TABLE 5 Comparative Example 1 2 3 4 5 EFG-85A*1 100 100 100 100 Triphenyl phosphate 10 PX-200*12 10 Heim RH-416*13 100 Pyrochek 68PB*14 6 FR-1808*15 10 Tipaque CR-60*6 1 *1Polyethylene terephthalate, manufactured by Kanebo Gohsen, Ltd. *12Condensed phosphate flame retardant, manufactured by Daihachi Chemical Industry Co., Ltd. *13Phosphorus flame retardant copolymer polyester, manufactured by Toyobo Co., Ltd. *14Brominated polystyrene flame retardant, manufactured by Nissan Ferro Organic Chemical Co., Ltd. *15Octabromotrimethylphenylindane, manufactured by Bromokem Far East Ltd. *6Titanium oxide, manufactured by Ishihara Sangyo Kaisha, Ltd. TABLE 6 Comparative Example 1 2 3 4 5 Nozzle shape Round Round Round Round Round Size (dtex) 52 48 47 47 50 Amount of KWC-Q 0.2 0.2 0.2 0.2 0.2 fiber treating agents KRE-103 0.2 0.2 0.2 0.2 0.2 attached (% omf) Strength (cN/dtex) 2.2 2.0 1.9 2.9 2.6 Elongation (%) 68 63 42 52 47 Flame Flammability Fair Fair Good Very Very retardance good good Drip Bad Bad Bad Very Very resistance good good Gloss Bad Fair Fair Very Bad good Transparence Fair Fair Fair Bad Fair Devitrification Fair Fair Bad Fair Fair resistance Combing properties Bad Bad Fair Fair Bad Feeling Stickiness Bad Bad Bad Good Bad reduction Smooth Bad Bad Bad Good Bad feeling Surface Arithmetic 0.1 0.6 0.5 1.2 0.1 roughness mean roughness (μm) Ten-point 0.1 0.4 0.4 0.5 0.4 mean roughness (μm) Iron setting properties Adhesion Good Good Good Good Good (180° C.) Crimping/end Good Good Good Good Good breakage Rod out Good Good Good Good Good Holding Good Good Good Good Good properties Curl setting properties Good Good Good Good Good (110° C.) As shown in Tables 3 and 4, it was confirmed that the fibers of Examples are superior to the fibers of Comparative Examples in terms of flame retardance, gloss, transparence, devitrification resistance, combing properties, feeling, iron setting properties, and curl setting properties. Accordingly, it was confirmed that the fiber for artificial hair of interest using a brominated epoxy flame retardant can be effectively used as artificial hair with improved flame retardance, gloss, transparence, setting properties, devitrification resistance, and combing properties, while maintaining mechanical properties and thermal properties possessed by polyester. Examples 16 to 22 To a composition made of polyethylene terephthalate dried to have a moisture content of 100 ppm or less, a brominated epoxy flame retardant, and inorganic fine particles at a composition ratio shown in Table 7, 2 parts of a coloring polyester pellet PESM6100 BLACK (manufactured by Dainichiseika Color & Chemicals Mfg. Co., Ltd., carbon black content: 30%, polyester contained in the component (A)) was added, and the components were dry blended. The blend was fed into a twin-screw extruder and melt kneaded at 280° C. to form a pellet. Then, the pellet was dried to have a moisture content of 100 ppm or less. Next, the pellet was put into a melt spinning machine, and the molten polymer was discharged from a spinneret having nozzle holes with a cross-section of FIGS. 8 to 10 at 280° C., air-cooled, and wound up at a rate of 100 m/min to obtain a spun yarn. The resulting spun yarn was drawn in a hot water bath at 80° C. to prepare a yarn at a draw ratio of 4. The drawn yarn was wound up around a heat roll heated to 200° C. at a rate of 30 m/min and heat-treated. Fiber treating agents KWC-Q (ethylene oxide-propylene oxide random copolymer polyether, manufactured by Marubishi Oil Chemical Co., Ltd.) and KRE-103 (cationic surfactant, manufactured by Matsumoto Yushi-Seiyaku Co., Ltd.) were attached to the yarn in an amount of 0.20% omf, respectively, to obtain a polyester fiber (multifilament) having a monofilament size of about 60 to 70 dtex. TABLE 7 Example 16 17 18 19 20 21 22 EFG-85A*1 100 100 100 100 100 100 100 SR-T20000*10 10 10 10 10 10 YPB-43M*11 15 15 PKP-53*7 0.5 0.5 0.5 0.5 0.5 Imsil A-8*16 0.5 0.5 0.5 0.5 0.5 *1Polyethylene terephthalate, manufactured by Kanebo Gohsen, Ltd. *10Terminal non-blocked brominated epoxy flame retardant, number average molecular weight: 30,000, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd. *11Terminal non-blocked brominated epoxy flame retardant, number average molecular weight: 40,000, manufactured by Tohto Kasei Co., Ltd. *7Talc, manufactured by Fuji talc Industrial Co., Ltd. *16Silica, manufactured by Unimin Corp. (In FIG. 8, A is 0.9 mm, and B is 0.4 mm.) (In FIG. 9, A is 1.0 mm, B is 0.35 mm, and C is 0.25 mm.) (In FIG. 10, R is 0.6 mm, and r is 0.4 mm.) Strength and elongation, flame retardance, gloss, transparence, devitrification resistance, combing properties, feeling, surface roughness, iron setting properties, and curl setting properties of the resulting fiber were evaluated. The results are shown in Table 8. TABLE 8 Example 16 17 18 19 20 21 22 Nozzle shape Modified 1 Modified 2 Modified 3 Modified Modified Modified 1 Modified 2 1/Round = 67/ 1/Round = 50/ 33 50 Size (dtex) 67 65 68 62 59 70 68 Amount of KWC-Q 0.2 0.2 0.2 0.2 0.2 0.2 0.2 fiber KRE-103 0.2 0.2 0.2 0.2 0.2 0.2 0.2 treating agents attached (% omf) Strength (cN/dtex) 2.5 2.2 1.8 2.7 2.9 2.4 2.2 Elongation (%) 68 53 38 59 52 53 48 Flame Flammability Very Very Very Very Very Very Very retardance good good good good good good good Drip Very Very Very Very Very Very Very resistance good good good good good good good Gloss Good Good Good Good Good Very Very good good Transparence Good Good Good Good Good Good Good Devitrification Good Good Good Good Good Good Good resistance Combing properties Good Good Good Good Good Good Good Feeling Stickiness Good Good Good Good Good Good Good reduction Smooth Very Very Very Very Very Very Very feeling good good good good good good good Surface Arithmetic 1.0 1.0 1.1 1.0 1.1 1.4 1.3 roughness mean roughness (μm) Ten-point 0.8 0.9 0.8 0.7 0.8 1.1 1.1 surface roughness (μm) Iron Adhesion Good Good Good Good Good Good Good setting Crimping/ Good Good Good Good Good Good Good properties end (180° C.) breakage Rod out Good Good Good Good Good Good Good Holding Good Good Good Good Good Good Good properties Curl setting Good Good Good Good Good Good Good properties (110° C.) Examples 23 to 29 To a composition made of polyethylene terephthalate dried to have a moisture content of 100 ppm or less, a brominated epoxy flame retardant, and inorganic fine particles at a composition ratio shown in Table 9, 2 parts of a coloring polyester pellet PESM6100 BLACK (manufactured by Dainichiseika Color & Chemicals Mfg. Co., Ltd., carbon black content: 30%, polyester contained in the component (A)) was added, and the components were dry blended. The blend was fed into a twin-screw extruder and melt kneaded at 280° C. to form a pellet. Then, the pellet was dried to have a moisture content of 100 ppm or less. Next, the pellet was put into a melt spinning machine, and the molten polymer was spun through a spinneret having nozzle holes with a cross-section of FIGS. 8 and 9 at 280° C., air-cooled, and rolled up at a rate of 100 m/min to obtain a spun yarn. The resulting spun yarn was drawn in a hot water bath at 80° C. to prepare a yarn at a draw ratio of 4. The drawn yarn was rolled up around a heat roll heated to 200° C. at a rate of 30 m/min and heat-treated. Fiber treating agents shown in Table 10 were respectively attached to the yarn to obtain a polyester fiber (multifilament) having a monofilament size of about 70 dtex. TABLE 9 Example 23 24 25 26 27 28 29 EFG-85A*1 100 100 100 100 100 100 100 SR-T20000*10 16 16 16 16 16 YPB-43M*11 15 15 PKP-53*7 0.6 0.6 0.6 0.6 0.6 *1Polyethylene terephthalate, manufactured by Kanebo Gohsen, Ltd. *10Terminal non-blocked brominated epoxy flame retardant, number average molecular weight: 30,000, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd. *11Terminal non-blocked brominated epoxy flame retardant, number average molecular weight: 40,000, manufactured by Tohto Kasei Co., Ltd. *7Talc, manufactured by Fuji talc Industrial Co., Ltd. TABLE 10 Example 23 24 25 26 27 28 29 Nozzle shape Modified 1 Modified 1 Modified 1 Modified 1 Modified 1 Modified 2 Modified 2 Size (dtex) 70 70 70 70 70 68 68 Amount of KWC-Q*17 0.1 0.25 0.15 0.1 fiber KRE-103*18 0.1 0.1 treating KRE-102*19 0.2 0.1 agents KRE-15*20 0.2 0.1 0.1 attached KRE-16*21 0.14 0.07 0.07 (% omf) KRE-17*22 0.06 0.03 0.03 Strength (cN/dtex) 2.5 2.5 2.5 2.5 2.5 2.4 2.4 Elongation (%) 54 54 54 54 54 48 48 Flame Flammability Very Very Very Very Very Very Very retardance good good good good good good good Drip Very Very Very Very Very Very Very resistance good good good good good good good Gloss Good Good Good Good Good Very Very good good Transparence Good Good Good Good Good Good Good Devitrification Good Good Good Good Good Good Good resistance Combing properties Good Good Good Good Good Good Good Feeling Stickiness Good Good Good Good Good Good Good reduction Smooth Good Very Good Very Good Good Good feeling good good Surface Arithmetic 1.0 1.0 1.0 1.0 1.0 1.4 1.4 roughness surface roughness (μm) Ten-point 0.8 0.8 0.8 0.8 0.8 1.1 1.1 surface roughness (μm) Iron setting Adhesion Good Good Good Good Good Good Good properties Crimping/ Good Goo-d Good Good Good Good Good (180° C.) end breakage Rod out Good Good Good Good Good Good Good Holding Good Good Good Good Good Good Good properties Curl setting properties Good Good Good Good Good Good Good (110° C.) As shown in Tables 8 and 10, it was confirmed that a fiber for artificial hair having excellent properties and quality balance can be obtained by modifying the fiber cross-section or using a specific fiber treating agent. INDUSTRIAL APPLICABILITY An object of the present invention is to provide a flame retardant polyester fiber for artificial hair in which problems of the prior art are solved and which maintains fiber properties such as heat resistance and strength and elongation possessed by a common polyester fiber, has excellent flame retardance, setting properties, drip resistance, transparence, devitrification resistance, stickiness reduction, and combing properties required for artificial hair, and has fiber luster controlled according to need. Another object of the present invention is to provide a polyester fiber for artificial hair which maintains fiber properties such as heat resistance and strength and elongation possessed by a polyester fiber, improves defective curling properties of such a polyester fiber, and has excellent luster, feeling, and combing properties by using the above-described polyester fiber for artificial hair which has at least one modified cross-section, is a mixture with a fiber having a modified cross-section, and has a mixing ratio of the fiber having a round cross-section to the fiber having a modified cross-section is 8:2 to 1:9. The present invention further provides a flame retardant fiber for artificial hair which does not have reduced flame retardance as in the case where such a fiber is treated with a silicone fiber treating agent in order to improve smooth feeling and texture, for example; has slip feeling and combing properties the same as in the case where such a fiber is treated with a silicone oil agent for the same purpose; and has excellent flame retardance.

<SOH> BACKGROUND ART <EOH>Fibers made of polyethylene terephthalate or a polyester comprising polyethylene terephthalate as a main component has excellent heat resistance, chemical resistance, a high melting point and a high modulus of elasticity, therefore are thus widely used in curtains, carpets, clothes, blankets, sheetings, table clothes, upholstery fabrics, wall coverings, artificial hair, interior materials for automobiles, outdoor reinforcing materials, and safety nets. On the other hand, human hair, artificial hair (modacrylic fibers, polyvinyl chloride fibers), or the like has been conventionally used in hair products such as wigs, hair wigs, extensions, hair bands, and doll hair. However, it has now become difficult to provide human hair for hair products, and thus artificial hair has become more important. Modacrylic fibers have been often used as artificial hair materials due to their flame retardance, but have only insufficient heat resistance. In recent years, there has been proposed artificial hair using, as a main component, a polyester typified by polyethylene terephthalate having excellent heat resistance. However, fibers made of a polyester typified by polyethylene terephthalate are flammable materials, and thus have insufficient flame resistance. Conventionally, various attempts have been made to improve flame resistance of polyester fibers. Known examples of such attempts include a method comprising using a fiber made of a polyester obtained by copolymerizing a flame retardant monomer containing a phosphorus atom, and a method comprising adding a flame retardant to a polyester fiber. As the former method comprising copolymerizing a flame retardant monomer, a method comprising copolymerizing a phosphorus compound with excellent heat stability having a phosphorus atom as a ring member (Japanese Patent Publication No. 55-41610), a method comprising copolymerizing carboxyphosphinic acid (Japanese Patent Publication No. 53-13479), a method comprising copolymerizing a polyester containing a polyallylate with a phosphorus compound (Japanese Patent Laid-open No. 11-124732), or the like has been proposed. As artificial hair to which the above flame retardant technology is applied, a polyester fiber copolymerized with a phosphorus compound has been proposed (Japanese Patent Laid-open No. 03-27105, Japanese Patent Laid-open No. 05-339805, etc.), for example. However, since artificial hair is demanded to be highly flame resistant, such a copolymer polyester fiber must have a high copolymerization amount when used for artificial hair. This results in a significant decrease in flame resistance of the polyester, and causes other problems in which it is difficult to perform melt spinning, or, when flame approaches, the artificial hair does not catch fire and is not burned, but molten and dripped. When the phosphorus flame retardant is added, stickiness is increased because it must be added in a large amount to exhibit flame retardance, and the resulting artificial hair made of a polyester fiber tends to have a heat history and, under high humidity conditions, be devitrified to affect the appearance of the fiber. On the other hand, as the latter method comprising adding a flame retardant, a method comprising adding a halogenated cycloalkane compound as fine particles to a polyester fiber (Japanese Patent Publication No. 03-57990), a method comprising adding a bromine-containing alkylcyclohexane to a polyester fiber (Japanese Patent Publication No. 01-24913), or the like has been proposed. However, in the method comprising adding a flame retardant to a polyester fiber, in order to achieve sufficient flame retardance, the addition treatment temperature must be as high as 150° C. or more, the addition treatment time must be long, or a large amount of a flame retardant must be used, disadvantageously. This causes problems such as deteriorated fiber properties, reduced productivity, and an increased production cost. As described above, artificial hair has not yet been provided which maintains fiber properties possessed by a conventional polyester fiber such as flame resistance, heat resistance, and strength and elongation and has excellent setting properties, devitrification resistance, and stickiness reduction. Synthetic fibers conventionally used for hair include acrylonitrile fibers, vinyl chloride fibers, vinylidene chloride fibers, polyester fibers, nylon fibers, and polyolefin fibers. Conventionally, these fibers have been processed into products for artificial hair such as wigs, braids, and extension hair. However, these fibers do not have properties necessary for a fiber for artificial hair such as heat resistance, curling properties, and good feeling together. Thus, products with various properties satisfied cannot be produced from a single fiber, and products making use of properties of each fiber are produced and used. Fibers having a cross-section suitable to characteristics of each goods have also been studied and improved. Examples of such fibers include a filament for wigs having a cocoon cross-section with a length L of a longest part, a diameter W of round parts on both ends, and a width C of a central constriction, each within a specific range (Japanese Utility Model Laid-open No. 48-13277); a synthetic fiber for artificial hair having a largest diameter (L) passing through the gravity in the fiber cross-section within a specific range (Japanese Patent Publication No. 53-6253); a filament for wigs and braids having a Y-shaped cross-section in which four unit filaments having an almost round shape or an elliptical shape are provided with one unit filament radially adjacent to the other three unit filaments at the same intervals, and the adjacent unit filaments have contact points having a width almost equal to the radius of the unit filaments (Japanese Utility Model Laid-open No. 63-78026); and a filament for wigs having a cross-section with at least two flat circles lapped, in which the ratio L/W of the major axis length L to the minor axis length W, the distance between the centers of two adjacent flat circles, the angle between the straight line linking the centers of two adjacent flat circles and the major axes of the flat circles, and the like are limited (Japanese Patent Laid-open No. 55-51802). However, any of the above-described conventional fibers developed as fibers for artificial hair has a cross-section with a length and an angle extremely limited and with a unique shape, and cannot necessarily easily produced. In addition, such fibers do not necessarily have preferable texture when used for braids or extension hair, and tend to be felt hard because the fibers are intended to keep a hairstyle or make the resulting hair straight. Further, these fibers cannot be sufficiently easily handled manually. Ribbon-section fibers have conventionally widely used for piles, but have been assumed to be inappropriate for use as fibers for artificial hair such as wigs due to their disliked too much softness or the like. On the other hand, in the method comprising adding a flame retardant to a polyester fiber, in order to achieve sufficient flame retardance, the addition treatment temperature must be as high as 150° C. or higher, the addition treatment time must be long, or a large amount of a flame retardant must be used, disadvantageously. This causes problems such as deteriorated fiber properties, decreased productivity, and an increased production cost. In order to provide such synthetic fibers poorly flame retardant or not flame retardant with flexibility, smooth feeling, or the like, various silicone finishing agents have been provided. Examples of the finishing agents for providing the fibers with flexibility, crease resistance, elastic force, and compression recovery properties include dimethylpolysiloxane, methylhydrogenpolysiloxane, dimethylpolysiloxane having hydroxyl groups at both terminals, a vinyl group-containing organopolysiloxane, an epoxy group-containing organopolysiloxane, an amino group-containing organopolysiloxane, an ester group-containing organopolysiloxane, and a polyoxyalkylene-containing organopolysiloxane. A treating agent composed of a combination of alkoxysilanes and/or a polyacrylamide resin or a catalyst or the like has also been known. For example, there is disclosed a method using a treating agent composed of an organopolysiloxane containing at least two epoxy groups in one molecule and an organopolysiloxane containing an amino group, or a treating agent composed of an organopolysiloxane having hydroxyl groups at both terminals, and an organopolysiloxane containing an amino group and an alkoxy group in one molecule and/or its partial hydrolysate and condensate (Japanese Patent Publication No. 53-36079). Further, there are described a treating agent composed of an organopolysiloxane containing an epoxy group and an aminoalkyltrialkoxysilane (Japanese Patent Publication No. 53-197159 and Japanese Patent Publication No. 53-19716), and a diorganopolysiloxane having triorganosiloxy groups at both terminals, which contains two or more amino groups in one molecule (Japanese Patent Publication No. 53-98499). In addition, there is proposed a method using a treating agent composed of an aminopolysiloxane containing two or more amino groups in one molecule and an alkoxysilane containing one or more reactive groups such as amino groups or epoxy groups (Japanese Patent Publication No. 58-17310). Further, there are disclosed a method using a treating agent composed of a diorganosiloxane containing at least two amino groups in one molecule and a diorganopolysiloxane containing at least two ester bonds in one molecule (Japanese Patent Laid-open No. 55-152864), and a method using a polysiloxane containing an amino group, a hydroxyl group-terminated polysiloxane, and an alkylalkoxysilane containing a reactive group (Japanese Patent Laid-open No. 58-214585). In addition, there are disclosed a method using a treating agent composed of an organopolysiloxane containing an epoxy group, an aminosilane compound, and a curing catalyst (Japanese Patent Laid-open No. 59-144683), and a method using an organopolysiloxane containing at least two epoxy groups in one molecule and a polyacrylamide resin (Japanese Patent Laid-open No. 60-94680). However, fibers to which these silicone-containing fiber treating agents are attached exhibit improved smooth feeling, combing properties, and the like, but the silicone-containing fiber treating agents are flammable, and thus provide significantly reduce flame retardance of flame retardant synthetic fibers, disadvantageously.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIGS. 1 to 10 are schematic views respectively showing a cross-section of a polyester fiber made of the composition of the present invention, with the figures corresponding to the following: FIG. 1 : A view of a cross-section in the shape of crossed circles FIG. 2 : A view of a cross-section in the shape of crossed flat circles FIG. 3 : A view of a cross-section in the shape of a dog bone FIG. 4 : A view of a cross-section in the shape of three leaves FIG. 5 : A view of a cross-section in the shape of five leaves FIG. 6 : A view of a cross-section in the shape of seven leaves FIG. 7 : A view for describing a flatness ratio of a modified cross-section FIG. 8 : A modified nozzle 1 FIG. 9 : A modified nozzle 2 FIG. 10 : A modified nozzle 3 detailed-description description="Detailed Description" end="lead"?

20060123

20100720

20060831

65745.0

D02G300

DOLLINGER, MICHAEL M

FLAME-RETARDANT POLYESTER FIBERS FOR ARTIFICIAL HAIR

UNDISCOUNTED

ACCEPTED

D02G

ACCEPTED

Led and fabrication method thereof

A light emitting diode is provided. The diode includes: a substrate; a first nitride gallium layer disposed above the substrate; a first electrode provided at one portion of and above the first nitride gallium layer; an active layer provided above the first nitride gallium layer, for emitting light; a second nitride gallium layer provided above the active layer; and transparent electrodes spaced apart from one another above the second nitride gallium layer.

1. An LED comprising: a first nitride gallium layer; a first electrode provided at one portion of and above the first nitride gallium layer; an active layer provided above the first nitride gallium layer; a second nitride gallium layer provided above the active layer; and transparent electrodes spaced apart from one another above the second nitride gallium layer. 2. The LED according to claim 1, wherein the transparent electrodes have stripe shapes spaced apart from one another. 3. The LED according to claim 1, wherein the transparent electrode are disposed at a region excepting contact portion regions of the first electrode. 4. The LED according to claim 1, further comprising: a third nitride gallium layer formed above the second nitride gallium layer. 5. An LED having a first nitride gallium layer, an active layer, a second nitride gallium layer, a first electrode, and a second electrode above a sapphire substrate, the diode comprising: a plurality of transparent electrodes respectively provided at a plurality of partitioned regions excepting regions of the first electrode and the second electrode; and a plurality of connection units for electrically connecting the plurality of transparent electrodes with the second electrode. 6. The LED according to claim 5, wherein the first electrode is disposed along a circumference of an upper edge of the diode. 7. The LED according to claim 5, wherein the connection unit are metal films. 8. The LED according to claim 5, wherein the connection units have resistances different from one another. 9. The LED according to claim 5, wherein the edges of the plurality of transparent electrodes, which are electrically connected with the connection units, have the same thicknesses as the second electrode. 10. The LED according to claim 5, wherein the plurality of transparent electrodes is disposed to space apart from one another along an upper edge of the light emitting diode at which the first electrode is disposed. 11. The LED according to claim 5, wherein at least one transparent electrode is provided such that a pair of transparent electrodes faces with each other. 12. The LED according to claim 5, wherein the plurality of transparent electrodes is disposed at an adjacent region to the first electrode to have a step shape. 13. The LED according to claim 5, wherein the connection unit is formed above the second nitride gallium layer to have a concavo-convex shape. 14. The LED according to claim 5, further comprising: a third nitride gallium layer formed above the second nitride gallium layer. 15. A method of fabricating an LED, the method comprising the steps of: forming a stripe-shaped transparent electrode pattern using a stripe-shaped mask above a nitride gallium layer; depositing a transparent electrode above the stripe-shaped transparent electrode pattern; and etching-out the stripe-shaped transparent electrode pattern to form a stripe-shaped transparent electrode. 16. The method according to claim 15, wherein the stripe-shaped transparent electrode pattern is formed of SiO2-based material. 17. A method of fabricating an LED, the method comprising the steps of: depositing a transparent electrode film above a nitride gallium layer, and coating a photoresist film above the transparent electrode film; exposing and developing the photoresist film by using a slit-shaped mask above the photoresist film, to form a stripe-shaped photoresist pattern; and etching the transparent electrode film along the stripe-shaped photoresist pattern to form a stripe-shaped transparent electrode. 18. An LED comprising: a substrate; a first nitride gallium layer formed above the substrate; an active layer formed above the second nitride gallium layer; a second nitride gallium layer formed above the active layer; a first electrode formed above the first nitride gallium layer; a second electrode formed above the second nitride gallium layer; and a plurality of transparent electrodes spaced apart from one another above the second nitride gallium layer. 19. The LED according to claim 18, further comprising: an electrical connection unit for connecting the transparent electrode with the second electrode. 20. The LED according to claim 18, wherein the transparent electrodes are provided at least three. 21. The LED according to claim 18, wherein the transparent electrodes have stripe shapes.

TECHNICAL FIELD The present invention relates to a light emitting diode and a fabrication method thereof, and more particularly, to a light emitting diode and a fabrication method thereof in which a transparent electrode can be partitioned at a light emission region to improve a light efficiency. BACKGROUND ART Generally, light emitting diode (LED) is a kind of a semiconductor device, and it converts electricity into infrared ray or light by using a characteristic of a compound semiconductor, to send and receive a signal. The LED is used for home appliances, a remote controller, an electronic display board, a displaying apparatus, a variety of automation apparatuses and the like. An operation principle of the LED will be briefly described in the following. When a forward voltage is applied to a semiconductor of a specific chemical element, electrons and holes are recombined with each other while moving through a positive-negative junction. The recombination of the electrons and the holes causes an energy level to fall down, thereby emitting light. Further, the LED is generally manufactured to have a very small size of 0.25 mm2 and is mounted on a lead frame or a printed circuit board (PCB) using has an epoxy mold. Representative of the LEDs is a plastic package of 5 mm (T 1¾) or a new package being developed in a specific application field. A color of light emitted from the LED is determined by a wavelength obtained depending on a combination of elements constituting a semiconductor chip. Particularly, as an information communication apparatus is in a trend of a small size and slimness, the communication apparatus has more miniaturized parts such as a resistance, a condenser, and a noise filter. The LED is manufactured in a form of a Surface mounted Device (Hereinafter, referred to as “SMD”) so as to be directly mounted on a Printed Circuit Board (Hereinafter, referred to as “PCB”). Accordingly, an LED lamp for a display device is being developed in the form of the SMD. Such an SMD can substitute a related-art simple lamp. The SMD is used for a lamp display, a character display, an image display and the like that express various colors. Further, as a high-density integration technology for a semiconductor device is developed and a consumer prefers a more compact electronic product, Semiconductor Mounting Technology (SMT) is widely used, and a packaging technology of the semiconductor device employs a technology for minimizing an installation space such as a Ball Grid Array (BGA), a wire bonding, and a flip chip bonding. FIG. 1 is a view illustrating a related art light emitting diode. As shown in FIG. 1, after an N-type nitride gallium layer 102 is formed on a sapphire substrate 101, an N-type electrode 105 is formed at one portion of and on the N-type nitride gallium layer 102. A metal organic chemical vapor deposition (MOCVD) is used to form a film using a Group 3-based element on the sapphire substrate 101. Silicon using silane (SiH4) gas is used to form N-type dopants. All three-component nitride films are grown in an atmosphere of Hydrogen gas. Nitrogen gas is used to grow a nitride gallium. After the N-type nitride gallium 102 is formed, an active layer 104 is formed on the N-type nitride gallium layer 102. The active layer 104 corresponding to a light emission region has a quantum well structure comprising a Indium gallium nitride. After the active layer 104 is formed, a P-type nitride gallium (GaN) layer 106 is formed. The P-type nitride gallium layer 106, which is contrasted with the N-type nitride gallium layer 102, is formed by the addition of P-type dopants. Therefore, in the N-type nitride gallium layer 102, electrons are drifted by an external voltage. In the P-type nitride gallium layer 106, holes are drifted by the external voltage. The electrons and the holes are recombined with each other to emit light. The transparent metal-based transparent electrode 107 is formed on the P-type nitride gallium layer 106 to allow light generated from the active layer 104 to be transmitted therethrough, and allow the generated light to be emitted to the external. After the transparent electrode 107 is formed, a P-type electrode 103 is formed to compose the light emitting diode. However, since the related-art light emitting diode using the sapphire substrate has a nitride film having a larger refractive index than the substrate, the light generated from the active layer is transmitted through the nitride film to be emitted toward the transparent electrode. FIG. 2 is a plan view illustrating the transparent electrode, the P-type electrode, and the N-type electrode of the light emitting diode of FIG. 1. As shown in FIG. 2, the P-type electrode 103 and the N-type electrode 105 are disposed at both portions of the light emitting diode 100, and the transparent electrode 107 is disposed on a whole region of the light emitting diode 100. The transparent electrode 107 corresponds to a region at which the light generated from the active layer of the light emitting diode 100 is emitted. The transparent electrode 107 is formed of a transparent conductive metal. FIGS. 3a and 3b are views illustrating a light emission region of a related art light emitting diode. As shown, it can be appreciated that the generated light is biased and concentrated at a predetermined region. In other words, a light biased-concentration phenomenon occurs since a voltage applied to combine the holes and the electrons in the active layer is varied due to a resistance component centering on the N-type electrode. As a distance is increased from the N-type electrode, resistance is increased. Therefore, the increased resistance again results in a voltage drop. Unlike this, the resistance is not varied depending on the distance at a region far away from the N-type electrode comparing to a region close to the N-type electrode. Therefore, a high current is applied to the active layer when a high voltage is applied to an electrode region. If the high voltage is applied to the region close to the electrode region as described above, a temperature of the active layer rises. The rise of the temperature of the active layer causes a drop of a turn-on voltage of the light emitting diode to make worse the biased-concentration of a driving current. Further, as shown in FIG. 3b, in case where the N-type electrode is disposed along a circumference of an upper edge of the light emitting diode, the light is biased and concentrated only at an N-type electrode region, which is close to the P-type electrode. Specifically, the P-type electrode itself functions to block or absorb a portion of photons incident on the P-type electrode, thereby deteriorating an efficiency of light emission. If a thickness of the P-type electrode is decreased to prevent this, the resistance of the P-type electrode is relatively greatly increased. Accordingly, it cannot be expected that the light is emitted from the region far away from the n-type electrode. The light biased-concentration phenomenon occurs because the voltage applied to the active layer is not constantly maintained at the whole region along the P-type electrode and the transparent electrode, due to the resistance increased at each distance away from the electrode and different voltage drops caused by the increased resistance at each upper electrode region. Further, in case where the emitted light is reflected or absorbed by the P-type electrode, the light efficiency is deteriorated. Specifically, the light is absorbed at the transparent electrode formed of the transparent metal, an emitted amount of light is reduced. Additionally, since most of the generated light of the light emitting diode is emitted through the transparent electrode to the external, the reduction of the light efficiency causes the reduction of an external quantum efficiency. DISCLOSURE OF THE INVENTION Accordingly, the present invention is directed to a light emitting diode and a fabrication method thereof that substantially obviate one or more problems due to limitations and disadvantages of the related art. An object of the present invention is to provide a light emitting diode and a fabrication method thereof in which a plurality of transparent electrodes is partitioned and provided in the light emitting diode to constantly maintain a magnitude of a voltage applied to an active layer, thereby generating regular light from an upper region of the light emitting diode. Another object of the present invention is to provide a light emitting diode and a fabrication method thereof in which a transparent electrode has a wholly stripe-shaped surface to improve an efficiency of light emitted to the external. Additional features and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and claims thereof as well as the appended drawings. To achieve these and other advantages and in accordance with the purpose of the present invention, as embodied and broadly described, there is provided a light emitting diode including: a substrate; a first nitride gallium layer disposed above the substrate; a first electrode provided at one portion of and above the first nitride gallium layer; an active layer provided at the other portion of and above the first nitride gallium layer, for emitting light; a second nitride gallium layer provided above the active layer; and transparent electrodes spaced apart from one another above the second nitride gallium layer. In another aspect of the present invention, there is provided a light emitting diode having a first nitride gallium layer, an active layer, a second nitride gallium layer, a first electrode, and a second electrode above a sapphire substrate, the diode including: a plurality of transparent electrodes respectively provided at a plurality of partitioned regions excepting regions of the first electrode and the second electrode disposed at an upper layer; and a plurality of connection units for electrically connecting the plurality of transparent electrodes with the second electrode. In a further another aspect of the present invention, there is provided a method of fabricating a light emitting diode, the method including the steps of: forming a stripe-shaped transparent electrode pattern using a stripe-shaped mask above a nitride gallium layer; depositing a transparent electrode above the stripe-shaped transparent electrode pattern; and etching-out the stripe-shaped transparent electrode pattern to form a stripe-shaped transparent electrode. In a still another aspect of the present invention, there is provided a method of fabricating a light emitting diode, the method including the steps of: depositing a transparent electrode film above a nitride gallium layer, and coating a photoresist film above the transparent electrode film; exposing and developing the photoresist film by using a slit-shaped mask above the photoresist film, to form a stripe-shaped photoresist pattern; and etching the transparent electrode film along the stripe-shaped photoresist pattern to form a stripe-shaped transparent electrode. In a still further another aspect of the present invention, there is provided a light emitting diode including: a substrate; a first nitride gallium layer formed above the substrate; an active layer formed above the second nitride gallium layer; a second nitride gallium layer formed above the active layer; a first electrode formed above the first nitride gallium layer; a second electrode formed above the second nitride gallium layer; and a plurality of transparent electrodes spaced apart from one another above the second nitride gallium layer. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention. In the drawings: FIG. 1 is a view illustrating a related-art light emitting diode; FIG. 2 is a plan view illustrating a transparent electrode, a P-type electrode, and an N-type electrode of a light emitting diode of FIG. 1; FIGS. 3a and 3b are views illustrating a light emission region of a related-art light emitting diode; FIG. 4 is a view illustrating a light emitting diode according to the first embodiment of the present invention; FIG. 5 is a plan view illustrating a transparent electrode, a P-type electrode, and an N-type electrode of a light emitting diode according to the first embodiment of the present invention; FIGS. 6a through 6c are views illustrating a method of forming a stripe-structured transparent electrode according to the first embodiment of the present invention; FIGS. 7a through 7c are views illustrating a method of forming a transparent electrode according to another embodiment of the present invention; FIG. 8 is a view illustrating an electrode structure of a light emitting diode according to the second embodiment of the present invention; FIGS. 9 through 12 are views illustrating electrode structures of light emitting diodes according to the third to sixth embodiments of the present invention; FIGS. 13a and 13b are views illustrating an electrode structure and its circuit diagram of a light emitting diode according to the present invention. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, preferred embodiments of the present invention will be described in detail with reference to accompanying drawings. FIG. 4 is a view illustrating a light emitting diode according to the first embodiment of the present invention. As shown in FIG. 4, an N-type nitride gallium (GaN) layer 102 is formed on a sapphire substrate 201 and then, an N-type electrode 205 is formed at one portion of and on the N-type nitride gallium layer 202. After that, an active layer 204 is formed at the other portion of and on the N-type nitride gallium layer 202. The active layer 204 functioning as a light emission region has a quantum well structure comprising a Indium gallium Nitride. After the active layer 204 is formed, a P-type nitride gallium layer 206 is formed. The P-type nitride gallium layer 206 is contrasted with the N-type nitride gallium layer 202, and is formed by the addition of P-type dopants. Therefore, in the N-type nitride gallium layer 202, electrons are drifted by an external voltage. In the P-type nitride gallium layer 206, holes are drifted by the external voltage. The electrons and the holes are recombined with each other to emit light. The transparent metal-based transparent electrode 207 is formed to have a stripe structure on the P-type nitride gallium layer 206, thereby improving a transmittance of light generated from the active layer 204. The transparent electrode 207 can be a Transparent Metal (TM) layer using a transparent metal material. FIG. 5 is a plan view illustrating a transparent electrode, a P-type electrode, and an N-type electrode of a light emitting diode according to the first embodiment of the present invention. As shown in FIG. 5, the P-type electrode 203 and the N-type electrode 205 of the light emitting diode 200 are disposed at both portions of the light emitting diode 200. The N-type electrode 205 is disposed to have a predetermined step height. The sapphire substrate 201, the nitride gallium layer, the active layer and the like are disposed down of the P-type electrode 203. Accordingly, the P-type electrode 203 is disposed higher than the N-type electrode 205. The transparent electrode 207 has a stripe structure on a whole surface of the light emitting diode 200 excepting a contact portion of the P-type electrode 203 and the n-type electrode. In detail, the transparent electrodes 207 are regularly spaced apart from one another at a whole region of the light emitting diode 200. Accordingly, after the P-type nitride gallium layer 206 is formed on the active layer, the transparent electrode 207 is disposed on the P-type nitride gallium layer 206 to have a slit shape, thereby partially exposing the P-type nitride gallium layer 206. Therefore, an amount of light generated from the active layer is minimally absorbed by the transparent electrode 207, thereby increasing an amount of an externally emitting light. As described above, the stripe-shaped transparent electrode 207 can be formed using a silicon oxide (SiO2) or an exposure process. A description thereof is made with reference to FIGS. 6a through 6c and FIGS. 7a through 7c. A process of forming the transparent electrode 207 is as follows. FIGS. 6a through 6c are views illustrating a method of forming the stripe-structured transparent electrode according to the first embodiment of the present invention. As shown in FIG. 6a, if a P-type nitride gallium layer 303 is formed, a transparent electrode pattern 301 is formed with a stripe shape by using a mask for a P-type electrode, an N-type electrode and a stripe-shaped transparent electrode, and using a silicon oxide (SiO2) material. After that, as shown in FIG. 6b, a transparent electrode 307 layer is deposited on the P-type nitride gallium layer 303 having the transparent electrode pattern 301. After that, as shown in FIG. 6c, the SiO2 transparent electrode pattern 301 is etched out to form the stripe-shaped transparent electrode 307. FIGS. 7a through 7c are views illustrating a method of forming a transparent electrode according to another embodiment of the present invention. As shown in FIG. 7a, a transparent metal film 401 is deposited on a P-type nitride gallium 403. After that, a photoresist film 402 is coated on the resultant. A slit-structured mask 500 is positioned on the photoresist film 402. An exposure process and a developing process are performed to form a stripe-shaped photoresist pattern 402 as shown in FIG. 7b. After that, as shown in FIG. 7c, an etching process using the photoresist pattern 402 is performed to form a stripe-shaped transparent electrode 407. As such, the present invention allows the transparent electrode 407 to have a stripe structure at a P-type region of the light emitting diode, thereby reducing an absorbed amount of light of the transparent electrode before the light of the active layer is emitted to the external. Meanwhile, the above-described embodiment exemplarily illustrates an NP-type light emitting diode, but can be easily applied to an NPN-type light emitting diode as well as the NP-type light emitting diode. In detail, assuming that the N-type nitride gallium layer 202 is a first nitride gallium layer and the P-type nitride gallium layer 206 is a second nitride gallium layer, an N-type third nitride gallium layer can be additionally formed on the second nitride gallium layer. The present invention can be also applied to an NPN-type light emitting diode. It can be also easily understood, from the following other embodiments of the present invention, that the present invention can be applied to the NP-type, NPN-type or other-type light emitting diode. FIG. 8 is a view illustrating an electrode structure of a light emitting diode according to the second embodiment of the present invention. As shown in FIG. 8, a top view of the electrode structure of the light emitting diode is illustrated. After an N-type nitride gallium layer 601, an active layer, and a P-type nitride gallium layer are sequentially formed above a sapphire substrate, a P-type electrode 603 and an N-type electrode 605 are formed as shown in FIG. 8. The inventive light emitting diode has a plurality of partition regions excepting a P-type electrode 603 and an N-type electrode 605 disposed at an upper layer of the light emitting diode. Transparent electrodes 620 are disposed at the plurality of partition regions. The plurality of partitioned transparent electrodes 620 is disposed at a region at which a majority of light substantially is emitted from the active layer. The transparent electrode 620 can be a transparent metal layer, as in other embodiments below. Additionally, the plurality of partitioned transparent electrodes 620 and the P-type electrode 603 are connected using metal films 630. The metal film 630 has an in-series resistance having a resistance value, which is different depending on its length and width. Additionally, a connection portion of the transparent electrode 620 and the metal film 630 has the same thickness as the P-type electrode, thereby constantly maintaining an electrical connection and a voltage applied to the active layer. Since the P-type nitride gallium layer generally has a very low conductivity, the plurality of transparent electrodes 620 is electrically disconnected with one another excepting the metal film 630 having the in-series resistance value. Each of the plurality of partitioned transparent electrodes can independently control voltages for allowing holes and electrons to be recombined with each other. Accordingly, this can be used to control a light biased-concentration phenomenon caused by a voltage drop. For example, the metal films 630 can be selected to apply a constant voltage to each of the partitioned transparent electrodes 620 under a constant driving current for driving the light emitting diode. Accordingly, since the voltage applied to the active layer is constantly maintained at a whole region of each of the transparent electrodes 620, the light biased-concentration can be prevented. Further, in case where an over current unnecessarily flows through any one of the metal films 630 for connecting the partitioned transparent electrodes 620 with the P-type electrode 603, the any one metal film 630 has a voltage drop increased at its resistance value. At this time, a rise of the voltage applied to the active layer is suppressed as much as the voltage drop increased at the resistance value. As such, a negative feedback phenomenon for suppressing the current applied to the active layer is caused, thereby providing an effect of stabilizing a driving current. From a phenomenon in which a turn-on voltage of the active layer is reduced depending on a temperature rise, it can be understood that a stabilization effect of the in-series resistance is of much importance for the driving current. FIGS. 9 through 12 are views illustrating electrode structures of light emitting diodes according to the third to sixth embodiments of the present invention. As shown in FIG. 9, an electrode structure of the light emitting diode has a P-type electrode 703 disposed at an upper portion of the light emitting diode, and an N-type electrode 705 disposed along an upper circumference of the light emitting diode. As shown in FIG. 8, four transparent electrodes 720 are partitioned and provided. The transparent electrodes 720 disposed at an adjacent region of the N-type electrode 705 have step-shapes. The metal films 730, which electrically connect the P-type electrode 703 with the transparent electrodes 720, can be controlled in length and width to control the resistance value. An electrode structure of the light emitting diode of FIG. 10 has eight transparent electrodes unlike that of FIG. 9. In other words, eight transparent electrodes 820 are partitioned and disposed along an N-type electrode 805 disposed along an upper circumference of the light emitting diode. Metal films 830, which electrically connect the eight transparent electrodes 820 and the P-type electrode 803, have a concavo-convex shape on a P-type nitride gallium layer to respectively have different resistance values. In the fifth and sixth embodiments of FIGS. 11 and 12, ten transparent electrodes 920 and 920a are respectively partitioned and disposed at upper electrode regions of the light emitting diodes. Patterns of the transparent electrodes 920 and 920a are different from each other in FIGS. 11 and 12. As the same effect, a voltage applied to an active layer is constantly maintained to prevent a light biased-concentration phenomenon. In the electrode structures of the light emitting diodes of FIG. 8 through 12, the transparent electrodes are partitioned in plural, and the metal films are disposed to electrically connect the P-type electrodes with the transparent electrodes. The metal films vary in length and width to control their resistance values. Additionally, the transparent electrodes have the same thickness as the P-type electrodes such that constant voltages can be applied to the active layers. FIGS. 13a and 13b are views illustrating an electrode structure and its circuit diagram of a light emitting diode according to the present invention. As shown in FIGS. 13a and 13b, a constant current is always applied to a plurality of partitioned transparent electrodes and an N-type electrode. This is proved as in the following Equation. A—T=A—1+A—2+A—3 (Equation) where, A: areas of the partitioned transparent electrodes. I D ⁢ ⁢ 1 = A 1 A T ⁢ I O 2 ⁢ I D ⁢ ⁢ 2 = A 2 A T ⁢ I O 2 ⁢ I D ⁢ ⁢ 3 = A 3 A T ⁢ I O 2 where, ID: currents applied to the partitioned transparent electrodes IO: driving current. V_D1==V_D2==V_D3 where, VD: voltages applied to the transparent electrodes. Since the same voltage is applied to the transparent electrodes, it can be understood that the transparent electrodes are connected in parallel. V_D ⁢ ⁢ 1 = V_ ⁢ 0 - R_P ⁢ ⁢ 1 ⁢ ⁢ I_D ⁢ ⁢ 1 - R_N ⁢ ⁢ 1 ⁢ ⁢ ( I_D ⁢ ⁢ 1 + I_D2 + I_D3 ) V_D ⁢ ⁢ 2 = V_ ⁢ 0 - R_P ⁢ ⁢ 2 ⁢ ⁢ I_D ⁢ ⁢ 2 - R_N ⁢ ⁢ 2 ⁢ ⁢ ( I_D2 + I_D3 ) - R_N1 ⁢ ( I_D ⁢ ⁢ 1 + I_D2 + I_D3 ) V_D ⁢ ⁢ 3 = V_ ⁢ 0 - R_P ⁢ ⁢ 3 ⁢ ⁢ I_D ⁢ ⁢ 3 - R_N2 ⁢ ⁢ ( I_D2 + I_D3 ) - R_N1 ⁢ ( I_D ⁢ ⁢ 1 + I_D2 + I_D3 ) - R_N3I ⁢ _D3 R P ⁢ ⁢ 2 = R P ⁢ ⁢ 1 ⁢ I D ⁢ ⁢ 1 I D ⁢ ⁢ 2 - R N ⁢ ⁢ 2 ⁢ I D ⁢ ⁢ 2 + I D ⁢ ⁢ 3 I D ⁢ ⁢ 2 = R P ⁢ ⁢ 1 ⁢ A 1 A 2 - R N ⁢ ⁢ 2 ⁢ A 2 + A 3 A 2 R P ⁢ ⁢ 3 = R P ⁢ ⁢ 2 ⁢ I D ⁢ ⁢ 2 I D ⁢ ⁢ 3 - R N ⁢ ⁢ 3 ⁢ I D ⁢ ⁢ 3 I D ⁢ ⁢ 2 = R P ⁢ ⁢ 2 ⁢ A 2 A 3 - R N ⁢ ⁢ 3 ⁢ A 3 A 2 where, Rp: resistance value of the metal film Rn: resistance value between the metal film and the N-type electrode. As such, in order to prevent the light emission of the related-art light emitting diode from being biased and concentrated only at a specific portion of the electrode, the present invention has the plurality of transparent electrodes disposed to connect with the P-type electrode, thereby constantly maintaining the voltage applied to the active layer. INDUSTRIAL APPLICABILITY As described above, the inventive light emitting diode has an effect in that the transparent electrode is disposed at the contact portion of the P-type electrode to have the stripe shape such that the amount of light generated from the active layer is minimally absorbed by the transparent electrode, thereby enhancing the light efficiency. Further, the inventive light emitting diode has an effect in that the plurality of transparent electrodes is partitioned and disposed at the contact portion of the P-type electrode, thereby emitting a constant high brightness of light. Furthermore, the inventive light emitting diode has an effect in that the constant voltage can be maintained in the active layer. While the present invention has been described and illustrated herein with reference to the preferred embodiments thereof, it will be apparent to those skilled in the art that various modifications and variations can be made therein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of the appended claims and their equivalents.

<SOH> BACKGROUND ART <EOH>Generally, light emitting diode (LED) is a kind of a semiconductor device, and it converts electricity into infrared ray or light by using a characteristic of a compound semiconductor, to send and receive a signal. The LED is used for home appliances, a remote controller, an electronic display board, a displaying apparatus, a variety of automation apparatuses and the like. An operation principle of the LED will be briefly described in the following. When a forward voltage is applied to a semiconductor of a specific chemical element, electrons and holes are recombined with each other while moving through a positive-negative junction. The recombination of the electrons and the holes causes an energy level to fall down, thereby emitting light. Further, the LED is generally manufactured to have a very small size of 0.25 mm 2 and is mounted on a lead frame or a printed circuit board (PCB) using has an epoxy mold. Representative of the LEDs is a plastic package of 5 mm (T 1¾) or a new package being developed in a specific application field. A color of light emitted from the LED is determined by a wavelength obtained depending on a combination of elements constituting a semiconductor chip. Particularly, as an information communication apparatus is in a trend of a small size and slimness, the communication apparatus has more miniaturized parts such as a resistance, a condenser, and a noise filter. The LED is manufactured in a form of a Surface mounted Device (Hereinafter, referred to as “SMD”) so as to be directly mounted on a Printed Circuit Board (Hereinafter, referred to as “PCB”). Accordingly, an LED lamp for a display device is being developed in the form of the SMD. Such an SMD can substitute a related-art simple lamp. The SMD is used for a lamp display, a character display, an image display and the like that express various colors. Further, as a high-density integration technology for a semiconductor device is developed and a consumer prefers a more compact electronic product, Semiconductor Mounting Technology (SMT) is widely used, and a packaging technology of the semiconductor device employs a technology for minimizing an installation space such as a Ball Grid Array (BGA), a wire bonding, and a flip chip bonding. FIG. 1 is a view illustrating a related art light emitting diode. As shown in FIG. 1 , after an N-type nitride gallium layer 102 is formed on a sapphire substrate 101 , an N-type electrode 105 is formed at one portion of and on the N-type nitride gallium layer 102 . A metal organic chemical vapor deposition (MOCVD) is used to form a film using a Group 3-based element on the sapphire substrate 101 . Silicon using silane (SiH 4 ) gas is used to form N-type dopants. All three-component nitride films are grown in an atmosphere of Hydrogen gas. Nitrogen gas is used to grow a nitride gallium. After the N-type nitride gallium 102 is formed, an active layer 104 is formed on the N-type nitride gallium layer 102 . The active layer 104 corresponding to a light emission region has a quantum well structure comprising a Indium gallium nitride. After the active layer 104 is formed, a P-type nitride gallium (GaN) layer 106 is formed. The P-type nitride gallium layer 106 , which is contrasted with the N-type nitride gallium layer 102 , is formed by the addition of P-type dopants. Therefore, in the N-type nitride gallium layer 102 , electrons are drifted by an external voltage. In the P-type nitride gallium layer 106 , holes are drifted by the external voltage. The electrons and the holes are recombined with each other to emit light. The transparent metal-based transparent electrode 107 is formed on the P-type nitride gallium layer 106 to allow light generated from the active layer 104 to be transmitted therethrough, and allow the generated light to be emitted to the external. After the transparent electrode 107 is formed, a P-type electrode 103 is formed to compose the light emitting diode. However, since the related-art light emitting diode using the sapphire substrate has a nitride film having a larger refractive index than the substrate, the light generated from the active layer is transmitted through the nitride film to be emitted toward the transparent electrode. FIG. 2 is a plan view illustrating the transparent electrode, the P-type electrode, and the N-type electrode of the light emitting diode of FIG. 1 . As shown in FIG. 2 , the P-type electrode 103 and the N-type electrode 105 are disposed at both portions of the light emitting diode 100 , and the transparent electrode 107 is disposed on a whole region of the light emitting diode 100 . The transparent electrode 107 corresponds to a region at which the light generated from the active layer of the light emitting diode 100 is emitted. The transparent electrode 107 is formed of a transparent conductive metal. FIGS. 3 a and 3 b are views illustrating a light emission region of a related art light emitting diode. As shown, it can be appreciated that the generated light is biased and concentrated at a predetermined region. In other words, a light biased-concentration phenomenon occurs since a voltage applied to combine the holes and the electrons in the active layer is varied due to a resistance component centering on the N-type electrode. As a distance is increased from the N-type electrode, resistance is increased. Therefore, the increased resistance again results in a voltage drop. Unlike this, the resistance is not varied depending on the distance at a region far away from the N-type electrode comparing to a region close to the N-type electrode. Therefore, a high current is applied to the active layer when a high voltage is applied to an electrode region. If the high voltage is applied to the region close to the electrode region as described above, a temperature of the active layer rises. The rise of the temperature of the active layer causes a drop of a turn-on voltage of the light emitting diode to make worse the biased-concentration of a driving current. Further, as shown in FIG. 3 b , in case where the N-type electrode is disposed along a circumference of an upper edge of the light emitting diode, the light is biased and concentrated only at an N-type electrode region, which is close to the P-type electrode. Specifically, the P-type electrode itself functions to block or absorb a portion of photons incident on the P-type electrode, thereby deteriorating an efficiency of light emission. If a thickness of the P-type electrode is decreased to prevent this, the resistance of the P-type electrode is relatively greatly increased. Accordingly, it cannot be expected that the light is emitted from the region far away from the n-type electrode. The light biased-concentration phenomenon occurs because the voltage applied to the active layer is not constantly maintained at the whole region along the P-type electrode and the transparent electrode, due to the resistance increased at each distance away from the electrode and different voltage drops caused by the increased resistance at each upper electrode region. Further, in case where the emitted light is reflected or absorbed by the P-type electrode, the light efficiency is deteriorated. Specifically, the light is absorbed at the transparent electrode formed of the transparent metal, an emitted amount of light is reduced. Additionally, since most of the generated light of the light emitting diode is emitted through the transparent electrode to the external, the reduction of the light efficiency causes the reduction of an external quantum efficiency.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention. In the drawings: FIG. 1 is a view illustrating a related-art light emitting diode; FIG. 2 is a plan view illustrating a transparent electrode, a P-type electrode, and an N-type electrode of a light emitting diode of FIG. 1 ; FIGS. 3 a and 3 b are views illustrating a light emission region of a related-art light emitting diode; FIG. 4 is a view illustrating a light emitting diode according to the first embodiment of the present invention; FIG. 5 is a plan view illustrating a transparent electrode, a P-type electrode, and an N-type electrode of a light emitting diode according to the first embodiment of the present invention; FIGS. 6 a through 6 c are views illustrating a method of forming a stripe-structured transparent electrode according to the first embodiment of the present invention; FIGS. 7 a through 7 c are views illustrating a method of forming a transparent electrode according to another embodiment of the present invention; FIG. 8 is a view illustrating an electrode structure of a light emitting diode according to the second embodiment of the present invention; FIGS. 9 through 12 are views illustrating electrode structures of light emitting diodes according to the third to sixth embodiments of the present invention; FIGS. 13 a and 13 b are views illustrating an electrode structure and its circuit diagram of a light emitting diode according to the present invention. detailed-description description="Detailed Description" end="lead"?

20060717

20120313

20070201

60481.0

H01L3300

JACKSON JR, JEROME

LED AND FABRICATION METHOD THEREOF

UNDISCOUNTED

ACCEPTED

H01L

ACCEPTED

Method for shielding the magnetic field generated by an electrical power transmission line and electrical power transmission line so shielded

A method for shielding the magnetic field generated by an electrical power transmission line and an electrical power transmission line so shielded. The electrical power transmission line has at least one electrical cable and at least one shielding element made of ferromagnetic material arranged in a radially outer position with respect to the at least one cable which shielding element has a base and a cover. The line also has a supporting element coupled to at least the base of the shielding element. In particular, the ferromagnetic material of the shielding element is selected from grain oriented silicon steel, preferably containing a silicon content between about 1% and about 5%, non-grain oriented silicon steel, Permalloyè and Supermalloyè.

1-42. (canceled) 43. An electrical power transmission line comprising: at least one electrical cable; at least one shielding element made of at least one ferromagnetic material arranged in a radially outer position with respect to said at least one cable for shielding the magnetic field generated by said cable, said at least one shielding element comprising a base and a cover; and at least one supporting element coupled to at least said base of the shielding element. 44. The electrical power transmission line according to claim 43, wherein said at least one cable comprises three cables arranged according to a trefoil arrangement. 45. The electrical power transmission line according to claim 43, wherein said line is placed underground. 46. The electrical power transmission line according to claim 43, wherein said base and said cover are substantially continuous. 47. The electrical power transmission line according to claim 43, wherein said base comprises a bottom wall and a pair of side walls. 48. The electrical power transmission line according to claim 47, wherein said bottom wall and said pair of side walls are substantially flat. 49. The electrical power transmission line according to claim 47, wherein said side walls extend in a direction substantially perpendicular to said bottom wall. 50. The electrical power transmission line according to claim 47, wherein said base further comprises a pair of flanges extending in a predetermined direction from the end portions of the side walls of the base. 51. The electrical power transmission line according to claim 50, wherein said flanges extend outwardly from the end portions of the side walls of the base. 52. The electrical power transmission line according to claim 50, wherein said flanges extend inwardly from the end portions of the side walls of the base. 53. The electrical power transmission line according to claim 47, wherein said flanges extend in a direction substantially perpendicular to the end portions of the side walls of the base. 54. The electrical power transmission line according to claim 43, wherein said cover is substantially continuous. 55. The electrical power transmission line according to claim 54, wherein said cover comprises a main wall and a pair of flanges extending from the main wall in a predetermined direction. 56. The electrical power transmission line according to claim 55, wherein said flanges extend in a direction substantially perpendicular to said main wall. 57. The electrical power transmission line according to claim 43, wherein said base and said cover comprise walls having a thickness of about 0.20 mm to about 0.35 mm. 58. The electrical power transmission line according to claim 43, wherein said base and said cover comprise respective sides superimposed for a portion of predetermined length in lateral direction. 59. The electrical power transmission line according to claim 58, wherein a material having a permeability greater than air is interposed at the superimposed sides of the base and of the cover. 60. The electrical power transmission line according to claim 43, wherein said base and said cover comprise walls having a rolling direction substantially perpendicular to the axis of said at least one cable. 61. The electrical power transmission line according to claim 43, wherein said shielding element comprises a plurality of shielding modules arranged side by side, each of said shielding modules comprising a modular base and a modular cover. 62. The electrical power transmission line according to claim 61, wherein said shielding modules are longitudinally superimposed for a portion of predetermined length. 63. The electrical power transmission line according to claim 62, wherein said predetermined length is 25% to 100% of the width of said shielding element. 64. The electrical power transmission line according to claim 61, further comprising a respective connecting element made of ferromagnetic material for connecting said shielding modules arranged side by side. 65. The electrical power transmission line according to claim 61, wherein, in each of said shielding modules, said modular base and said modular cover are reciprocally staggered in longitudinal direction by a predetermined distance. 66. The electrical power transmission line according to claim 61, wherein, in each of said shielding modules, said modular base is coupled to a respective supporting element. 67. The electrical power transmission line according to claim 61, wherein at least two adjacent shielding modules extend along different directions, said shielding element further comprising a respective connecting element made of ferromagnetic material for connecting said at least two adjacent shielding modules. 68. The electrical power transmission line according to claim 43 or 67, wherein said ferromagnetic material has a maximum value of relative magnetic permeability greater than about 20000. 69. The electrical power transmission line according to claim 43 or 67, wherein said ferromagnetic material has a maximum value of relative magnetic permeability μmax of about 20000 to about 60000. 70. The electrical power transmission line according to claim 43 or 67, wherein said ferromagnetic material is selected from the group of: grain oriented silicon steel, non-grain oriented silicon steel, Permalloy®, and Supermalloy®. 71. The electrical power transmission line according to claim 70, wherein the silicon content is about 1% to about 5%. 72. The electrical power transmission line according to claim 43, wherein said base is made of a first ferromagnetic material having a maximum value of relative magnetic permeability μmax greater than about 40, and wherein said cover is made of a second ferromagnetic material having a maximum value of relative magnetic permeability μmax greater than about 20. 73. The electrical power transmission line according to claim 43, further comprising a supporting element coupled to said cover of the shielding element. 74. The electrical power transmission line according to claim 43 or 73, wherein said at least one supporting element is arranged in a radially outer position with respect to said at least one shielding element. 75. The electrical power transmission line according to claim 43 or 73, wherein said at least one supporting element is arranged in a radially inner position with respect to said at least one shielding element. 76. The electrical power transmission line according to claim 43 or 73, wherein said at least one shielding element is interposed between a pair of supporting elements; 77. The electrical power transmission line according to claim 43 or 73, wherein said at least one supporting element is substantially flat. 78. The electrical power transmission line according to claim 43 or 73, wherein said at least one supporting element comprises a respective wall having a thickness of about 1 to about 20 mm. 79. The electrical power transmission line according to claim 43 or 73, wherein said at least one supporting element is made of an electrically non-conductive and non-ferromagnetic material. 80. The electrical power transmission line according to claim 79, wherein said electrically non-conductive and non-ferromagnetic material is selected from the group of: plastics materials, cement, terracotta, carbon fibres, glass fibres, and wood. 81. The electrical power transmission line according to claim 80, wherein said plastics materials are selected from the group of: polyethylene (PE), low-density polyethylene (LPDE), medium-density polyethylene (MPDE), high-density polyethylene (HPDE), linear low-density polyethylene (LLPDE), polypropylene (PP), ethylene/propylene elastomer copolymers (EPM), ethylene/propylene/diene terpolymers (EPDM), natural rubber, butyl rubber, ethylene/vinyl copolymers, ethylene/acrylate copolymers, ethylene/α-olefin thermoplastic copolymers, polystyrene, acrylonitrile/butadiene/styrene resins (ABS), halogenated polymers, polyurethane (PUR), polyamides, aromatic polyesters. 82. The electrical power transmission line according to claim 43, wherein said shielding element further comprises a plurality of fixing means longitudinally arranged at predetermined distances from each other, said fixing means being intended to fix said cover on said base. 83. The electrical power transmission line according to claim 82, wherein said fixing means are arranged in a plurality of pairs positioned along the sides of the shielding element at a reciprocal longitudinal distance of about 20 to about 100 cm. 84. A method for shielding the magnetic field generated by an electrical power transmission line comprising at least one electrical cable, comprising the following steps of: providing at least one shielding element made of at least one ferromagnetic material for shielding the magnetic field generated by at least one electrical cable, said at least one shielding element comprising a base and a cover; coupling at least one supporting element to at least said base; laying said at least one electrical cable into said base of the shielding element; and leaning said cover onto said base so as to substantially close said shielding element.

FIELD OF THE INVENTION The present invention relates to a method for shielding the magnetic field generated by an electrical power transmission line and to an electrical power transmission line so shielded. Generally, an electrical power transmission line operates at medium voltage (typically from 10 to 60 kV) or at high voltage (typically greater than 60 kV) and at currents of the order of hundreds-thousands of amperes (typically from 500 to 2000 A). The electrical power carried by these lines can reach values of the order of hundreds of MVA, typically 400 MVA. Normally, the carried current is an alternating current at low frequency, in other words generally below 400 Hz and typically equal to 50 or 60 Hz. In general, the electrical power transmission lines are used for transmitting power from electrical power stations to urban centres, over distances of the order of tens of kilometres (normally 10-100 km). Typically, electrical power transmission lines are three-phase lines comprising three cables arranged in a trench at a depth of 1-1.5 m. In the space immediately surrounding the cables, the magnetic induction H may reach relatively high values and, at ground level (i.e. at a distance of 1-1.5 m from the line), a magnetic induction having a value comprised between 20 and 60 μT may be detected, depending on the geometrical arrangement of the cables and on the intensity of the carried current. There are circumstances in which it is particularly recommended to minimize the intensity of the magnetic field, both to protect the human body from exposure to alternating magnetic fields of the above-mentioned intensity, in particular with reference to subjects with the highest potential risk, such as children, and to avoid potential interferences with particularly sensitive or delicate electrical equipment, typically in the proximity of hospitals and airports. In order to avoid possible biological effects and/or interference phenomena with electrical equipment due to exposure to magnetic fields generated by low-frequency sources (for example equal to 50 Hz), there is therefore the need of “mitigating” the magnetic field generated by the cables for the transmission of the electrical current. In the present description and in the following claims, the expression “mitigation of the magnetic field” is used to indicate the reduction of the effective value of the magnetic field measured in a given position of a factor of about 10 to about 100 with respect to the value of the magnetic field which would be measured in the same position in the absence of shielding application. More in particular, with reference to cables placed underground, in the present description and in the following claims, the expression “measurement of the magnetic field” is used to indicate the measurement of the magnetic field performed at ground level at nominal current. As is known, when electrical cables are laid into shielded conduits the magnetic field generated by the cables can be mitigated. The article by P. Argaut, J. Y. Daurelle, F. Protat, K. Savina, and C. A. Wallaert “Shielding technique to reduce magnetic fields from buried cables” A 10.5, JICABLE 1999, considers and compares the shielding effect provided by an open-section shield, such as a sheet of ferromagnetic material, placed above the cables, and the effect provided by a closed-section shield, such as a conduit of rectangular cross-section made of ferromagnetic material placed around the cables. According to this article, attenuation factors of about 5-7 can be obtained with open-section shields, attenuation factors of about 15-20 can be obtained with closed-section shields and attenuation factors of about 30-50 can be obtained when the closed-section shield is provided very close to the cables, for example in the form of a ferromagnetic tape wound directly around the cables. These shields have a number of disadvantages which have not been overcome yet. Firstly, such shields need to be sensibly thick (1-10 mm) in order to provide a sufficiently effective shielding action, with negative consequences on the total weight of the transmission line, on the simplicity and on the rapidity of the installation and maintenance operations and, last but not least, on the cost of the line and of the maintenance thereof. Secondly, although the closed-section conduits described above provide the best shielding effects of the magnetic field, the Applicant noted that the installation and maintenance of the cables into closed conduits is a difficult and costly operation since the cables need to be inserted into the conduits and, in case of maintenance, the cables cannot be inspected because they are surrounded by the conduit. Thirdly, the prior art shields, whether open-section or closed-section shields, are subject to unacceptable electrical losses (i.e. due to eddy currents) and/or hysteretic losses. The hysteretic losses cause the overheating and reduce, in this way, the electrical power transmission capacity through the cable. A further example of closed-section shielding conduits is described in patent application WO 01/93394 of the Applicant, which describes the shielding of electrical power transmission cables by means of conduits comprising at least one layer of ferromagnetic material. In order to ensure an effective magnetic field shielding action, the thickness of the shield is quite high (in the order of 10 mm), which implies an increase of the weight of the transmission line and an ensuing increased difficulty in cable laying operations, which are already quite difficult due to the closed geometry of the conduit. A further example of closed-section shielding conduits is described in patent application WO 03/003382 of the Applicant. In particular, this document describes a conduit supporting two shielding layers, a first radially inner layer made of a first ferromagnetic material, and a second radially outer layer made of a second ferromagnetic material having a relative magnetic permeability greater than the relative magnetic permeability of the first ferromagnetic material. Also in this case, the closed section of the conduit makes the cable laying operations complicated. Patent application (Kokai) JP 10-117083 describes a further example of shielding of the magnetic field generated by an electrical cable of an electrical power transmission line, essentially consisting of a tube made of ferromagnetic material within which the electrical power transmission line cables are laid. More in particular, such tube is manufactured by spirally winding a tape made of ferromagnetic material on a tubular support, such as for example a tube of resin or metal within which the cables are laid. Such spirally winding can be carried out in a single step to form a single shielding layer, or in a plurality of steps to form a respective plurality of superimposed shielding layers constituted by the same shielding material. In the example described, the tape is constituted by grain oriented steel having a greater magnetic permeability in a direction parallel to the winding direction with respect to the magnetic permeability in a direction perpendicular to the above-mentioned winding direction. In the present direction and in the following claims, the expression “grain oriented material” is used to indicate a material in which the crystalline domains have a preferential alignment direction and an extended dimension in the direction of alignment of the crystalline domains, as described, for example, by Alex Goldman in “Handbook of modern ferromagnetic materials”, pages 119-120, Kluwer Academic Publishers, 1999. Said alignment can be evaluated by means of known methods, such as for example by means of an optical microscope or by X-ray diffractometry, and can be carried out by means of rolling processes and thermal annealing treatments according to predetermined times and temperatures and in the presence of recrystallization inhibitors, as described, for example, in document EP-A-0 606 884. Although substantially achieving the purpose, the shielding method described in document JP 10-117083 involves a step or a plurality of steps of spirally winding a single tape or a plurality of tapes made of ferromagnetic material, which makes the manufacture of the line rather laborious, with negative effects on the time and costs required for manufacturing and laying the line. The optimum shielding effect of the magnetic field is achieved at a null angle between the direction of action of the magnetic field generated by the cable and the rolling direction of the ferromagnetic material, which constitutes the preferential magnetization axis. However, the choice of said null angle is incompatible with a shielding spirally wound around the cable as described in document JP 10-117083, whereby the above-mentioned angle must be necessarily greater than 0°, with ensuing lack of exploitation of the maximum shielding effect. On the other hand, the dependence of such angle on the preferential magnetization axis depends very strongly on the intensity of the magnetic field, whereby the appropriate angle must be elected each time as a function of the intensity of the magnetic field, resulting in a poor applicative flexibility of the line and in a further complication of the installation operations of the line. Finally, at the regions where adjacent portions of tape wound in a spiral manner overlap, the magnetic shielding effect is ineffective because of the unavoidable presence of defects, such as for example lack of homogeneity and undulations of the contacting surfaces of the tape wound in a spiral manner. Since the tape has a limited width (in the order of a few centimetres), in fact, the tape is not able to limit the effect of leakage of the magnetic field due to the presence of these defects. In order to overcome the drawbacks of the prior art described above, the Applicant has identified the need of providing an electrical power transmission line comprising at least one electrical cable and at least one shielding element for shielding the magnetic field generated by such cable, which is easy to be installed and which has a limited weight, while allowing to achieve an effective mitigation action of the magnetic field. Moreover, the Applicant has identified the need of providing a method for shielding the magnetic field of such a line which is easier to be carried out and less costly, especially in terms of time required for installing the line with respect to the prior art methods. The Applicant has found that it is possible to manufacture an electrical power transmission line which is easy to be installed by providing a shielding element comprising two components, in particular a base and a cover, while obtaining an effective mitigation action of the magnetic field, without resulting in an excessive weight of the shielding element, thanks to the coupling of at least one shielding element to at least one supporting element to which the function of mechanically supporting the shielding element is given. According to a first aspect thereof, the present invention therefore refers to an electrical power transmission line comprising: at least one electrical cable; at least one shielding element made of at least one ferromagnetic material arranged in a radially outer position with respect to said at least one cable for shielding the magnetic field generated by said cable, said at least one shielding element comprising a base and a cover, and at least one supporting element coupled to at least said base of the shielding element. The use of a shielding element arranged in a radially outer position with respect to the cable and comprising at least two separate components, in particular a base and a cover, allows to mitigate the magnetic field in a satisfactory manner, while ensuring a simplification of the installation and laying procedure of the line, as well as of the subsequent maintenance operations of the same, whereas the provision of at least one supporting element coupled at least to the base allows to optimize the thickness of the shielding element, thus reducing the weight of the latter, with a further advantageous simplification and rapidity of the installation procedure. Thanks to the presence of a shielding element comprising two components, in fact, subsequently to the positioning of the base, preferably in a trench, the cables are laid into the base and the cover is then leaned onto the base to substantially complete the shielding element. The use of shielding elements comprising two components therefore allows to use greater laying lengths and to realize winding paths and all those paths which normally make difficult the laying of the cable(s) into closed shielding elements constituted by a single component. Moreover, the shielding elements comprising two components allow the inspection of the cables both during the laying of the line and subsequently, when the line is in use. In the electrical power transmission line according to the present invention, therefore, the best shielding effects of the magnetic field ensured by the closed-section shielding elements, to which the shielding element of the present invention can be assimilated, are advantageously exploited, while overcoming the drawbacks posed by the closed-section shielding elements of the prior art in terms of difficulty of installation and maintenance. By selecting, in fact, a ferromagnetic material which is effective in terms of mitigation action of the magnetic field as material for the shielding element and by selecting a material having suitable mechanical properties as material for the supporting element, it is advantageously possible to limit the thickness of the shielding element to a considerable extent, giving the function of support and mechanical resistance to the supporting element alone. Finally, differently from to the electrical power transmission lines of the prior art, in which the shielding is obtained by spirally winding a tape made of ferromagnetic material around a tubular support, with ensuing unavoidable formation of a non-null angle between the tape helix thus formed and the straight circumferential direction of the action of the magnetic field, in the transmission line according to the present invention such angle is null, with advantageous increase of the magnetic permeability and improvement of the shielding effect. The transmission line according to the present invention may be placed underground, preferably at 1 to 1.5 metres below the ground level, so as to maximize the mitigation effect of the magnetic field generated by the cable. The transmission line according to this invention may also be placed within the wall constructions of large-scale buildings, in which electrical power is transmitted at medium or high voltage along a main line before being converted into low voltage at each single user point. According to a preferred embodiment of the electrical power transmission line of the invention, the line comprises three cables, preferably arranged according to a trefoil arrangement. The trefoil arrangement of the cables allows to obtain a mitigation of the magnetic field which is about twice the mitigation of the magnetic field obtainable by three cables arranged side by side on a plane. In the present description and in the following claims, the expression “trefoil arrangement” is used to indicate an arrangement at which the centres of the three cables occupy the vertices of an equilateral triangle. More in particular, the trefoil arrangement may be either of the so-called “open” type or of the so-called “closed” type, depending on the fact that there is a reciprocal contact among the cables or not. In other words, in the case of an open type trefoil arrangement, the length of each side of the equilateral triangle at the vertices of which the cables are placed is greater than the diameter of each cable, while, in the case of a closed type trefoil arrangement, the length of each side of the equilateral triangle at the vertices of which the cables are placed is substantially equal to the diameter of each cable. Although the trefoil arrangement is preferred, and the closed type arrangement is particularly preferred, any other arrangement intended to attenuate the magnetic field is equally possible. In an alternative embodiment, cables may be arranged side by side on a plane, in a base sufficiently wide to contain the cables according to this arrangement. Although this arrangement increases the electrical losses as well as the magnetic field, it may be advantageously applied when a slight mitigation of the magnetic field is required, since an arrangement of this type allows to use a shielding element having a size of lower height, with ensuing advantageous minimization of the weight of the shielding element and, with this, of the transmission line. In order to obtain an effective mitigation action of the magnetic field, both the base and the cover of the transmission line of the invention are substantially continuous, i.e. the outer surface of said base and of said cover is substantially devoid of any macroscopic interruption. Preferably, the base comprises a bottom wall, for example substantially flat, and a pair of side walls, for example substantially flat. In such way, the manufacture of the base is advantageously simplified. Preferably, the side walls of the base extend in a direction substantially perpendicular to the bottom wall. Preferably, in a trefoil arrangement of the cables of the closed type, the width of the bottom wall is equal to about 2.1 times the diameter of the electrical cables housed within the shielding element. Preferably, in a trefoil arrangement of the cables of the closed type, the height of the side walls, defining the height of the shielding element, is equal to about 2.2 times the diameter of the electrical cable housed within the shielding element. The base of the shielding element may have a U-shaped cross-section provided with bevelled corners according to a predetermined bending radius, which advantageously allows to preserve the ferromagnetic characteristics of the material of the shielding element, or a U-shaped cross-section provided with sharp corners. The latter embodiment, although involving a degradation of the ferromagnetic characteristics of the material of the shielding element at said sharp corners, is preferable because such embodiment allows to achieve an attenuation of the magnetic field at ground level of about 25% with respect to the embodiment providing a base with bevelled corners. In this connection, the Applicant has found that the greater length of the curve of the shielding element in the embodiment with bevelled corners exerts a negative effect having a greater role with respect to the degradation effect of the ferromagnetic characteristics due to the bending of the shielding element provided with sharp corners. In the case of the embodiment with a U-shaped cross-section provided with bevelled corners, the bending radius is preferably equal to about 0.4-0.7 times the diameter of the electrical cables housed within the shielding element. Preferably, the base of the shielding element further comprises a pair of flanges extending in a predetermined direction from the end portions of the side walls of the base. Advantageously, in such way a wider supporting base for the cover and an improved closure of the shielding element are provided. According to a preferred embodiment of the line of the invention, the flanges extend outwardly from the end portions of the side walls of the base. According to an alternative embodiment of the line of the invention, the flanges extend inwardly from the end portions of the side walls of the base. Preferably, the flanges extend from the end portions of the side walls of the base in a direction substantially perpendicular to the side walls. Advantageously, in such way, the cover of the shielding element may be leaned onto the shielding element base in a stable manner. Preferably, the above-mentioned flanges have a width equal to about 25% of the width of the base bottom wall. Preferably, the minimum width of said flanges is equal to about 20 mm. According to a preferred embodiment, the cover of the shielding element is substantially flat, for example in the form of a rectangular sheet made of ferromagnetic material. Such particularly simplified preferred embodiment advantageously allows to limit the manufacturing costs of the electrical power transmission lines of the invention. According to a preferred embodiment, the cover is substantially continuous, i.e. the outer surface of said cover is devoid of macroscopic interruptions so as to maximize the mitigation action of the magnetic field. The above-mentioned possibility of sensibly limiting the thickness of the shielding element of the line of the invention allows to use long shielding elements, for example in the order of about 1 m, while maintaining the shielding element weight within acceptable limits and, in such way, to overcome the insufficient shielding action detected in the regions at which the prior art tapes wound in a spiral manner overlap. According to a preferred embodiment, the flanges may be provided on the cover instead of on the base. In such a case, the cover comprises a main wall and a pair of flanges extending from the main wall in a predetermined direction, preferably in a direction substantially perpendicular to the main wall. In this way, it is advantageously ensured an improved closure of the shielding element, and an ensuing improved effectiveness of the shielding action of the magnetic field generated by the transmission line. According to such embodiment, the corners defined between the main wall of the cover and the flanges may be sharp or bevelled, preferably according to a bending radius equal to about half the outer diameter of the cable or cables housed within the shielding element. Preferably, the base and the cover of the shielding element comprise walls having a thickness comprised between about 0.10 mm and about 0.60 mm and, still more preferably, comprised between about 0.20 mm and about 0.35 mm. Such values of thickness advantageously allow to manufacture a transmission line in which the shielding element has an advantageously limited weight, which allows in turn to limit the costs imputable to the use of the ferromagnetic material. The cover may have a thickness which is lower than the thickness of the base, because the cover, which is positioned farther from the cables with respect to the base, is crossed by a lower magnetic flow with respect to the magnetic flow crossing the base. As an illustrative example, the cover may have a thickness between about 0.10 and about 0.50 mm and the base may have a thickness between about 0.20 and about 0.60 mm. Preferably, the base and the cover of the shielding element comprise respective sides reciprocally superimposed for a portion of predetermined length in lateral direction. In the present direction and in the following claims, the term “sides” of the base or of the cover of the shielding element is used to indicate the lateral portions of the base or, respectively, of the cover, which are opposite with respect to the longitudinal axis of the shielding element. According to a preferred embodiment of the electrical power transmission line of the invention, a material having a permeability greater than air, such as for example a magnetic rubber, is interposed at the superimposed sides of the base and of the cover. In this way, the gap between the base and the cover at the region in which the cover leans onto the base is substantially closed, with advantageous further attenuation of the magnetic field generated by the cable. Preferably, the base and the cover of the shielding element comprise respective walls having a rolling direction substantially perpendicular to the axis of the at least one cable. In this way, an improved shielding effect of the magnetic field is advantageously achieved. According to an alternative embodiment, the base and the cover of the shielding element comprise respective walls having a rolling direction substantially parallel to the axis of the at least one cable. According to a preferred embodiment, the shielding element comprises a plurality of shielding modules arranged side by side, each of these shielding modules comprising a modular base and a modular cover. A configuration of the modular type of the shielding element advantageously facilitates both the installation operations of the electrical power transmission line and the subsequent maintenance operations, in particular the replacement of damaged sections of the shielding element. Preferably, such shielding modules are longitudinally superimposed for a portion of predetermined length, preferably comprised between 25% and 100% of the width of the shielding element. Preferably, each modular base has a frustoconical longitudinal section so as to facilitate the partial longitudinal superimposition between adjacent modular bases and to form, in such way, a substantially continuous shielding element. In the case of this embodiment, the modular bases and covers are preferably produced by stamping. According to an alternative embodiment of the transmission line of the invention, when the shielding modules are not reciprocally superimposed, but just reciprocally arranged side by side, the shielding element further comprises a respective connecting element made of ferromagnetic material for connecting such modules arranged side by side. In this way, the connecting element has shielding properties substantially analogous to the properties of a substantially continuous shielding element. In the case of the latter embodiment the modular bases and covers may be conveniently manufactured by extrusion, which advantageously results in a reduction in manufacturing costs. According to a preferred embodiment, in each of said shielding modules, the modular base and the modular cover are reciprocally staggered in longitudinal direction by a predetermined distance, preferably equal to the length of the above-mentioned portion of longitudinal superimposition of the shielding modules. Preferably, the modular base is coupled to a supporting element. Preferably, each wall of the modular base is coupled to respective supporting elements. In this way, supporting elements of limited size and, as such, easily transportable and applicable to the shielding element, are advantageously used. More preferably, both the modular base and the modular cover are coupled to respective supporting elements. According to a preferred embodiment of the power transmission line of the invention, at least two adjacent shielding modules extend along different directions, the shielding element further comprising a respective connecting element made of ferromagnetic material for connecting these at least two adjacent modules. In this way, it is advantageously possible to manufacture lines provided with curved sections, elbows and similar sections. In order to form such curved sections, the modular bases may be shaped in a substantially rectangular form and advantageously produced by extrusion, in which case the curved sections may be laid out by reciprocally angulating at least two adjacent modular bases in such a manner that the adjoining sides of such adjacent bases define a substantially triangular free space therebetween or, alternatively, the modular bases may be shaped in a such a manner that the adjoining sides of such adjacent bases are substantially parallel so as to minimize such free space. According to a preferred embodiment, the ferromagnetic material of which the at least one shielding element is made has a maximum value of relative magnetic permeability μmax greater than about 20000. The use of at least one shielding element made of ferromagnetic material having a maximum value of relative magnetic permeability greater than such numerical value advantageously allows to minimize the magnetic losses unavoidably present in the base and in the cover of the shielding element. More preferably, the ferromagnetic material has a maximum value of relative magnetic permeability μmax comprised between about 20000 and about 60000 and, still more preferably, a maximum value of relative magnetic permeability μmax equal to about 40000, with advantageous further reduction of the magnetic losses. Moreover, the use of materials having said ferromagnetic characteristics allows to use a more limited thickness of the shielding element with respect to the prior art lines, with advantageous reduction of the line weight. The electrical power transmission line may comprise two shielding elements, preferably having a controlled magnetic permeability, i.e. preferably reciprocally coupled so as to form a first radially inner layer made of a first ferromagnetic material and a second radially outer layer made of a second ferromagnetic material. Preferably, the first ferromagnetic material has a maximum value of relative magnetic permeability greater than the maximum value of relative magnetic permeability of the second ferromagnetic material. In the case in which the line comprises two shielding elements having a controlled magnetic permeability, the maximum value of relative magnetic permeability of the radially inner layer is preferably equal to about 40000, and the maximum value of relative magnetic permeability of the material of the radially outer layer is preferably equal to about 3000. Preferably, the ferromagnetic material is selected from the group comprising: grain oriented silicon steel, non-grain oriented silicon steel, Permalloy®, Supermalloy®. The Permalloy® and the Supermalloy® are nickel-iron-molybdenum alloys having a high nickel content (equal to about 80%), in which the molybdenum content is comprised between 4 and 5% and, respectively, is greater than 5%, both alloys being manufactured by Western Electric Company, Georgia, USA. Alloys having magnetization curves similar to the magnetization curves of these alloys may also be used. When silicon steel is used, whether grain oriented or not, thanks to the presence of the silicon, on the one hand the value of the losses determined by the hysteresis cycle present in the ferromagnetic material is advantageously reduced to a considerable extent and, on the other hand, the electrical conductivity of the steel is advantageously reduced, which also allows to reduce the losses due to eddy currents. Thanks to this double beneficial effect, the power transmission capacity of a line shielded by a shielding element made of silicon steel is advantageously improved. As an illustrative example, with a current equal to about 400 A, three cables having a diameter of about 100 mm arranged according to a trefoil arrangement of the closed type within a shielding element made of grain oriented silicon steel having a thickness of about 0.27 mm placed about 1.4 m below the ground level, the magnetic field induction is equal to about 0.2 μT at the ground level As to the losses due to eddy currents and the losses due to magnetic hysteresis, both losses, at the above-mentioned values of thickness of the shielding element, trench depth and magnetic induction, are equal to about 1.7·106 Siemens m and, respectively, equal to about 1.1 W/kg at a magnetization level of about 1.5 T at 50 cycles per second. Among the different types of grain oriented silicon steels, the steel referred to as M4T27 according to the AST standard is particularly preferred. According to a preferred embodiment of the power transmission line of the invention, the silicone content is comprised between about 1% and about 5% and, more preferably, between about 3% and about 4%. Advantageously, within this preferred range of values, the electrical conductivity of the silicon steel is further reduced, allowing in such way a further corresponding reduction of the losses due to eddy currents. According to a preferred embodiment of the line of the invention, the base and the cover of the shielding element may be made of different materials, preferably using a poorer material, i.e. a material having a lower maximum value of relative magnetic permeability, for the cover, since the latter is crossed by a lower magnetic field flow with respect to the base. Preferably, the base is made of a first ferromagnetic material having a maximum value of relative magnetic permeability greater than about 40 and the cover is made of a second ferromagnetic material having a maximum value of relative magnetic permeability greater than about 20. Preferably, the line of the invention, in addition to at least one supporting element coupled to the base of the shielding element, further comprises a supporting element coupled to the cover of the shielding element. According to a preferred embodiment of the electrical power transmission line of the invention, the above-mentioned at least one supporting element coupled to the base and optionally also to the cover of the shielding element is arranged in a radially outer position with respect to the above-mentioned at least one shielding element. In this way, the mechanical resistance conferred to the cable is advantageously further improved. According to an alternative embodiment, the at least one supporting element is arranged in a radially inner position with respect to the at least one shielding element. In this way, it is advantageously possible to exploit the presence of the supporting element for supporting, in addition to the shielding element, also a plurality of cables maintained in a desired spatial configuration. According to an alternative embodiment, the at least one shielding element is interposed between a pair of supporting elements. In this way, the above-mentioned advantages correlated to an improved mechanical resistance and to the possibility of maintaining a plurality of cables in a desired spatial configuration can be simultaneously achieved. According to a preferred embodiment, the at least one supporting element is substantially flat. In this way, one or more supporting elements may be easily coupled to the base and optionally also to the cover of the shielding element, preferably according to one of the following ways. According to a first way, the at least one supporting element is firstly coupled to the base and optionally also to the cover of the shielding element by means of glue, and subsequently the at least one supporting element and the shielding element so coupled are shaped according to the desired geometry. For example, the base of the shielding element associated with the respective supporting element may be shaped in the form of a U-shaped cross-section, preferably provided with lateral flanges, by longitudinally hot-bending the base and respective supporting element coupled thereto at four points. When the cover is provided with a pair of flanges, at least one supporting element, for example in the form of a flat plate, is firstly coupled to the cover, for example in the form of a flat plate as well and, subsequently, the at least one supporting element and the cover so coupled are longitudinally hot-bent at two points. According to a second way, the at least one supporting element is manufactured by extrusion and coupled to the base of the shielding element, and optionally also to the cover, which are both manufactured by stamping. The coupling may be carried out by means of glue or by means of a plurality of fixing means, described in greater detail in the following, longitudinally arranged at predetermined distances from each other. According to a third way, both the at least one supporting element and the base and cover of the shielding element are manufactured by stamping and subsequently coupled by means of glue or by means of a plurality of fixing means. According to an additional way, the base of the shielding element comprises three sheets advantageously manufactured by extrusion, which are coupled, for example by means of glue, to respective walls of a substantially U-shaped supporting element. According to a preferred embodiment of the power transmission line of the invention, the at least one supporting element comprises a wall having a thickness equal to about 2-10 mm and, still more preferably, equal to about 3-5 mm. According to a preferred embodiment of the power transmission line of the invention, the at least one supporting element is made of an electrically non-conductive and non-ferromagnetic material. Preferably, the electrically non-conductive and non-ferromagnetic material of which the at least one supporting element may be made is selected from the group comprising: plastics materials, cement, terracotta, carbon fibres, glass fibres, wood or other materials able to exert an advantageous supporting function while being advantageously produced by means of simple low cost technologies. Still more preferably, said plastics materials are selected from the group comprising: polyethylene (PE), low-density polyethylene (LPDE), medium-density polyethylene (MPDE), high-density polyethylene (HPDE), linear low-density polyethylene (LLPDE), polypropylene (PP), ethylene/propylene elastomer copolymers (EPM), ethylene/propylene/diene terpolymers (EPDM), natural rubber, butyl rubber, ethylene/vinyl copolymers (such as for example ethylene/vinyl acetate (EVA)), ethylene/acrylate copolymers (such as for example ethylene/methyl acrylate (EMA), ethylene/ethyl acrylate (EEA), ethylene/butyl acrylate (EBA)), ethylene/α-olefin thermoplastic copolymers, polystyrene, acrylonitriletbutadiene/styrene resins (ABS), halogenated polymers (such as for example polyvinyl chloride (PVC)), polyurethane (PUR), polyamides, aromatic polyesters (such as for example polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)). Alternatively, the supporting element may be made of a ferromagnetic or metallic material. Materials of such type, although causing weak magnetic losses, are advantageous in terms of stampability, thus facilitating the coupling between the supporting element and the shielding element. Preferably, the shielding element further comprises a plurality of fixing means, such as for example in the form of hooks made for example of a plastics material. When the at least one supporting element is electrically conductive, or when the same is electrically non-conductive but does not completely cover the portions of the base and the cover intended to be superimposed, the fixing means are preferably made of metal, so as to ensure an electrical continuity between the base and the cover. Preferably, the fixing means are longitudinally arranged at predetermined distances so as to fix the cover onto the base. The fixing means advantageously allow to improve the coupling stability between the base and the cover of the shielding element. As an alternative to the hooks, plastic or metal clips or binder spines or other fixing means suitable for this aim may be used. Preferably, the fixing means are arranged in pairs, wherein each pair comprises fixing elements arranged on opposite sides with respect to the longitudinal axis of the shielding element. According to a further embodiment, the base and cover may be reciprocally associated, for example by means of a longitudinal hinge, so as to simplify the laying operations and to improve the coupling precision between the two parts. According to a preferred embodiment of the power transmission line of the invention, the fixing means are arranged in a plurality of pairs positioned along the sides of the shielding element at a predetermined reciprocal distance, preferably comprised between about 20 and about 100 cm. According to a second aspect thereof, the present invention refers to a method for shielding the magnetic field generated by an electrical power transmission line comprising at least one electrical cable, the method comprising the steps of: providing at least one shielding element made of at least one ferromagnetic material for shielding the magnetic field generated by the at least one electrical cable, the shielding element comprising a base and a cover; coupling at least one supporting element to at least the above-mentioned base; laying the at least one electrical cable into the base of the shielding element; and leaning the cover onto the base so as to substantially close the shielding element. Thanks to these steps, the method according to the invention allows an easy and rapid installation of a shielded electrical power transmission line, particularly in the case in which the line is placed underground. In a similar manner, any maintenance interventions which may be necessary subsequently to the installation are facilitated. According to a preferred embodiment of the method of the invention, the ferromagnetic material is selected from the group comprising: grain oriented silicon steel, non-grain oriented silicon steel, Permalloy®, Supermalloy®, these last two alloys being manufactured by Western Electric Company. When the ferromagnetic material is a grain oriented material, the step of providing the shielding element preferably includes the arrangement of the walls of the base and of the cover according to a configuration such that the rolling direction of these is substantially perpendicular to the axis of the at least one cable. Preferably, the step of providing the shielding element includes the arrangement side by side and the partial superimposition in longitudinal direction of a plurality of shielding modules comprising respective modular bases and modular covers. According to a preferred embodiment of the method of the invention, the shielding modules are reciprocally superimposed in longitudinal direction for a portion having a predetermined length, preferably comprised between 25% and 100% of the width of the shielding element. Preferably, the method of the invention further comprises the step of staggering, in each of the above-mentioned plurality of shielding modules, the modular base with respect to the modular cover in longitudinal direction by a predetermined distance. According to a preferred embodiment of the method of the invention, in order to form curved sections, at least two adjacent shielding modules are laid along different directions, and are then connected by means of a respective connecting element made of ferromagnetic material. When the cables are in number of three, the method of the invention preferably comprises the step of arranging such cables according to a trefoil arrangement, preferably of the closed type as described above. Preferably, the above-mentioned step of leaning the cover onto the base of the shielding element comprises the step of superimposing the respective sides of the base and the cover for a portion of predetermined length in lateral direction. According to a preferred embodiment, the method of the invention includes the step of coupling at least one supporting element also to the cover of the shielding element. Preferably, the step of coupling the at least one supporting element to the base and optionally also to the cover of the shielding element includes the arrangement of the supporting element in a radially outer position with respect to the base and optionally also to the cover. According to an alternative embodiment of the invention, the step of coupling the at least one supporting element to the base and optionally also to the cover of the shielding element includes the arrangement of the supporting element in a radially inner position with respect to the shielding element and optionally to the base. According to a further alternative embodiment of the method of the invention, the step of coupling the at least one supporting element to the base and optionally also to the cover of the shielding element includes the interposition of the base and optionally also of the cover between a pair of respective supporting elements. According to a preferred embodiment of the method of the invention, this further comprises the step of placing underground the electrical power transmission line. Preferably, the method comprises the further step of arranging a plurality of fixing means, preferably in the form of hooks, longitudinally at predetermined distances from each other so as to fix the cover onto said base. Preferably, such step of arranging the fixing means includes the arrangement of the fixing means in pairs, wherein each pair comprises fixing elements arranged on opposite sides with respect to the longitudinal axis of the shielding element. Preferably, such hooks are arranged in a plurality of pairs positioned along the sides of the shielding element at a predetermined reciprocal longitudinal distance, comprised between about 20 and about 100 cm. BRIEF DESCRIPTION OF THE DRAWINGS Additional features and advantages of the invention will become more readily apparent from the description of some embodiments of a method for shielding the magnetic field generated by an electrical power transmission line according to the invention, made in the following with reference to the attached drawing figures in which, for illustrative and non-limiting purposes, an electrical power transmission line so shielded is shown. In the drawings: FIG. 1 is a perspective view of an electrical power transmission line shielded according to a first preferred embodiment of the invention; FIG. 2 is a cross-sectional view of the line shown in FIG. 1; FIG. 3 is a top view of two curved sections of the line of FIG. 1; FIG. 4 is a cross-sectional view of a second preferred embodiment of the electrical power transmission line according to the invention; FIG. 5 is a cross-sectional view of a further preferred embodiment of the electrical power transmission line according to the invention; FIG. 6 is a side view, in partial cross-section, of a further preferred embodiment of the electrical power transmission line according to the invention; FIG. 7 is an enlarged view of the detail marked with a circle in FIG. 6; FIG. 8 is a schematic top view of a further preferred embodiment of the electrical power transmission line according to the invention; FIGS. 9-11 show results of experimental tests. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS With reference to FIGS. 1-3, an electrical power transmission line in accordance with a first preferred embodiment according to the invention is generally indicated with 1. The line 1 shown in the above-mentioned figures is intended to transmit high voltage three phase electrical power, for example equal to about 132 kV, and is able to carry currents up to about 860 A. In particular, the line 1 shown in the above-mentioned figures is intended to operate with a current of about 400 A. The line 1 is particularly adapted to be placed underground. According to the illustrated preferred embodiment, the line 1 comprises three electrical cables, all indicated by 2, and a shielding element 6 made of ferromagnetic material, such as for example grain oriented silicon steel referred to as M4T27 according to the AST standard. Such material has a maximum value of relative magnetic permeability μmax equal to about 40000 and a silicon content equal to about 3%. Alternatively, any material having a maximum value of relative magnetic permeability μmax comprised between about 20000 and about 60000, for example a non-grain oriented silicon steel, a Permalloy® alloy or a Supermalloy® alloy, or similars could be used. The shielding element 6 is arranged in a radially outer position with respect to the cables 2 in such a manner as to surround the cables 2 and to mitigate the magnetic field generated thereby. The cables 2 are intended to carry an alternating current at a frequency typically equal to 50 or 60 Hz, and are arranged in contact with each other according to a trefoil arrangement of the closed type, which is particularly advantageous in terms of reduction of the magnetic field generated by the cables 2. Alternatively, the cables 2 may be aligned on the bottom of the shielding element 6, although this alternative arrangement, not illustrated, could increase the magnetic field generated by the cables 2. According to the preferred embodiment shown in the above-mentioned figures, each of the cables 2 comprises, starting from a radially inner position to a radially outer position, a conductor 4, for example an enamelled copper Milliken conductor, and a radially outer construction, schematically illustrated and identified by 5, which preferably includes an inner semiconductor layer, a layer of extruded polymeric insulator, for example constituted by cross-linked polyethylene (XLPE), an outer semiconductor layer, a metallic shield and an outer sheath, not illustrated in detail. The Milliken conductor may have, for example, a cross-sectional area equal to about 1600 mm2. The total outer diameter of each cable 2 is preferably comprised between about 40 and about 160 mm, for example equal to about 100 mm. The trefoil of cables 2 may be raised by means of suitable shims from the bottom of the shielding element 6 to a position which is closer to the geometrical centre of such element, which position is more favourable in terms of mitigation of the magnetic field. According to the preferred embodiment illustrated in FIG. 1, the shielding element 6 comprises a plurality of shielding modules 12 arranged side by side and partially superimposed in longitudinal direction. Each shielding module 12 comprises a modular base 10 and a modular cover 11 and is coupled to respective substantially flat supporting elements 7. In particular, the shielding modules 12 are reciprocally longitudinally superimposed for a portion of predetermined length, for example equal to at least 25% of the width of the shielding element 6. Moreover, in each of the shielding elements 12, the modular base 10 and the modular cover 11 are reciprocally staggered in longitudinal direction by a predetermined distance, for example equal to 25% of the width of the shielding element 6. In the preferred embodiment illustrated in FIGS. 1 and 2, each modular base 10 and each modular cover 11 of the shielding element 6 comprise respective sides reciprocally superimposed for a portion of predetermined length in lateral direction. In each shielding module 12, the modular base 10 and the modular cover 11 may be manufactured starting from folded sheets, which are obtained starting from M4T27 steel strips previously subjected to rolling and thermal treatments intended to obtain the orientation of the grams. Each modular base 10 comprises in particular a bottom wall 10a and a pair of side walls 10b, 10c extending in a direction substantially perpendicular to the bottom wall 10a. Moreover, according to the preferred embodiment illustrated in FIGS. 1 and 2, each modular base 10 further comprises a pair of flanges 10d, 10e outwardly extending in a direction substantially perpendicular to the end portions of the side walls 10b, 10c of the base 10. The above-mentioned walls 10a, 10b and 10c of each modular base 10 are arranged in such a manner that the respective rolling direction to which the walls have been subjected is substantially perpendicular to the axis of the cables 2. Each modular cover 11 is substantially flat and, in the preferred embodiment illustrated in FIG. 2, for reasons of simplicity of construction, protrudes with respect to the flanges 10d, 10e of the modular bases 10. Alternatively, each modular cover 11 may be advantageously terminated flush with the flanges 10d, 10e of the modular base 10, because in the coupling between the flanges 10d, 10e of the modular base 10 and the modular cover 11 it is the width of the superimposed lateral portions which affects the mitigation of the magnetic field, whereas the portion of the cover 11 possibly protruding with respect to the sides of the base 10 does not have any effect in such sense. In FIG. 4, in which an alternative embodiment of the line of the invention is shown, the line elements which are structurally or functionally equivalent to those previously illustrated with reference to the line 1 illustrated in FIG. 1 will be indicated by the same reference numerals and will not be further described. According to such alternative embodiment, the base 10 comprises a bottom wall 10a and a pair of side walls 10b, 10c extending in a direction substantially perpendicular to the bottom wall 10a, while the cover 11 comprises a main wall 11a and a pair of flanges 11b, 11c extending in a direction substantially perpendicular to the main wall. FIG. 3 shows two curved sections 1a, 1b of the line 1 of FIG. 1, each section comprising a pair of adjacent shielding modules 12. The adjacent shielding modules 12 belonging to each of such pairs extend in different directions. In particular, the bases 10 are shaped in such a manner that the sides placed side by side of the bases 10 belonging to adjacent shielding modules 12 are substantially parallel, so as to minimize the free space between adjacent shielding modules 12. In such case, the shielding element 6 further comprises two connecting elements 13 made of ferromagnetic material, for example of the same steel indicated above, for connecting respectively the adjacent shielding modules 12 of the two pairs. In the preferred embodiment shown in FIGS. 1 and 2, in each shielding module 12, the supporting elements 7 are in number of four, one for each of the above-mentioned walls 10a, 10b, 10c of the base 10 and for the cover 11. Alternatively, instead of three separate supporting elements 7, an integral supporting element 7, preferably made by extrusion and able to simultaneously support the three walls 10a, 10b, and 10c may be coupled to the base 10. The supporting elements 7 according to the preferred embodiment shown in FIGS. 1 and 2 are arranged in a radially outer position with respect to the shielding element 6. However, in an alternative embodiment (not shown), the supporting elements 7 may be arranged in a radially inner position with respect to the shielding element 6. According to a further alternative embodiment, shown in FIG. 5, in each shielding module 12 the base 10 of the shielding element 6 is interposed between a pair of supporting elements 7. According to the preferred embodiment shown in FIGS. 6 and 7, the shielding element 6 further comprises fixing means, for example in the form of hooks 14, arranged in a plurality of pairs positioned along the sides of the shielding element 6 at a predetermined longitudinal distance from each other, which fixing means are intended to fix the cover 11 onto the base 10 of each shielding module 12. With reference to the embodiment of the electrical power transmission line described above, a preferred embodiment of the method according to the invention for shielding a line of such type involves the following steps. According to a first step of the method, the shielding element 6 comprising the above-mentioned plurality of shielding modules 12 made of grain oriented silicon steel M4T27 is provided. In a second step, the walls 10a, 10b and 10c of the base 10 and the cover 11 of each shielding module 12 are coupled to the respective supporting elements 7 arranging the latter in a radially outer position with respect to the shielding module 12. Such coupling is previously carried out for example by gluing. Each modular base 10 is shaped according to a U-shaped cross-section provided with lateral flanges 10d, 10e preferably by longitudinally hot-bending the base 10 and the respective three supporting elements 7 coupled thereto at four points. The modular bases 10 of the shielding modules 12, so coupled to the respective supporting elements 7, are then placed in the trench and partially longitudinally superimposed. The walls 10a, 10b and 10c of the base 10 are preferably arranged according to such a configuration that, after having laid the cables into the base 10, as will be explained in more detail in the following, the rolling direction of the walls is substantially perpendicular to the axis of the cables 2. In a further step of the method, the electrical cables 2 are laid into the modular bases 10 so assembled of the shielding element 6 after fixation of the cables 2 in the desired trefoil arrangement of the closed type. Subsequently to the step of laying the electrical cables 2 into the bases 10, a preferred embodiment of the method of the invention involves the further step of inserting a filing material, such as for example cement (not shown in the figure), in the bases 10. Subsequently, in each shielding module 12, the cover 11, coupled to the respective supporting element 7, is leaned onto the base 10 by superimposing respective sides of the base 10 and of the cover 11 so as to substantially close the shielding element 6. In particular, in each shielding module 12, the cover 11 is staggered with respect to the base 10 in longitudinal direction by a predetermined distance. With reference to the two curved sections 1a, 1b of FIG. 3, these may be manufactured by extending, for two pairs of adjacent shielding modules 12, the adjacent modules 12 belonging to each pair in different directions and by connecting the same by means of the respective connecting element 13. Finally, the hooks 14 are longitudinally arranged in a plurality of pairs positioned along the sides of the shielding element 6 at a predetermined longitudinal distance from each other in order to fix the covers 11 onto the respective bases 10. FIG. 8 shows a further embodiment of the line of the invention: the line elements which are structurally or functionally equivalent to those illustrated previously with reference to the line 1′ shown in FIG. 1 will be indicated by the same reference numerals and will not be further described. In particular, such figure shows an electrical power transmission line 1 comprising a joining portion 3 of the cables of said line. According to the embodiment shown in FIG. 8, the joining portion 3 of the line 1 comprises in particular three cables 2 joined with a same number of cables, all indicated by 2′, by means of respective joints 8. A plurality of shielding modules 12′, made for example of grain oriented silicon steel, having a frustoconical longitudinal section and reciprocally longitudinally superimposed, is arranged at the joining portion 3 of the line 1, which is wider in size than the other portions of the line 1. The shielding modules 12′ arranged in the joining portion 3 of the line 1 are wider than the shielding modules 12 arranged in the other portions of the line 1, the modules 12 being preferably made of grain oriented silicon steel as well. Thanks to such measure, it is advantageously possible to shield also those portions of the line which are wider in size, while allowing—thanks to the modular type configuration—to facilitate the transport and laying operations of the line. Considering the effectiveness of the mitigation effect of the magnetic field ensured by the shielding modules 12 and 12′, a possible superimposition of layers of shielding material in each module 12, 12′ would not cause substantial effects in terms of reduction of the magnetic field: as a consequence, it is preferable that, in the region of superimposition of two adjacent shielding modules, the ferromagnetic material is provided only on one of the two modules instead of on both modules, with advantageous lower consumption of ferromagnetic material. EXAMPLE 1 Invention The Applicant manufactured an electrical power transmission line comprising three 150 kV electrical cables, having a section equal to about 1000 mm2 and a diameter equal to about 92 mm, arranged according to a trefoil arrangement of the closed type, and a shielding element comprising 5 modules, each of said modules comprising a modular base and a modular cover. The shielding element was made of grain oriented silicon steel starting from a strip having a width of 470 mm and a thickness of 0.27 mm In particular, the steel referred to as M4T27 according to the AST standard was used. For each module, a steel strip was cut into rectangular sheets (460 mm×690 mm) and subsequently folded by means of a manual bending apparatus to form a modular base comprising a 190 mm wide substantially flat bottom wall, a pair of substantially flat side walls (200 mm long) extending in a direction substantially perpendicular to the bottom wall, and a pair of substantially flat flanges (50 mm wide) outwardly extending in a direction substantially perpendicular to the end portions of the side walls of the modular base. The corners between the modular base and the side walls were not bevelled (sharp corners). The walls of the modular base were provided according to a configuration such that, after the cables have been laid into the modular base as will be explained in the following, the rolling direction of the walls of the modular base was perpendicular to the cable axis. Subsequently, rectangular sheets measuring 470 mm×450 mm were cut to form the modular covers. The modular bases and covers were painted to protect the steel from corrosion by means of a layer of epoxy paint having a thickness of about 100 μm, which is capable of protecting the steel for long periods of useful life. 20 sheets of 40 mm thick expanded polyester which is advantageously workable in an easy and inexpensive manner, were provided to form a same number of supporting elements. The modular bases and covers were coupled to respective supporting elements formed in this manner by gluing the latter to the bases and to the covers. The modular bases coupled to the respective supporting elements and longitudinally superimposed for a portion of length of about 50 mm were placed in a trench at a depth of 1.4 m. Subsequently, the three cables were laid into the modular bases assembled in this manner after fixation of the cables in the desired trefoil arrangement of the closed type by means of shims made of expanded polystyrene interposed between the modular bases and the cables. The modular covers, coupled to the respective supporting elements, were then leaned onto the above-mentioned modular bases assembled in this manner by staggering, with reference to each shielding element, the modular cover by 50 mm with respect to the corresponding modular base in order to substantially close the shielding element and, in this manner, to improve the shielding effectiveness thereof. For the same purpose, the covers were also reciprocally longitudinally superimposed of 50 mm. In order to simulate a defective coupling, which can occur due to defects in the bases and/or in the covers (which may not be perfectly flat) or due to the penetration of earth between the flanges of the bases and the covers, a gap of about 3 mm was deliberately left between the flanges of the bases and the covers. Finally, along the sides of the shielding element assembled in this manner, 8 plastic hooks (4 for each side) were longitudinally positioned in the region in which the bases and the covers were superimposed, and 6 hooks (3 for each side) were longitudinally positioned in the other regions, so as to ensure a mechanical strength between the base and the cover in the order of about 1-10 kg for each metre of shielding element. In such manner, a shielding element with a width of 190 mm and a height of 200 mm, capable of housing three cables, was manufactured. The electrical power transmission line manufactured in this manner was 6 metres long. A set of weights was positioned above the covers in order to simulate the effect of mechanical crushing exerted, in normal working conditions of the line, by the layer of earth standing above the line. The cables were connected, at one end, to a plant capable of supplying a symmetrical three phase current up to 1000 A and, at the other end, the cables were short-circuited one to each other. A symmetrical three phase electrical current was circulated through the cables at an increasing intensity up to 800 A. EXAMPLE 2 Comparison A non-shielded electrical power transmission line comprising three electrical cables arranged according to a trefoil arrangement, laid in a trench at a depth of 1.4 metres, having the same constructive characteristics and subject to the same working conditions of the cables of the shielded line described in Example 1 was manufactured. EXAMPLE 3 Invention An electrical power transmission line as described in Example 1, except for the fact that the covers were arranged with the axis of the grains oriented in the direction parallel to the cable axis, was manufactured. EXAMPLE 4 Invention An electrical power transmission line as described in Example 1, except for the fact that the base was shaped so as to have a U-shaped cross-section with bevelled corners defined between the bottom wall and the side walls, was manufactured. In particular, such corners were bevelled according to a bending radius approximately equal to half the outer diameter of the cables in order to preserve the ferromagnetic material from degradation of the magnetic characteristics, degradation which occurs in consequence of a bending step giving a base having sharp corners. Experimental Measures The maximum value of magnetic field Bmax generated at ground level by the electrical power transmission line of Examples 1-4 was measured according to a measuring method essentially consisting of positioning a measuring sensor at ground level (i.e. at 1.4 m from the line), measuring the radial and circumferential components of the magnetic induction, and finally calculating the modulus of the maximum value of magnetic induction starting from such components, as is described in patent application WO 03/003382. Such measuring method was in particular carried out by means of a measuring device comprising a measuring sensor which is horizontally and vertically movable, so as to be positionable at a predetermined distance from the line, namely at ground level, as described in the above-mentioned patent application. The measurements performed are shown in FIGS. 9, 10, and 11. FIG. 9 is a graph showing the experimental measurements of the magnetic field performed in the case of the non-shielded electrical power transmission line of Example 2, operating at a current of 400 A. As shown in such figure, the experimental measurements revealed that the maximum value of magnetic field Bmax at ground level without shielding protection, as described in Example 2, was equal to 5.04 μT. FIG. 10 is a graph showing the tendency of the magnetic field measured at ground level as a function of the current circulating in the cables of the shielded electrical power transmission line of Example 1. As shown in FIG. 10, the experimental measurements revealed that the maximum value of magnetic field Bmax at ground level in the presence of a shielding according to the invention as described in Example 1, by circulating a symmetrical three phase electrical current having an intensity equal to 400 A in the cables, was equal to 0.20 μT. Therefore, the mitigation of the magnetic field in a shielded line according to the present invention is about 25 times lower than the magnetic field generated by a similar non-shielded line. Moreover, as can be seen in FIG. 10, the value of the magnetic field increases rather rapidly for currents higher than 400 A, since the M4T27 steel employed in the experimental tests is optimized for a current of 400 A and above this value the magnetic permeability thereof is lower than the maximum magnetic permeability. FIG. 11 is a graph showing the tendency of the magnetic field value generated by the cables of the electrical power transmission line shielded according to Example 1 as a function of the gap deliberately left between the flanges of the bases and the covers. As can be seen in said figure, as the gap between the flanges of the bases and covers increases, the ensuing increase of the magnetic field is substantially limited thanks to the arrangement of the shielding element of the invention. In the case of the line of Example 3, i.e. in the case of covers arranged with the axis of the grain oriented in parallel direction to the axis of the cables, the magnetic field, at a current of 400 A, was equal to 0.6 μT at ground level, i.e. about three times higher than the magnetic field obtained with the covers having the grains oriented perpendicularly to the cable axis. Moreover, the experimental measurements performed demonstrated that in the case of the line of Example 4, all other conditions being equal, the magnetic field at ground level was about 25% higher than the magnetic field found in the case of the line of Example 1, comprising a base having sharp corners. In other words, the increase of the extension of the bent surface due to the bevelling of the above-mentioned corners exerts a negative effect having a greater role on the attenuation of the magnetic field with respect to the role exerted by the degradation of the characteristics of the material in consequence of a bending step giving a base having sharp corners.

<SOH> FIELD OF THE INVENTION <EOH>The present invention relates to a method for shielding the magnetic field generated by an electrical power transmission line and to an electrical power transmission line so shielded. Generally, an electrical power transmission line operates at medium voltage (typically from 10 to 60 kV) or at high voltage (typically greater than 60 kV) and at currents of the order of hundreds-thousands of amperes (typically from 500 to 2000 A). The electrical power carried by these lines can reach values of the order of hundreds of MVA, typically 400 MVA. Normally, the carried current is an alternating current at low frequency, in other words generally below 400 Hz and typically equal to 50 or 60 Hz. In general, the electrical power transmission lines are used for transmitting power from electrical power stations to urban centres, over distances of the order of tens of kilometres (normally 10-100 km). Typically, electrical power transmission lines are three-phase lines comprising three cables arranged in a trench at a depth of 1-1.5 m. In the space immediately surrounding the cables, the magnetic induction H may reach relatively high values and, at ground level (i.e. at a distance of 1-1.5 m from the line), a magnetic induction having a value comprised between 20 and 60 μT may be detected, depending on the geometrical arrangement of the cables and on the intensity of the carried current. There are circumstances in which it is particularly recommended to minimize the intensity of the magnetic field, both to protect the human body from exposure to alternating magnetic fields of the above-mentioned intensity, in particular with reference to subjects with the highest potential risk, such as children, and to avoid potential interferences with particularly sensitive or delicate electrical equipment, typically in the proximity of hospitals and airports. In order to avoid possible biological effects and/or interference phenomena with electrical equipment due to exposure to magnetic fields generated by low-frequency sources (for example equal to 50 Hz), there is therefore the need of “mitigating” the magnetic field generated by the cables for the transmission of the electrical current. In the present description and in the following claims, the expression “mitigation of the magnetic field” is used to indicate the reduction of the effective value of the magnetic field measured in a given position of a factor of about 10 to about 100 with respect to the value of the magnetic field which would be measured in the same position in the absence of shielding application. More in particular, with reference to cables placed underground, in the present description and in the following claims, the expression “measurement of the magnetic field” is used to indicate the measurement of the magnetic field performed at ground level at nominal current. As is known, when electrical cables are laid into shielded conduits the magnetic field generated by the cables can be mitigated. The article by P. Argaut, J. Y. Daurelle, F. Protat, K. Savina, and C. A. Wallaert “Shielding technique to reduce magnetic fields from buried cables” A 10.5, JICABLE 1999, considers and compares the shielding effect provided by an open-section shield, such as a sheet of ferromagnetic material, placed above the cables, and the effect provided by a closed-section shield, such as a conduit of rectangular cross-section made of ferromagnetic material placed around the cables. According to this article, attenuation factors of about 5-7 can be obtained with open-section shields, attenuation factors of about 15-20 can be obtained with closed-section shields and attenuation factors of about 30-50 can be obtained when the closed-section shield is provided very close to the cables, for example in the form of a ferromagnetic tape wound directly around the cables. These shields have a number of disadvantages which have not been overcome yet. Firstly, such shields need to be sensibly thick (1-10 mm) in order to provide a sufficiently effective shielding action, with negative consequences on the total weight of the transmission line, on the simplicity and on the rapidity of the installation and maintenance operations and, last but not least, on the cost of the line and of the maintenance thereof. Secondly, although the closed-section conduits described above provide the best shielding effects of the magnetic field, the Applicant noted that the installation and maintenance of the cables into closed conduits is a difficult and costly operation since the cables need to be inserted into the conduits and, in case of maintenance, the cables cannot be inspected because they are surrounded by the conduit. Thirdly, the prior art shields, whether open-section or closed-section shields, are subject to unacceptable electrical losses (i.e. due to eddy currents) and/or hysteretic losses. The hysteretic losses cause the overheating and reduce, in this way, the electrical power transmission capacity through the cable. A further example of closed-section shielding conduits is described in patent application WO 01/93394 of the Applicant, which describes the shielding of electrical power transmission cables by means of conduits comprising at least one layer of ferromagnetic material. In order to ensure an effective magnetic field shielding action, the thickness of the shield is quite high (in the order of 10 mm), which implies an increase of the weight of the transmission line and an ensuing increased difficulty in cable laying operations, which are already quite difficult due to the closed geometry of the conduit. A further example of closed-section shielding conduits is described in patent application WO 03/003382 of the Applicant. In particular, this document describes a conduit supporting two shielding layers, a first radially inner layer made of a first ferromagnetic material, and a second radially outer layer made of a second ferromagnetic material having a relative magnetic permeability greater than the relative magnetic permeability of the first ferromagnetic material. Also in this case, the closed section of the conduit makes the cable laying operations complicated. Patent application (Kokai) JP 10-117083 describes a further example of shielding of the magnetic field generated by an electrical cable of an electrical power transmission line, essentially consisting of a tube made of ferromagnetic material within which the electrical power transmission line cables are laid. More in particular, such tube is manufactured by spirally winding a tape made of ferromagnetic material on a tubular support, such as for example a tube of resin or metal within which the cables are laid. Such spirally winding can be carried out in a single step to form a single shielding layer, or in a plurality of steps to form a respective plurality of superimposed shielding layers constituted by the same shielding material. In the example described, the tape is constituted by grain oriented steel having a greater magnetic permeability in a direction parallel to the winding direction with respect to the magnetic permeability in a direction perpendicular to the above-mentioned winding direction. In the present direction and in the following claims, the expression “grain oriented material” is used to indicate a material in which the crystalline domains have a preferential alignment direction and an extended dimension in the direction of alignment of the crystalline domains, as described, for example, by Alex Goldman in “Handbook of modern ferromagnetic materials”, pages 119-120, Kluwer Academic Publishers, 1999. Said alignment can be evaluated by means of known methods, such as for example by means of an optical microscope or by X-ray diffractometry, and can be carried out by means of rolling processes and thermal annealing treatments according to predetermined times and temperatures and in the presence of recrystallization inhibitors, as described, for example, in document EP-A-0 606 884. Although substantially achieving the purpose, the shielding method described in document JP 10-117083 involves a step or a plurality of steps of spirally winding a single tape or a plurality of tapes made of ferromagnetic material, which makes the manufacture of the line rather laborious, with negative effects on the time and costs required for manufacturing and laying the line. The optimum shielding effect of the magnetic field is achieved at a null angle between the direction of action of the magnetic field generated by the cable and the rolling direction of the ferromagnetic material, which constitutes the preferential magnetization axis. However, the choice of said null angle is incompatible with a shielding spirally wound around the cable as described in document JP 10-117083, whereby the above-mentioned angle must be necessarily greater than 0°, with ensuing lack of exploitation of the maximum shielding effect. On the other hand, the dependence of such angle on the preferential magnetization axis depends very strongly on the intensity of the magnetic field, whereby the appropriate angle must be elected each time as a function of the intensity of the magnetic field, resulting in a poor applicative flexibility of the line and in a further complication of the installation operations of the line. Finally, at the regions where adjacent portions of tape wound in a spiral manner overlap, the magnetic shielding effect is ineffective because of the unavoidable presence of defects, such as for example lack of homogeneity and undulations of the contacting surfaces of the tape wound in a spiral manner. Since the tape has a limited width (in the order of a few centimetres), in fact, the tape is not able to limit the effect of leakage of the magnetic field due to the presence of these defects. In order to overcome the drawbacks of the prior art described above, the Applicant has identified the need of providing an electrical power transmission line comprising at least one electrical cable and at least one shielding element for shielding the magnetic field generated by such cable, which is easy to be installed and which has a limited weight, while allowing to achieve an effective mitigation action of the magnetic field. Moreover, the Applicant has identified the need of providing a method for shielding the magnetic field of such a line which is easier to be carried out and less costly, especially in terms of time required for installing the line with respect to the prior art methods. The Applicant has found that it is possible to manufacture an electrical power transmission line which is easy to be installed by providing a shielding element comprising two components, in particular a base and a cover, while obtaining an effective mitigation action of the magnetic field, without resulting in an excessive weight of the shielding element, thanks to the coupling of at least one shielding element to at least one supporting element to which the function of mechanically supporting the shielding element is given. According to a first aspect thereof, the present invention therefore refers to an electrical power transmission line comprising: at least one electrical cable; at least one shielding element made of at least one ferromagnetic material arranged in a radially outer position with respect to said at least one cable for shielding the magnetic field generated by said cable, said at least one shielding element comprising a base and a cover, and at least one supporting element coupled to at least said base of the shielding element. The use of a shielding element arranged in a radially outer position with respect to the cable and comprising at least two separate components, in particular a base and a cover, allows to mitigate the magnetic field in a satisfactory manner, while ensuring a simplification of the installation and laying procedure of the line, as well as of the subsequent maintenance operations of the same, whereas the provision of at least one supporting element coupled at least to the base allows to optimize the thickness of the shielding element, thus reducing the weight of the latter, with a further advantageous simplification and rapidity of the installation procedure. Thanks to the presence of a shielding element comprising two components, in fact, subsequently to the positioning of the base, preferably in a trench, the cables are laid into the base and the cover is then leaned onto the base to substantially complete the shielding element. The use of shielding elements comprising two components therefore allows to use greater laying lengths and to realize winding paths and all those paths which normally make difficult the laying of the cable(s) into closed shielding elements constituted by a single component. Moreover, the shielding elements comprising two components allow the inspection of the cables both during the laying of the line and subsequently, when the line is in use. In the electrical power transmission line according to the present invention, therefore, the best shielding effects of the magnetic field ensured by the closed-section shielding elements, to which the shielding element of the present invention can be assimilated, are advantageously exploited, while overcoming the drawbacks posed by the closed-section shielding elements of the prior art in terms of difficulty of installation and maintenance. By selecting, in fact, a ferromagnetic material which is effective in terms of mitigation action of the magnetic field as material for the shielding element and by selecting a material having suitable mechanical properties as material for the supporting element, it is advantageously possible to limit the thickness of the shielding element to a considerable extent, giving the function of support and mechanical resistance to the supporting element alone. Finally, differently from to the electrical power transmission lines of the prior art, in which the shielding is obtained by spirally winding a tape made of ferromagnetic material around a tubular support, with ensuing unavoidable formation of a non-null angle between the tape helix thus formed and the straight circumferential direction of the action of the magnetic field, in the transmission line according to the present invention such angle is null, with advantageous increase of the magnetic permeability and improvement of the shielding effect. The transmission line according to the present invention may be placed underground, preferably at 1 to 1.5 metres below the ground level, so as to maximize the mitigation effect of the magnetic field generated by the cable. The transmission line according to this invention may also be placed within the wall constructions of large-scale buildings, in which electrical power is transmitted at medium or high voltage along a main line before being converted into low voltage at each single user point. According to a preferred embodiment of the electrical power transmission line of the invention, the line comprises three cables, preferably arranged according to a trefoil arrangement. The trefoil arrangement of the cables allows to obtain a mitigation of the magnetic field which is about twice the mitigation of the magnetic field obtainable by three cables arranged side by side on a plane. In the present description and in the following claims, the expression “trefoil arrangement” is used to indicate an arrangement at which the centres of the three cables occupy the vertices of an equilateral triangle. More in particular, the trefoil arrangement may be either of the so-called “open” type or of the so-called “closed” type, depending on the fact that there is a reciprocal contact among the cables or not. In other words, in the case of an open type trefoil arrangement, the length of each side of the equilateral triangle at the vertices of which the cables are placed is greater than the diameter of each cable, while, in the case of a closed type trefoil arrangement, the length of each side of the equilateral triangle at the vertices of which the cables are placed is substantially equal to the diameter of each cable. Although the trefoil arrangement is preferred, and the closed type arrangement is particularly preferred, any other arrangement intended to attenuate the magnetic field is equally possible. In an alternative embodiment, cables may be arranged side by side on a plane, in a base sufficiently wide to contain the cables according to this arrangement. Although this arrangement increases the electrical losses as well as the magnetic field, it may be advantageously applied when a slight mitigation of the magnetic field is required, since an arrangement of this type allows to use a shielding element having a size of lower height, with ensuing advantageous minimization of the weight of the shielding element and, with this, of the transmission line. In order to obtain an effective mitigation action of the magnetic field, both the base and the cover of the transmission line of the invention are substantially continuous, i.e. the outer surface of said base and of said cover is substantially devoid of any macroscopic interruption. Preferably, the base comprises a bottom wall, for example substantially flat, and a pair of side walls, for example substantially flat. In such way, the manufacture of the base is advantageously simplified. Preferably, the side walls of the base extend in a direction substantially perpendicular to the bottom wall. Preferably, in a trefoil arrangement of the cables of the closed type, the width of the bottom wall is equal to about 2.1 times the diameter of the electrical cables housed within the shielding element. Preferably, in a trefoil arrangement of the cables of the closed type, the height of the side walls, defining the height of the shielding element, is equal to about 2.2 times the diameter of the electrical cable housed within the shielding element. The base of the shielding element may have a U-shaped cross-section provided with bevelled corners according to a predetermined bending radius, which advantageously allows to preserve the ferromagnetic characteristics of the material of the shielding element, or a U-shaped cross-section provided with sharp corners. The latter embodiment, although involving a degradation of the ferromagnetic characteristics of the material of the shielding element at said sharp corners, is preferable because such embodiment allows to achieve an attenuation of the magnetic field at ground level of about 25% with respect to the embodiment providing a base with bevelled corners. In this connection, the Applicant has found that the greater length of the curve of the shielding element in the embodiment with bevelled corners exerts a negative effect having a greater role with respect to the degradation effect of the ferromagnetic characteristics due to the bending of the shielding element provided with sharp corners. In the case of the embodiment with a U-shaped cross-section provided with bevelled corners, the bending radius is preferably equal to about 0.4-0.7 times the diameter of the electrical cables housed within the shielding element. Preferably, the base of the shielding element further comprises a pair of flanges extending in a predetermined direction from the end portions of the side walls of the base. Advantageously, in such way a wider supporting base for the cover and an improved closure of the shielding element are provided. According to a preferred embodiment of the line of the invention, the flanges extend outwardly from the end portions of the side walls of the base. According to an alternative embodiment of the line of the invention, the flanges extend inwardly from the end portions of the side walls of the base. Preferably, the flanges extend from the end portions of the side walls of the base in a direction substantially perpendicular to the side walls. Advantageously, in such way, the cover of the shielding element may be leaned onto the shielding element base in a stable manner. Preferably, the above-mentioned flanges have a width equal to about 25% of the width of the base bottom wall. Preferably, the minimum width of said flanges is equal to about 20 mm. According to a preferred embodiment, the cover of the shielding element is substantially flat, for example in the form of a rectangular sheet made of ferromagnetic material. Such particularly simplified preferred embodiment advantageously allows to limit the manufacturing costs of the electrical power transmission lines of the invention. According to a preferred embodiment, the cover is substantially continuous, i.e. the outer surface of said cover is devoid of macroscopic interruptions so as to maximize the mitigation action of the magnetic field. The above-mentioned possibility of sensibly limiting the thickness of the shielding element of the line of the invention allows to use long shielding elements, for example in the order of about 1 m, while maintaining the shielding element weight within acceptable limits and, in such way, to overcome the insufficient shielding action detected in the regions at which the prior art tapes wound in a spiral manner overlap. According to a preferred embodiment, the flanges may be provided on the cover instead of on the base. In such a case, the cover comprises a main wall and a pair of flanges extending from the main wall in a predetermined direction, preferably in a direction substantially perpendicular to the main wall. In this way, it is advantageously ensured an improved closure of the shielding element, and an ensuing improved effectiveness of the shielding action of the magnetic field generated by the transmission line. According to such embodiment, the corners defined between the main wall of the cover and the flanges may be sharp or bevelled, preferably according to a bending radius equal to about half the outer diameter of the cable or cables housed within the shielding element. Preferably, the base and the cover of the shielding element comprise walls having a thickness comprised between about 0.10 mm and about 0.60 mm and, still more preferably, comprised between about 0.20 mm and about 0.35 mm. Such values of thickness advantageously allow to manufacture a transmission line in which the shielding element has an advantageously limited weight, which allows in turn to limit the costs imputable to the use of the ferromagnetic material. The cover may have a thickness which is lower than the thickness of the base, because the cover, which is positioned farther from the cables with respect to the base, is crossed by a lower magnetic flow with respect to the magnetic flow crossing the base. As an illustrative example, the cover may have a thickness between about 0.10 and about 0.50 mm and the base may have a thickness between about 0.20 and about 0.60 mm. Preferably, the base and the cover of the shielding element comprise respective sides reciprocally superimposed for a portion of predetermined length in lateral direction. In the present direction and in the following claims, the term “sides” of the base or of the cover of the shielding element is used to indicate the lateral portions of the base or, respectively, of the cover, which are opposite with respect to the longitudinal axis of the shielding element. According to a preferred embodiment of the electrical power transmission line of the invention, a material having a permeability greater than air, such as for example a magnetic rubber, is interposed at the superimposed sides of the base and of the cover. In this way, the gap between the base and the cover at the region in which the cover leans onto the base is substantially closed, with advantageous further attenuation of the magnetic field generated by the cable. Preferably, the base and the cover of the shielding element comprise respective walls having a rolling direction substantially perpendicular to the axis of the at least one cable. In this way, an improved shielding effect of the magnetic field is advantageously achieved. According to an alternative embodiment, the base and the cover of the shielding element comprise respective walls having a rolling direction substantially parallel to the axis of the at least one cable. According to a preferred embodiment, the shielding element comprises a plurality of shielding modules arranged side by side, each of these shielding modules comprising a modular base and a modular cover. A configuration of the modular type of the shielding element advantageously facilitates both the installation operations of the electrical power transmission line and the subsequent maintenance operations, in particular the replacement of damaged sections of the shielding element. Preferably, such shielding modules are longitudinally superimposed for a portion of predetermined length, preferably comprised between 25% and 100% of the width of the shielding element. Preferably, each modular base has a frustoconical longitudinal section so as to facilitate the partial longitudinal superimposition between adjacent modular bases and to form, in such way, a substantially continuous shielding element. In the case of this embodiment, the modular bases and covers are preferably produced by stamping. According to an alternative embodiment of the transmission line of the invention, when the shielding modules are not reciprocally superimposed, but just reciprocally arranged side by side, the shielding element further comprises a respective connecting element made of ferromagnetic material for connecting such modules arranged side by side. In this way, the connecting element has shielding properties substantially analogous to the properties of a substantially continuous shielding element. In the case of the latter embodiment the modular bases and covers may be conveniently manufactured by extrusion, which advantageously results in a reduction in manufacturing costs. According to a preferred embodiment, in each of said shielding modules, the modular base and the modular cover are reciprocally staggered in longitudinal direction by a predetermined distance, preferably equal to the length of the above-mentioned portion of longitudinal superimposition of the shielding modules. Preferably, the modular base is coupled to a supporting element. Preferably, each wall of the modular base is coupled to respective supporting elements. In this way, supporting elements of limited size and, as such, easily transportable and applicable to the shielding element, are advantageously used. More preferably, both the modular base and the modular cover are coupled to respective supporting elements. According to a preferred embodiment of the power transmission line of the invention, at least two adjacent shielding modules extend along different directions, the shielding element further comprising a respective connecting element made of ferromagnetic material for connecting these at least two adjacent modules. In this way, it is advantageously possible to manufacture lines provided with curved sections, elbows and similar sections. In order to form such curved sections, the modular bases may be shaped in a substantially rectangular form and advantageously produced by extrusion, in which case the curved sections may be laid out by reciprocally angulating at least two adjacent modular bases in such a manner that the adjoining sides of such adjacent bases define a substantially triangular free space therebetween or, alternatively, the modular bases may be shaped in a such a manner that the adjoining sides of such adjacent bases are substantially parallel so as to minimize such free space. According to a preferred embodiment, the ferromagnetic material of which the at least one shielding element is made has a maximum value of relative magnetic permeability μ max greater than about 20000. The use of at least one shielding element made of ferromagnetic material having a maximum value of relative magnetic permeability greater than such numerical value advantageously allows to minimize the magnetic losses unavoidably present in the base and in the cover of the shielding element. More preferably, the ferromagnetic material has a maximum value of relative magnetic permeability μ max comprised between about 20000 and about 60000 and, still more preferably, a maximum value of relative magnetic permeability μ max equal to about 40000, with advantageous further reduction of the magnetic losses. Moreover, the use of materials having said ferromagnetic characteristics allows to use a more limited thickness of the shielding element with respect to the prior art lines, with advantageous reduction of the line weight. The electrical power transmission line may comprise two shielding elements, preferably having a controlled magnetic permeability, i.e. preferably reciprocally coupled so as to form a first radially inner layer made of a first ferromagnetic material and a second radially outer layer made of a second ferromagnetic material. Preferably, the first ferromagnetic material has a maximum value of relative magnetic permeability greater than the maximum value of relative magnetic permeability of the second ferromagnetic material. In the case in which the line comprises two shielding elements having a controlled magnetic permeability, the maximum value of relative magnetic permeability of the radially inner layer is preferably equal to about 40000, and the maximum value of relative magnetic permeability of the material of the radially outer layer is preferably equal to about 3000. Preferably, the ferromagnetic material is selected from the group comprising: grain oriented silicon steel, non-grain oriented silicon steel, Permalloy®, Supermalloy®. The Permalloy® and the Supermalloy® are nickel-iron-molybdenum alloys having a high nickel content (equal to about 80%), in which the molybdenum content is comprised between 4 and 5% and, respectively, is greater than 5%, both alloys being manufactured by Western Electric Company, Georgia, USA. Alloys having magnetization curves similar to the magnetization curves of these alloys may also be used. When silicon steel is used, whether grain oriented or not, thanks to the presence of the silicon, on the one hand the value of the losses determined by the hysteresis cycle present in the ferromagnetic material is advantageously reduced to a considerable extent and, on the other hand, the electrical conductivity of the steel is advantageously reduced, which also allows to reduce the losses due to eddy currents. Thanks to this double beneficial effect, the power transmission capacity of a line shielded by a shielding element made of silicon steel is advantageously improved. As an illustrative example, with a current equal to about 400 A, three cables having a diameter of about 100 mm arranged according to a trefoil arrangement of the closed type within a shielding element made of grain oriented silicon steel having a thickness of about 0.27 mm placed about 1.4 m below the ground level, the magnetic field induction is equal to about 0.2 μT at the ground level As to the losses due to eddy currents and the losses due to magnetic hysteresis, both losses, at the above-mentioned values of thickness of the shielding element, trench depth and magnetic induction, are equal to about 1.7·10 6 Siemens m and, respectively, equal to about 1.1 W/kg at a magnetization level of about 1.5 T at 50 cycles per second. Among the different types of grain oriented silicon steels, the steel referred to as M4T27 according to the AST standard is particularly preferred. According to a preferred embodiment of the power transmission line of the invention, the silicone content is comprised between about 1% and about 5% and, more preferably, between about 3% and about 4%. Advantageously, within this preferred range of values, the electrical conductivity of the silicon steel is further reduced, allowing in such way a further corresponding reduction of the losses due to eddy currents. According to a preferred embodiment of the line of the invention, the base and the cover of the shielding element may be made of different materials, preferably using a poorer material, i.e. a material having a lower maximum value of relative magnetic permeability, for the cover, since the latter is crossed by a lower magnetic field flow with respect to the base. Preferably, the base is made of a first ferromagnetic material having a maximum value of relative magnetic permeability greater than about 40 and the cover is made of a second ferromagnetic material having a maximum value of relative magnetic permeability greater than about 20. Preferably, the line of the invention, in addition to at least one supporting element coupled to the base of the shielding element, further comprises a supporting element coupled to the cover of the shielding element. According to a preferred embodiment of the electrical power transmission line of the invention, the above-mentioned at least one supporting element coupled to the base and optionally also to the cover of the shielding element is arranged in a radially outer position with respect to the above-mentioned at least one shielding element. In this way, the mechanical resistance conferred to the cable is advantageously further improved. According to an alternative embodiment, the at least one supporting element is arranged in a radially inner position with respect to the at least one shielding element. In this way, it is advantageously possible to exploit the presence of the supporting element for supporting, in addition to the shielding element, also a plurality of cables maintained in a desired spatial configuration. According to an alternative embodiment, the at least one shielding element is interposed between a pair of supporting elements. In this way, the above-mentioned advantages correlated to an improved mechanical resistance and to the possibility of maintaining a plurality of cables in a desired spatial configuration can be simultaneously achieved. According to a preferred embodiment, the at least one supporting element is substantially flat. In this way, one or more supporting elements may be easily coupled to the base and optionally also to the cover of the shielding element, preferably according to one of the following ways. According to a first way, the at least one supporting element is firstly coupled to the base and optionally also to the cover of the shielding element by means of glue, and subsequently the at least one supporting element and the shielding element so coupled are shaped according to the desired geometry. For example, the base of the shielding element associated with the respective supporting element may be shaped in the form of a U-shaped cross-section, preferably provided with lateral flanges, by longitudinally hot-bending the base and respective supporting element coupled thereto at four points. When the cover is provided with a pair of flanges, at least one supporting element, for example in the form of a flat plate, is firstly coupled to the cover, for example in the form of a flat plate as well and, subsequently, the at least one supporting element and the cover so coupled are longitudinally hot-bent at two points. According to a second way, the at least one supporting element is manufactured by extrusion and coupled to the base of the shielding element, and optionally also to the cover, which are both manufactured by stamping. The coupling may be carried out by means of glue or by means of a plurality of fixing means, described in greater detail in the following, longitudinally arranged at predetermined distances from each other. According to a third way, both the at least one supporting element and the base and cover of the shielding element are manufactured by stamping and subsequently coupled by means of glue or by means of a plurality of fixing means. According to an additional way, the base of the shielding element comprises three sheets advantageously manufactured by extrusion, which are coupled, for example by means of glue, to respective walls of a substantially U-shaped supporting element. According to a preferred embodiment of the power transmission line of the invention, the at least one supporting element comprises a wall having a thickness equal to about 2-10 mm and, still more preferably, equal to about 3-5 mm. According to a preferred embodiment of the power transmission line of the invention, the at least one supporting element is made of an electrically non-conductive and non-ferromagnetic material. Preferably, the electrically non-conductive and non-ferromagnetic material of which the at least one supporting element may be made is selected from the group comprising: plastics materials, cement, terracotta, carbon fibres, glass fibres, wood or other materials able to exert an advantageous supporting function while being advantageously produced by means of simple low cost technologies. Still more preferably, said plastics materials are selected from the group comprising: polyethylene (PE), low-density polyethylene (LPDE), medium-density polyethylene (MPDE), high-density polyethylene (HPDE), linear low-density polyethylene (LLPDE), polypropylene (PP), ethylene/propylene elastomer copolymers (EPM), ethylene/propylene/diene terpolymers (EPDM), natural rubber, butyl rubber, ethylene/vinyl copolymers (such as for example ethylene/vinyl acetate (EVA)), ethylene/acrylate copolymers (such as for example ethylene/methyl acrylate (EMA), ethylene/ethyl acrylate (EEA), ethylene/butyl acrylate (EBA)), ethylene/α-olefin thermoplastic copolymers, polystyrene, acrylonitriletbutadiene/styrene resins (ABS), halogenated polymers (such as for example polyvinyl chloride (PVC)), polyurethane (PUR), polyamides, aromatic polyesters (such as for example polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)). Alternatively, the supporting element may be made of a ferromagnetic or metallic material. Materials of such type, although causing weak magnetic losses, are advantageous in terms of stampability, thus facilitating the coupling between the supporting element and the shielding element. Preferably, the shielding element further comprises a plurality of fixing means, such as for example in the form of hooks made for example of a plastics material. When the at least one supporting element is electrically conductive, or when the same is electrically non-conductive but does not completely cover the portions of the base and the cover intended to be superimposed, the fixing means are preferably made of metal, so as to ensure an electrical continuity between the base and the cover. Preferably, the fixing means are longitudinally arranged at predetermined distances so as to fix the cover onto the base. The fixing means advantageously allow to improve the coupling stability between the base and the cover of the shielding element. As an alternative to the hooks, plastic or metal clips or binder spines or other fixing means suitable for this aim may be used. Preferably, the fixing means are arranged in pairs, wherein each pair comprises fixing elements arranged on opposite sides with respect to the longitudinal axis of the shielding element. According to a further embodiment, the base and cover may be reciprocally associated, for example by means of a longitudinal hinge, so as to simplify the laying operations and to improve the coupling precision between the two parts. According to a preferred embodiment of the power transmission line of the invention, the fixing means are arranged in a plurality of pairs positioned along the sides of the shielding element at a predetermined reciprocal distance, preferably comprised between about 20 and about 100 cm. According to a second aspect thereof, the present invention refers to a method for shielding the magnetic field generated by an electrical power transmission line comprising at least one electrical cable, the method comprising the steps of: providing at least one shielding element made of at least one ferromagnetic material for shielding the magnetic field generated by the at least one electrical cable, the shielding element comprising a base and a cover; coupling at least one supporting element to at least the above-mentioned base; laying the at least one electrical cable into the base of the shielding element; and leaning the cover onto the base so as to substantially close the shielding element. Thanks to these steps, the method according to the invention allows an easy and rapid installation of a shielded electrical power transmission line, particularly in the case in which the line is placed underground. In a similar manner, any maintenance interventions which may be necessary subsequently to the installation are facilitated. According to a preferred embodiment of the method of the invention, the ferromagnetic material is selected from the group comprising: grain oriented silicon steel, non-grain oriented silicon steel, Permalloy®, Supermalloy®, these last two alloys being manufactured by Western Electric Company. When the ferromagnetic material is a grain oriented material, the step of providing the shielding element preferably includes the arrangement of the walls of the base and of the cover according to a configuration such that the rolling direction of these is substantially perpendicular to the axis of the at least one cable. Preferably, the step of providing the shielding element includes the arrangement side by side and the partial superimposition in longitudinal direction of a plurality of shielding modules comprising respective modular bases and modular covers. According to a preferred embodiment of the method of the invention, the shielding modules are reciprocally superimposed in longitudinal direction for a portion having a predetermined length, preferably comprised between 25% and 100% of the width of the shielding element. Preferably, the method of the invention further comprises the step of staggering, in each of the above-mentioned plurality of shielding modules, the modular base with respect to the modular cover in longitudinal direction by a predetermined distance. According to a preferred embodiment of the method of the invention, in order to form curved sections, at least two adjacent shielding modules are laid along different directions, and are then connected by means of a respective connecting element made of ferromagnetic material. When the cables are in number of three, the method of the invention preferably comprises the step of arranging such cables according to a trefoil arrangement, preferably of the closed type as described above. Preferably, the above-mentioned step of leaning the cover onto the base of the shielding element comprises the step of superimposing the respective sides of the base and the cover for a portion of predetermined length in lateral direction. According to a preferred embodiment, the method of the invention includes the step of coupling at least one supporting element also to the cover of the shielding element. Preferably, the step of coupling the at least one supporting element to the base and optionally also to the cover of the shielding element includes the arrangement of the supporting element in a radially outer position with respect to the base and optionally also to the cover. According to an alternative embodiment of the invention, the step of coupling the at least one supporting element to the base and optionally also to the cover of the shielding element includes the arrangement of the supporting element in a radially inner position with respect to the shielding element and optionally to the base. According to a further alternative embodiment of the method of the invention, the step of coupling the at least one supporting element to the base and optionally also to the cover of the shielding element includes the interposition of the base and optionally also of the cover between a pair of respective supporting elements. According to a preferred embodiment of the method of the invention, this further comprises the step of placing underground the electrical power transmission line. Preferably, the method comprises the further step of arranging a plurality of fixing means, preferably in the form of hooks, longitudinally at predetermined distances from each other so as to fix the cover onto said base. Preferably, such step of arranging the fixing means includes the arrangement of the fixing means in pairs, wherein each pair comprises fixing elements arranged on opposite sides with respect to the longitudinal axis of the shielding element. Preferably, such hooks are arranged in a plurality of pairs positioned along the sides of the shielding element at a predetermined reciprocal longitudinal distance, comprised between about 20 and about 100 cm.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Additional features and advantages of the invention will become more readily apparent from the description of some embodiments of a method for shielding the magnetic field generated by an electrical power transmission line according to the invention, made in the following with reference to the attached drawing figures in which, for illustrative and non-limiting purposes, an electrical power transmission line so shielded is shown. In the drawings: FIG. 1 is a perspective view of an electrical power transmission line shielded according to a first preferred embodiment of the invention; FIG. 2 is a cross-sectional view of the line shown in FIG. 1 ; FIG. 3 is a top view of two curved sections of the line of FIG. 1 ; FIG. 4 is a cross-sectional view of a second preferred embodiment of the electrical power transmission line according to the invention; FIG. 5 is a cross-sectional view of a further preferred embodiment of the electrical power transmission line according to the invention; FIG. 6 is a side view, in partial cross-section, of a further preferred embodiment of the electrical power transmission line according to the invention; FIG. 7 is an enlarged view of the detail marked with a circle in FIG. 6 ; FIG. 8 is a schematic top view of a further preferred embodiment of the electrical power transmission line according to the invention; FIGS. 9-11 show results of experimental tests. detailed-description description="Detailed Description" end="lead"?

20060707

20091124

20070628

57513.0

H01B1102

NGUYEN, CHAU N

METHOD FOR SHIELDING THE MAGNETIC FIELD GENERATED BY AN ELECTRICAL POWER TRANSMISSION LINE AND ELECTRICAL POWER TRANSMISSION LINE SO SHIELDED

UNDISCOUNTED

ACCEPTED

H01B

ACCEPTED

Backside-illuminated photodetector and method for manufacturing same

The present invention provides a back illuminated photodetector having a sufficiently small package as well as being capable of suppressing the scattering of to-be-detected light and method for manufacturing the same. A back illuminated photodiode 1 comprises an N-type semiconductor substrate 10, a P+-type impurity semiconductor region 11, a recessed portion 12, and a window plate 13. In the surface layer on the upper surface S1 side of the N-type semiconductor substrate 10 is formed the P+-type impurity semiconductor region 11. In the rear surface S2 of the N-type semiconductor substrate 10 and in an area opposite the P+-type impurity semiconductor region 11 is formed the recessed portion 12 that functions as an incident part for to-be-detected light. Also, the window plate 13 is bonded to the outer edge portion 14 of the recessed portion 12. The window plate 13 covers the recessed portion 12 and seals the rear surface S2 of the N-type semiconductor substrate 10.

1. A back illuminated photodetector comprising: a first conductive type semiconductor substrate; a second conductive type impurity semiconductor region provided in the first superficial surface layer of the semiconductor substrate; a recessed portion for incidence of to-be-detected light formed in the second surface of the semiconductor substrate and in an area opposite the impurity semiconductor region; and a window plate bonded to the outer edge portion of the recessed portion in such a manner as to cover the recessed portion to transmit the to-be-detected light. 2. The back illuminated photodetector according to claim 1, further comprising a supporting film provided on the first surface of the semiconductor substrate to support the semiconductor substrate. 3. The back illuminated photodetector according to claim 2, further comprising a filling electrode penetrating through the supporting film and connected electrically to the impurity semiconductor region at one end thereof. 4. The back illuminated photodetector according to claim 1, wherein the window plate is made of an optically transparent material and is bonded to the outer edge portion by anodic bonding. 5. The back illuminated photodetector according to claim 4, wherein the optically transparent material is quartz, and wherein the window plate is bonded to the outer edge portion via a member containing alkali metal. 6. The back illuminated photodetector according to claim 1, wherein the window plate is bonded to the outer edge portion via a metal layer. 7. The back illuminated photodetector according to claim 1, wherein a stepped portion is formed in a side surface of the semiconductor substrate or in a side surface of the window plate. 8. The back illuminated photodetector according to claim 1, wherein a highly-doped impurity semiconductor layer with impurities of the first conductive type added thereto at a high concentration is provided in the second superficial surface layer in the outer edge portion of the semiconductor substrate. 9. The back illuminated photodetector according to claim 1, wherein a highly-doped impurity semiconductor layer with impurities of the first conductive type added thereto at a high concentration is provided in the bottom portion of the recessed portion within the second superficial surface layer of the semiconductor substrate. 10. The back illuminated photodetector according to claim 1, wherein a highly-doped impurity semiconductor region with impurities of the first conductive type added thereto at a high concentration is exposed across the entire side surface of the semiconductor substrate. 11. The back illuminated photodetector according to claim 1, wherein the window plate has a square cross-sectional shape with at least one corner being chamfered in a plane perpendicular to the thickness direction thereof. 12. A method for manufacturing a back illuminated photodetector comprising: a impurity semiconductor region forming step of forming a second conductive type impurity semiconductor region in the first superficial surface layer of a first conductive type semiconductor substrate; a recessed portion forming step of forming a recessed portion for incidence of to-be-detected light in the second surface of the semiconductor substrate and in an area opposite the impurity semiconductor region; and a window plate bonding step of bonding a window plate for transmitting the to-be-detected light to the outer edge portion of the recessed portion in such a manner as to cover the recessed portion. 13. The method for manufacturing a back illuminated photodetector according to claim 12, wherein the window plate is made of an optically transparent material, and wherein in the window plate bonding step, the window plate is bonded to the outer edge portion by anodic bonding. 14. The method for manufacturing a back illuminated photodetector according to claim 12, wherein in the window plate bonding step, the window plate is bonded to the outer edge portion via a metal layer. 15. The method for manufacturing a back illuminated photodetector according to 12, wherein in the impurity semiconductor region forming step, a plurality of the impurity semiconductor regions are formed; in the recessed portion forming step, a plurality of the recessed portions are formed, respectively, for the plurality of impurity semiconductor regions; and in the window plate bonding step, the window plate is bonded to the outer edge portion in such a manner as to cover the plurality of recessed portions, the method further comprising a dicing step of performing a plurality of dicing steps from the first surface of the semiconductor substrate to the surface of the window plate so that a plurality of pairs of the impurity semiconductor regions and the recessed portions provided opposite the respective impurity semiconductor regions are divided into respective pairs.

TECHNICAL FIELD The present invention relates to a back illuminated photodetector and method for manufacturing the same. BACKGROUND ART In such a conventional back illuminated photodiode 100 as shown in FIG. 69, in the superficial surface layer of an N-type silicon substrate 101 are formed a P+-type highly-doped impurity semiconductor region 102 and an N+-type highly-doped impurity semiconductor region 103. The P+-type highly-doped impurity semiconductor region 102 and the N+-type highly-doped impurity semiconductor region 103 are connected, respectively, with an anode electrode 104 and a cathode electrode 105. On the electrodes 104 and 105 are formed bump electrodes 106 made from solder. Also, the N-type silicon substrate 101 is thinned in the portion corresponding to the P+-type highly-doped impurity semiconductor region 102 from the rear surface side thereof. The thinned portion functions as an incident part for to-be-detected light. As shown in FIG. 69, the back illuminated back illuminated photodiode 100 is packed into a ceramic package 107 by flip-chip bonding. That is, the bump electrodes 106 of the back illuminated photodiode 100 are connected to solder pads 109 provided on a bottom wiring 108 of the ceramic package 107. The bottom wiring 108 is connected to output terminal pins 110 through wire bonding. Also, on the surface of the ceramic package 107 is seam-welded a window frame 111 using brazing material 112. In the window frame 1l is formed an opening at the position corresponding to the thinned portion of the back illuminated photodiode 100, and in the opening is provided a transparent window member 113 such as kovar glass for transmitting to-be-detected light. Patent Document 1: Japanese Published Unexamined Patent Application No. H09-219421 DISCLOSURE OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION However, in such an arrangement of using a ceramic package in a back illuminated photodiode as above, there is a problem in that the package becomes larger. Meanwhile, in Patent Document 1 is disclosed a CSP (Chip Size Package) technique for semiconductor electronic components. This technique is adapted to seal the both surfaces of a wafer with semiconductor electronic components built therein using organic material such as resin, and then to form an opening in the organic material provided on one surface side of the wafer by photolithography to form electrodes therein. Although it can be considered to apply such a CSP technique to a back illuminated photodiode to reduce the package size, there occurs the following problem in this case. That is, in the case of a back illuminated photodiode with the rear surface being sealed with resin, the resin surface functions as an incident plane for to-be-detected light. However, it may be difficult to flatten the resin surface sufficiently on the order of the wavelength of the to-be-detected light. Unless the resin surface is flattened sufficiently, the incident plane for to-be-detected light remains rough, resulting accordingly in a problem in that the to-be-detected light may be scattered at the incident plane. Then, the scattering of to-be-detected light also leads to a reduction in the sensitivity of the back illuminated photodiode. The present invention has been made to solve the above-described problems, and an object thereof is to provide a back illuminated photodetector having a sufficiently small package as well as being capable of suppressing the scattering of to-be-detected light and method for manufacturing the same. Means for Solving the Problems The present invention is directed to a back illuminated photodetector comprising: a first conductive type semiconductor substrate; a second conductive type impurity semiconductor region provided in the first superficial surface layer of the semiconductor substrate; a recessed portion for incidence of to-be-detected light formed in the second surface of the semiconductor substrate and in an area opposite the impurity semiconductor region; and a window plate bonded to the outer edge portion of the recessed portion in such a manner as to cover the recessed portion to transmit the to-be-detected light. In the back illuminated photodetector, the window plate is bonded to the outer edge portion of the semiconductor substrate. This eliminates the use of an external package such as a ceramic package, whereby it is possible to obtain a chip-sized back illuminated photodetector. Accordingly, it is possible to achieve a back illuminated photodetector having a sufficiently small package. Further, in the back illuminated photodetector, the surface of the window plate functions as an incident plane for to-be-detected light. Since the surface of the window plate can be flattened more easily than resin, it is possible to suppress the scattering of to-be-detected light at the incident plane. The back illuminated photodetector preferably comprises a supporting film provided on the first surface of the semiconductor substrate to support the semiconductor substrate. In this case, the mechanical strength of the back illuminated photodetector can be increased. The back illuminated photodetector preferably comprises a filling electrode penetrating through the supporting film and connected electrically to the impurity layer at one end thereof. In this case, it is possible to take a detected signal easily outside the back illuminated photodetector. It is preferred that the window plate is made of an optically transparent material and is bonded to the outer edge portion by anodic bonding. In this case, it is possible to bond the window plate and the outer edge portion solidly at the interface therebetween. It is preferred that the optically transparent material is quartz, and that the window plate is bonded to the outer edge portion via glass containing alkali metal and formed on the window plate. In this case, since quartz has an especially high transmissivity for visible light and UV light, the sensitivity of the back illuminated photodetector can be increased. Also, alkali metal, for example, Pyrex (registered trademark) glass can be cited, which ensures solid anodic -bonding between the window plate made of quartz and the outer edge-portion. It is preferred that the window plate is bonded to the outer edge portion via a metal layer. In this case, the window plate and the outer edge portion can be bonded solidly by metal bonding. The back illuminated photodetector may be characterized in that a stepped portion is formed in a side surface, of the semiconductor substrate or in a side surface of the window plate. The stepped portion can be formed by performing a plurality of dicing steps and using a blade having a different thickness in each step. Performing a plurality of dicing steps allows the semiconductor substrate and the window plate having their respective different hardnesses to be diced using a blade suitable for each thereof. It is therefore possible to prevent chipping at the interface between the semiconductor substrate and the window plate in a dicing operation. It is preferred that a highly-doped impurity semiconductor layer with impurities of the first conductive type added thereto at a high concentration is provided in the second superficial surface layer in the outer edge portion of the semiconductor substrate. In this case, even if there may be crystal defects in the vicinity of the second superficial surface in the outer edge portion, the provided highly-doped impurity semiconductor layer can suppress dark current and/or noise caused by unnecessary carriers due to the crystal defects. It is preferred that a highly-doped impurity semiconductor layer with impurities of the first conductive type added thereto at a high concentration is provided in the bottom portion of the recessed portion within the second superficial surface layer of the semiconductor substrate. The highly-doped impurity semiconductor layer functions as an accumulation layer. This allows carriers generated upon incidence of to-be-detected light to be guided to the PN junction effectively by the electric field distribution in the layer, resulting in an increase in sensitivity. It is preferred that a highly-doped impurity semiconductor region with impurities of the first conductive type added thereto at a high concentration is exposed across the entire side surface of the semiconductor substrate. In this case, even if a side surface of the semiconductor substrate may be damaged mechanically through dicing, etc., the provided highly-doped impurity semiconductor region can suppress dark current and/or noise caused by unnecessary carriers that are generated in the vicinity of the side surface of the semiconductor substrate. It is preferred for the back illuminated photodetector that the window plate has a square cross-sectional shape with at least one corner being chamfered in a plane perpendicular to the thickness direction thereof. In this case, it is possible to prevent chipping when dicing the back illuminated photodetector. A method for manufacturing a back illuminated photodetector according to the present invention is characterized by comprising a impurity semiconductor region forming step of forming a second conductive type impurity semiconductor region in the first superficial surface layer of a first conductive type semiconductor substrate; a recessed portion forming step of forming a recessed portion for incidence of to-be-detected light in the second surface of the semiconductor substrate and in an area opposite the impurity semiconductor region; and a window plate bonding step of bonding a window plate for transmitting the to-be-detected light to the outer edge portion of the recessed portion in such a manner as to cover the recessed portion. In accordance with the manufacturing method above, the window plate is bonded to the outer edge portion of the semiconductor substrate in the window plate bonding step. This eliminates the use of an external package such as a ceramic package, whereby it is possible to obtain a chip-sized back illuminated photodetector. In accordance with the present manufacturing method, it is therefore possible to achieve a back illuminated photodetector having a sufficiently small package. It is preferred that the window plate is made of an optically transparent material, and in the window plate bonding step, the window plate is bonded to the outer edge portion by anodic bonding. In this case, it is possible to bond the window plate and the outer edge portion solidly at the interface therebetween. It is preferred that in the window plate bonding step, the window plate is bonded to the outer edge portion via a metal layer. In this case, the window plate and the outer edge portion can be bonded solidly by metal bonding. It is preferred that in the impurity semiconductor region forming step, a plurality of the impurity semiconductor regions are formed; in the recessed portion forming step, a plurality of the recessed portions are formed, respectively, for the plurality of impurity semiconductor regions; and in the window plate bonding step, the window plate is bonded to the outer edge portion in such a manner as to cover the plurality of recessed portions, and that the method further comprises a dicing step of performing a plurality of dicing steps from the first surface of the semiconductor substrate to the surface of the window plate so that a plurality of pairs of the impurity semiconductor regions and the recessed portions provided opposite the respective impurity semiconductor regions are divided into respective pairs. In this case, it is possible to dice, the semiconductor substrate and the window plate in different steps separately. This allows the semiconductor substrate and the window plate having their respective different hardnesses to-be diced using a blade suitable for each thereof. It is therefore possible to prevent chipping at the interface between the semiconductor substrate and the window plate in a dicing operation. Additionally, “dicing from the first surface of the semiconductor substrate to the surface of the window plate” shall not restrict the direction of dicing. That is, in the dicing step, the semiconductor substrate may be diced from the first to the second surface side, or from the second to the first surface side. EFFECTS OF THE INVENTION In accordance with the present invention, it is possible to achieve a back illuminated photodetector having a sufficiently small package as well as being capable of suppressing the scattering of to-be-detected light and method for manufacturing the same. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a cross-sectional view showing a first embodiment of a back illuminated photodetector according to the present invention. FIG. 2 is a perspective view of the back illuminated photodiode 1 shown in FIG. 1. FIG. 3 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 4 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 5 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 6 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 7 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 8 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 9 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 10 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG 1. FIG. 11 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 12 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 13 is a step chart showing a method for manufacturing the back illuminated photodiode. 1 shown in FIG. 1. FIG. 14 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 15 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 16 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 17 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1. FIG. 18 is a view illustrating an exemplary variation of the dicing step shown in FIG. 16. FIG. 19 is a: cross-sectional view showing an exemplary structure of a back illuminated photodiode obtained through the dicing step illustrated in FIG. 18. FIG. 20 is a cross-sectional view showing- an exemplary structure of a back illuminated photodiode obtained through the dicing step illustrated in FIG. 18. FIG. 21 is a cross-sectional view showing an exemplary structure of a back illuminated photodiode obtained through the dicing step illustrated in FIG. 18. FIG. 22 is a cross-sectional view showing an exemplary structure of a back illuminated photodiode obtained through the dicing step illustrated in FIG. 18. FIG. 23 is a cross-sectional view showing a first exemplary variation of the back illuminated photodiode 1 shown in FIG. 1. FIG. 24 is a cross-sectional view showing a second exemplary variation of the back illuminated photodiode 1 shown in FIG. 1. FIG. 25 is a perspective view showing a third exemplary variation of the back illuminated photodiode 1 shown in FIG. 1. FIG. 26 is a plan view showing the appearance of the wafer of the back illuminated photodiode 1 shown in FIG. 1 before dicing when viewed from the side of the window plate 13. FIG. 27 is a plan view showing the appearance of the wafer of the back illuminated photodiode 1c shown in FIG. 25 before dicing when viewed from the side of the window plate 13. FIG. 28 is a cross-sectional view showing a second embodiment of a back illuminated photodetector according to the present invention. FIG. 29 is a view illustrating an exemplary method of forming the N+-type highly-doped impurity semiconductor region 28 shown in FIG. 28. FIG. 30 is a view illustrating an exemplary method of forming the N+-type highly-doped impurity semiconductor region 28 shown in FIG. 28. FIG. 31 is a view illustrating an exemplary method of forming the N+-type highly-doped impurity semiconductor region 28 shown in FIG. 28. FIG. 32 is a plan view showing a third embodiment of a back illuminated photodetector according to the present invention. FIG. 33 is a cross-sectional view of the back illuminated photodiode array 3 shown in FIG. 32 along the line XX-XX.: FIG. 34 is a cross-sectional view showing an exemplary variation of the back illuminated photodiode array 3 shown in FIG. 33. FIG. 35 is a cross-sectional view showing a fourth embodiment of a back illuminated photodetector according to the present invention. FIG. 36 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG 35. FIG. 37 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG 35. FIG. 38 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35. FIG. 39 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35. FIG. 40 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35. FIG. 41 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35. FIG. 42 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35. FIG. 43 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35. FIG. 44 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35. FIG. 45 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35. FIG. 46 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35. FIG. 47 is a cross-sectional view showing a fifth embodiment of a back illuminated photodetector according to the present invention. FIG. 48 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47. FIG. 49 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47. FIG. 50 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47. FIG. 51 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47. FIG. 52 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47. FIG. 53 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47. FIG. 54 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47. FIG. 55 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47. FIG. 56 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47. FIG. 57 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47. FIG. 58 is a cross-sectional view showing a sixth embodiment of a back illuminated photodetector according to the present invention. FIG. 59 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58. FIG. 60 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58. FIG. 61 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58. FIG. 62 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58. FIG. 63 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58. FIG. 64 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58. FIG. 65 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58. FIG. 66 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58. FIG. 67 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58. FIG. 68 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58. FIG. 69 is a cross-sectional view of a conventional back illuminated photodiode. Description of Symbols 1; 1a; 1b; 1c; 2; 4; 5 and 6: Back illuminated photodiodes, 3 and 3a: Back illuminated photodiode arrays, 10; 20 and 50: N-type semiconductor substrates, 11 and 51: P+-type impurity semiconductor regions, 12 and 52: Recessed portions, 13 and 53: Window plates, 13a: Chamfered portion, 13b: Hole portion, 14 and 54: Outer edge portions, 15 and 55: Resin layers, 16: Pyrex glass, 17a and 17b: Metal layers, 18: Intermediate metal layer, 21 and 61: N+-type highly-doped impurity semiconductor layers, 22; 28 and 62: N+-type highly-doped impurity semiconductor regions, 23; 24; 63 and 64: Insulating films, 25 and 65: Anode electrodes, 26 and 66: Cathode electrodes, 31 and 71: Passivating films, 32 and 72: Supporting films, 33a; 33b; 73aand 73b: Filling electrodes, 34a; 34b; 74a and 74b : UBMs, 35a; 35b; 75a and 75b : Bumps, S1: Upper surface, S2: Rear surface, S3: Bottom surface of recessed portion, S4: Side surface of the N-type semiconductor substrate BEST MODE FOR CARRYING OUT THE INVENTION Preferred embodiments of a back illuminated photodetector and method for manufacturing the same according to the present invention will hereinafter be described in detail with reference to the accompanying drawings. Additionally, in the descriptions of the drawings, identical components are designated by the same reference numerals to omit redundant description. Also, the dimensional ratios in the drawings do not necessarily correspond to those in the descriptions. FIG. 1 is a cross-sectional view showing a first embodiment of a back illuminated photodetector according to the present invention. The back illuminated photodiode 1 is adapted to receive to-be-detected light through the rear surface thereof, to generate carriers upon incidence of the to-be-detected light, and then to output the generated carriers as a detected signal via the superficial surface thereof. The back illuminated photodiode 1 comprises an N-type semiconductor substrate 10, a P+-type impurity semiconductor region 11, a recessed portion 12, and a window plate 13. As the N-type semiconductor substrate 10, for example, a silicon substrate with N-type impurities such as phosphorous added thereto can be used. The impurity concentration of the N-type semiconductor substrate 10 is 1012 to 1015/cm3, for example. Also, the thickness t1 of the N-type semiconductor substrate 10 is 200 to 500 μm, for example. In the surface layer on the upper surface (first surface) SI side of the N-type semiconductor substrate 10 is partially-formed the P+-type impurity semiconductor region 11. The P+-type impurity semiconductor region 11 is provided with P-type impurities such as boron to form a PN junction with the N-type semiconductor substrate 10. The impurity concentration of the P+-type impurity semiconductor region 11 is 1015 to 1020/cm3, for example. Also, the depth of the P+-type impurity semiconductor region 11 is 0.1 to 20 μm, for example. In the rear surface (second surface) S2 of the N-type semiconductor substrate 10 and in an area opposite the P+-type impurity semiconductor region 11 is formed the recessed portion 12. The recessed portion 12 functions as an incident part for to-be-detected light. The recessed portion 12 has a shape that narrows gradually from the rear surface S2 to the upper surface S1. More specifically, the recessed portion 12 may have, for example, a square pyramid shape or a tapered shape that narrows gradually from the rear surface S2 to the upper surface S1. The depth of the recessed portion 12 is 2 to 400 μm, for example. Also, due to the thus formed recessed portion 12, the area between the bottom surface S3 of the recessed portion and the P+-type impurity semiconductor region 11 within the N-type semiconductor substrate 10 is made thinner than the other areas so that carriers generated upon incidence of to-be-detected light via the rear surface S2 can easily reach near the P+-type impurity semiconductor region 11 provided in the surface layer on the upper surface S1 side. In addition, the thickness of the thinned area is 10 to 200 μm, for example. On the rear surface S2 of the N-type semiconductor substrate 10 is provided the window plate 13. The window plate 13 is bonded to the outer edge portion 14 of the recessed portion 12. The bonding is made via a resin layer 15 provided between the window plate 13 and the outer edge portion 14. The window plate 13 also has a flat plate shape and is made of a material that has a sufficient transmissivity for the wavelength of to-be-detected light. The window plate 13 covers the recessed portion 12 and seals the rear surface S2 of the N-type semiconductor substrate 10. As a material of the window plate 13, glass or optical crystal can be used. As a material of the window plate 13, quartz, sapphire, kovar glass, etc., can specifically be cited. Also, the thickness of the window plate 13 is 0.2 mm to 1 mm, for example. In addition, the window plate 13 may be coated with AR (Anti Reflection) coating. Additionally, the outer edge portion 14 indicates the portion laterally surrounding the recessed portion 12 within the N-type semiconductor substrate 10. Also, as a resin of the resin layer 15, for example, epoxy-based, silicon-based, acryl-based or polyimide-based one, or composite material thereof can be used. The back illuminated photodiode 1 also comprises an N-type highly-doped impurity semiconductor layer 21, an R-type highly-doped impurity semiconductor region 22, insulating films 23 and 24, an anode electrode 25, and a cathode electrode 26. The N+-type highly-doped impurity semiconductor layer 21 is formed in the entire surface layer on the rear surface S2 side of the N-type semiconductor substrate 10. The N+-type highly-doped impurity semiconductor layer 21 is provided with N-type impurities at a concentration higher than in the N-type semiconductor substrate 10. The impurity concentration of the N+-type highly-doped impurity semiconductor layer 21 is 1015 to 1020/cm3, for example. Also, the depth of the N+-type highly-doped impurity semiconductor layer 21, is 0.1 to 20 μm, for example. The *N+-type highly-doped impurity semiconductor region 22 is formed in the surface layer on the upper surface S1 side of the N-type semiconductor substrate 10 at a predetermined distance from the P+-type impurity semiconductor region 11. The N+-type highly-doped impurity semiconductor region 22 is also provided with N-type impurities at a high concentration, as is the case with the N+-type highly-doped impurity semiconductor layer 21, to be a contact layer for the cathode electrode 26 to be described hereinafter. The impurity concentration of the N+-type, highly-doped impurity semiconductor region 22 is 1015 to 1020/cm3, for example. Also, the depth of the N+-type highly-doped impurity semiconductor region 22 is 0.1 to 30 μm, for example. The insulating films 23 and 24 are formed, respectively, on the upper surface S1 and the rear surface S2 of the N-type semiconductor substrate 10. The insulating films 23 and 24 are made of SiO2, for example. The thickness of the insulating film 23 is 0.1 to 2 μm, for example. Meanwhile, the thickness of the insulating film 24 is 0.05 to m, for example. Also, in the insulating film 23 are formed openings (contact holes) 23a and 23b, one opening 23a being provided within the range of the P+-type impurity semiconductor region 11, while the other opening 23b being provided within the range of the N+-type highly-doped impurity semiconductor region 22. On the insulating film 23 and in the areas including the openings 23a and 23b are formed, respectively, the anode electrode 25 and the cathode electrode 26. The thickness of the electrodes 25 and 26 is 1 μm, for example. The electrodes 25 and 26 are provided in such a manner as to fill the respective openings 23a and 23b. Thus, the anode electrode 25 is connected directly to the P+-type impurity semiconductor region 11 through the opening 23a, while the cathode electrode 26 is connected directly to the N+-type highly-doped impurity semiconductor region 22 through the opening 23b. As the anode and cathode electrodes 25 and 26, for example, Al, can be used. The back illuminated photodiode 1 further comprises a passivating film 31, a supporting film 32, filling electrodes 33a and 33b, UBMs (Under Bump Metals) 34a and 34b, and bumps 35a and 35b. The passivating film 31 is provided on the upper surface S1 of the N-type semiconductor substrate 10 in such a manner as to cover the insulating film 23, anode electrode 25, and cathode electrode 26. Also, in the portions provided on the anode electrode 25 and the cathode electrode 26 within the passivating film 31 are formed through-holes 31a to be filled with the filling electrodes 33a and 33b to be described hereinafter. The passivating film 31 is made of SiN, for example, to protect the upper surface S1 of the N-type semiconductor substrate 10. The passivating film 31 can be formed by, for example, a plasma-CVD method. Also, the thickness of the passivating film 31 is 1 μm, for example. On the passivating film 31 is formed the supporting film 32. The supporting film 32 is adapted to support the N-type semiconductor substrate 10. Also, in-the portions corresponding to the through-holes 31a in the passivating film 31 within the supporting film 32 are formed through-holes 32a to be filled with the filling electrodes 33a and 33b that also fill the through-holes 3la. As a material of the supporting film 32, for example, resin or SiO2, etc., that can be formed by, for example, a plasma-CVD method can be used. Also, the thickness of the supporting film 32 is 2 to 100 μm, for example, and preferably about 50 μm. The filling electrodes 33a and 33b fill the through-holes 3 la and 32a, and are brought into contact, respectively, with the anode electrode 25 and the cathode electrode 26 at one end thereof to be connected electrically to the P+-type impurity semiconductor region 11 and the N+-type highly-doped impurity semiconductor region 22. Also, the other end of the filling electrodes 33a and 33b is exposed at the surface of the supporting film 32. That is, the filling electrodes 33a and 33b penetrate through the passivating film 31 and the supporting film 32 to extend, respectively, from the anode electrode 25 and the cathode electrode 26 to the surface of the supporting film 32. In addition, the filling electrodes 33a and 33b each have an approximately cylindrical shape. The filling electrodes 33a and 33b are adapted to connect, respectively, the electrodes 25 and 26 and the bumps 35a and 35b to be described hereinafter electrically with each other. The filling electrodes 33a and 33b are made of Cu, for example. Also, the diameter of the through-holes 31a and 32a is 10 to 200 μm, for example, and preferably about 100 μm. On the exposed portions of the filling electrodes 33a and 33b at the surface of the supporting film 32 are formed the UBMs 34a and 34b. The UBMs 34a and 34b are composed of laminated films made of Ni and Au, for example. Also, the thickness of the UBMs 34a and 34b is 0.1 to 100 μm, for example. On the surfaces of the UBMs 34a and 34b on the opposite side of the filling electrodes 33a and 33b are formed the bumps 35a and 35b. The bumps 35a and 35b are therefore connected, respectively, to the anode electrode 25 and the cathode electrode 26 electrically. The bumps 35a and 35b each have an approximately spherical shape except for the surfaces in contact with the UBMs 34a and 34b. As the bumps 35a and 35b, for example, solder, gold, Ni-Au, Cu, or resin containing metal filler can be used. FIG. 2 is a perspective view of the thus arranged back illuminated photodiode 1. As can be seen from this figure, the back illuminated photodiode 1 is obtained through dicing to be an approximately rectangular solid overall shape excluding the UBMs 34a and 34b and the bumps 35a and 35b. Additionally, the N+-type highly-doped impurity semiconductor layer 21 and the N+-type highly-doped impurity semiconductor region 22 exposed at the side surfaces of the N-type semiconductor substrate 10 are omitted in FIG. 2. The operation of the back illuminated photodiode 1 will here be described. It is assumed here that the back illuminated photodiode 1 is applied with a reverse bias voltage, and that there is generated a depletion layer around the thinned area in the N-type semiconductor substrate 10. When to-be-detected light penetrates through the window plate 13 and then enters the N-type semiconductor substrate 10 through the recessed portion 12, the light is absorbed mainly in the thinned area to generate carriers (holes and electrons) in the area. The generated holes and electrons are moved, respectively, to the P+-type impurity semiconductor region 11 and the N+-type highly-doped impurity semiconductor region 22 in accordance with the reverse bias electric field. Holes and electrons that have reached the P+-type impurity semiconductor region 11 and the N+-type highly-doped impurity semiconductor region 22 are moved to the bumps 35a and 35b through the filling electrodes 33a and 33b and the UBMs 34a and 34b to be output as a detected signal from the bumps 35a and 35b. The effect of the back illuminated photodiode 1 will here be described. In the back illuminated photodiode 1, the window plate 13 is bonded to the outer edge portion 14 of the N-type semiconductor substrate 10. This eliminates the use of an external package such as a ceramic package, whereby it is possible to obtain a chip-sized back illuminated photodiode 1. Accordingly, there is achieved a back illuminated photodiode 1 having a sufficiently small package. In addition, since there is no need for a ceramic package, etc., it is possible to reduce the cost of manufacturing a back illuminated photodiode 1. Further, the window plate 13 seals the rear surface S2 of the N-type semiconductor substrate 10 to increase the reliability of the back illuminated photodiode 1. There is thus achieved an inexpensive and highly reliable as well as small back illuminated photodiode 1. Further, in the back illuminated photodiode 1, the surface of the window plate 13 functions as an incident plane for to-be-detected light. Since the surface of the window plate 13 can be flattened more easily than resin, it is possible to suppress the scattering of to-be-detected light at the incident plane. There is thus achieved a back illuminated photodiode 1 capable of detecting light at a high sensitivity. Also, the provided window plate 13 increases the mechanical strength of the back illuminated photodiode 1. In addition, at the rear surface S2 of the N-type semiconductor substrate 10, the recessed portion 12 functions as an incident part for to-be-detected light. Therefore, the window plate 13 bonded to the outer edge portion 14 that has a structure of being protruded from the bottom surface S3 of the recessed portion 12 is not in contact with the bottom surface S3 that functions as an incident plane for to-be-detected light entering the N-type semiconductor substrate 10. This prevents the bottom surface S3 from being damaged by contact with the window plate 13, whereby it is possible to suppress sensitivity reduction, dark current and noise. The provided supporting film 32 increases the mechanical strength of the back illuminated photodiode 1. In back illuminated photodiodes with part of the substrate being thinned, it is generally required to pay attention to the handling of the thinned portion so as not to be damaged. On the contrary, the back illuminated photodiode 1, the mechanical strength of which is increased so as to be unlikely to be damaged, can be handled easily. The back illuminated photodiode 1, which is unlikely to be damaged, can also be diced easily. The provided filling electrodes 33a and 33b make it easy to take a detected signal outside from the electrodes 25 and 26. Additionally, the filling electrodes 33a and 33b may be formed on the sidewalls of the through holes 3 la and 32a to be connected electrically to the anode electrode 25 and the cathode electrode 26. The N+-type highly-doped impurity semiconductor layer 21 is formed in the entire surface layer on the rear surface S2 side of the N-type semiconductor substrate 10. The N+-type highly-doped impurity semiconductor layer 21 provided in the portion exposed at the bottom surface S3 of the recessed portion 12 within the surface layer of the rear surface S2 functions as an accumulation layer. It is thus possible to guide carriers generated in the N-type semiconductor substrate 10 effectively to the PN junction on the upper surface S1 side by the electric field distribution in the layer. There is thus achieved a more highly sensitive back illuminated photodiode 1. Here, the impurity concentration of the N+-type highly-doped impurity semiconductor layer 21 is preferably 1015/cm3 or more. In this case, the N+-type highly-doped impurity semiconductor layer 21 can suitably function as an accumulation layer. Also, even if there may be crystal defects in the outer edge portion 14, the N+-type highly-doped impurity semiconductor layer 21, which is provided in the surface layer on the rear surface S2 side within the outer edge portion 14 of the N-type semiconductor substrate 10, can suppress dark current and/or noise due to the crystal defects. Therefore, in accordance with the back illuminated photodiode 1, it is possible to obtain a detected signal at a high S/N ratio. Also, here, the impurity concentration of the N+-type highly-doped impurity semiconductor layer 21 is preferably 1015/cm3 or more. In this case, the N+-type highly-doped impurity semiconductor layer 21 can suppress dark current and/or noise due to crystal defects sufficiently. An exemplary method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 will here be described with reference to FIG. 3 to FIG. 17. First, there is prepared an N-type semiconductor substrate 10 made of an N-type silicon wafer with the upper surface S1 and the rear surface S2 thereof being formed into (100) planes. The N-type semiconductor substrate 10 is thermally oxidized to form an insulating film made of SiO2 on the upper surface S1 of the N-type semiconductor substrate 10. Also, in predetermined portions of the insulating film are formed openings, and then phosphorous is doped into the N-type semiconductor substrate 10 through the openings to form N+-type highly-doped impurity semiconductor regions 22. Subsequently, the N-type semiconductor substrate 10 is oxidized to form an insulating film on the upper surface S1. Similarly, in predetermined portions of the insulating film are formed openings, and then boron is doped into the N-type semiconductor substrate 10 through the openings to form P+-type impurity semiconductor regions 11 impurity semiconductor region forming step). Subsequently, the N-type semiconductor substrate 10 is oxidized to form an insulating film 23 on the upper surface S1. Then, the rear surface, S2 of the N-type semiconductor substrate 10 is polished (FIG. 3). Next, SiN 84 is deposited on the rear surface S2 of the N-type semiconductor substrate 10 by LP-CVD (FIG. 4). Also, in the SiN 84 on the rear surface S2 are formed openings 85 to form recessed portions 12 (FIG. 5). Then, an etching operation is performed using KOH, etc., through the openings 85 to form recessed portions 12 (recessed portion forming step; FIG. 6). Next, after the SiN 84 on the rear surface S2 is removed, ion implantation, etc., is performed against the rear surface S2 of the N-type semiconductor substrate 10 with the recessed portions 12 formed therein to dope N-type impurities and thereby to form an N+-type highly-doped impurity semiconductor layer 21 in the entire surface layer on the rear surface S2 side (FIG. 7). Then, the substrate is thermally oxidized to form an insulating film 24 on the rear surface S2 (FIG. 8). Contact holes for electrodes are formed in the insulating film 23 on the upper surface S1, and after aluminum is deposited on the upper surface S1, a predetermined pattern is made to form anode electrodes 25 and cathode electrodes 26 (FIG. 9). Next, a passivating film 31 made of SiN is deposited on the upper surface S1 of the N-type semiconductor substrate 10, on which the anode electrodes 25 and the cathode electrodes 26 are formed, by a plasma-CVD method. Also, through-holes 31a are formed in portions corresponding to bumps 35a and 35b within the passivating film 31 (FIG. 10). Further, a thick supporting film 32 made of resin or inorganic insulating films is formed on the upper surface S1, and through-holes 32a are formed in the portions corresponding to the through-holes 31a in the passivating film 31. Here, as the supporting film 32 resin such as epoxy-based, acryl-based or polyimide-based one, or inorganic insulating films such as SiO2 that can be formed by, for example, CVD or SOG (Spin On Glass) can be used. Also, the through-holes 32a in the supporting film 32 can be formed by a photolithography method using, for example, photosensitive resin or by a patterning process such as etching (FIG. 11). Further, a conductive material 33 made of Cu is deposited on the upper surface S1 in such a manner as to fill the through-holes 31a and 32a. This can be made through the steps of, for example, depositing a Cu seed layer, etc., by sputtering, etc., on the surface of the anode electrodes 25 and the cathode electrodes 26 that are exposed from the through-holes 31 a and 32a, and depositing Cu, etc., by plating on the Cu seed layer. Additionally, on the anode electrodes 25 and the cathode electrodes 26 are provided intermediate metals (not shown in the figure) for improving the bonding to the conductive material 33 (FIG. 12). Next, the surface of the conductive material 33 is polished to remove the conductive material 33 deposited on the supporting film 32. Thus, filling electrodes 33a and 33b are formed (FIG 13). Also, a window plate 13 is bonded to the rear surface S2 of the N-type semiconductor substrate using the outer edge portions 14 of the recessed portions 12 as bond parts (window plate bonding step). The bonding is to be performed by preliminarily forming resin layers 15 by printing, etc., at the positions within the window plate 13 corresponding to the outer edge portions 14, and then by using the resin layers 15. This allows the rear surface S2 of the N-type semiconductor substrate 10 to be sealed. Additionally, as the resin layers 15 is preferably used B-stage resin or thermoplastic resin. Also, in the case of bonding the window plate 13 and the outer edge portions 14 with the resin being in a liquid state, it is preferable to use high-viscosity resin. 5 Further, the bonding between the window plate 13 and the outer edge portions 14 is preferably performed under a dry N2 atmosphere (FIG. 14). In addition, UBMs 34a and 34b composed of laminated films made of Ni and Au, etc., are formed on the filling electrodes 33a and 33b on the upper surface S1 by electroless plating. Further, bumps 35a and 35b made of solder, etc., are formed on the UBMs 34a and 34b by printing or a ball-mounting method (FIG. 15). Finally, in order to obtain individually separated back illuminated photodiodes 1, a dicing step is performed (dicing step). As indicated by the alternate long and short dashed lines L1 in FIG. 16, the N-type semiconductor substrate 10 is diced at the center of each outer edge portion 14 on the rear surface S2 side. The dicing operation is performed from the upper surface S1 side to the rear surface S2 side of the N-type semiconductor substrate 10. More specifically, the wafer shown in FIG. 16 is diced in the order of the supporting film 32, passivating film 31, insulating film 23, N-type semiconductor substrate 10, insulating film 24, resin layers 15, and window plate 13. Thus, the wafer shown in FIG. 16 is to be separated individually to obtain back illuminated photodiodes 1 each having a pair of a P+-type impurity semiconductor region l l and a recessed portion 12 (FIG. 17). In accordance with the manufacturing method shown in FIG. 3 to FIG. 17, the window plate 13 is bonded to the outer edge portions 14 of the N-type semiconductor substrate 10 in the window plate bonding step (refer to FIG. 14). This eliminates the use of an external package such as a ceramic package, whereby it is possible to obtain a chip-sized back illuminated photodiode 1. In accordance with the present manufacturing method, it is therefore possible to achieve a back illuminated photodiode 1 having a sufficiently small package. Since this also eliminates the use of a step of packing a back illuminated photodiode 1 into a ceramic package, etc., the manufacturing process for the entire back illuminated photo diode 1 is simplified. Also, in the case of bonding the window plate 13 and the outer edge portions 14 under a dry N2 atmosphere in the window plate bonding step, the areas between the recessed portions 12 and the window plate 13 are to be sealed with N2, especially resulting in the possibility of highly reliable sealing. FIG. 18 is a view illustrating an exemplary variation of the dicing step shown in FIG. 16. In the dicing step shown in FIG. 16, a plurality of dicing steps may be performed. For example, a first dicing step is performed from the supporting film 32 to part of the window plate 13. In FIG. 18 is shown a state of the wafer immediately after the first step. In the diced portions are formed slits C. Then, the rest of the window plate 13 is to be diced in a second step. In the second dicing step, there is shown the case of using a blade of a width smaller than that used in the first step. Thus, performing a plurality of dicing steps allows the N-type semiconductor substrate 10 and the window plate 13 to be diced separately in different steps. This allows the N-type semiconductor substrate 10 and the window plate 13 having their respective different hardnesses to be diced using a blade suitable for each thereof. That is, it is possible to dice the N-type semiconductor substrate 10 and the window plate 13 using blades made of different material suitable for their respective hardnesses. It is therefore possible to prevent chipping (crack) at the interface between the N-type semiconductor substrate 10 and the window plate 13 in a dicing operation. Additionally, from the viewpoint of dicing the N-type semiconductor substrate 10 and the window plate 13 separately in different steps, the position where the first dicing step is to be completed (i.e. the position where the second dicing step is to be started) is preferably in the vicinity of the interface between the N-type semiconductor substrate 10 and the window plate 13. In FIG. 19 to FIG. 22 are shown exemplary structures of a back illuminated photodiode obtained through the dicing step illustrated in FIG. 18. Since in the first and second steps blades having their respective different thickness to perform a dicing operation are used, in the side surfaces of the window plate 13 and at predetermined positions in the vicinity of the interface between the N-type semiconductor substrate 10 and the window plate 13 are formed stepped portions ST correspondingly to the position where the first dicing step is completed as shown in FIG. 19. Also, in the case where the first dicing step has been completed within the N-type semiconductor substrate 10, in the side surfaces of the N-type semiconductor substrate 10 and in the vicinity of the interface between the N-type semiconductor substrate 10 and the window plate 13 are formed stepped portions ST as shown in FIG. 20. In FIG. 19 and FIG. 20, the window plate 13 side is raised higher than the N-type semiconductor substrate 10 side with respect to the stepped portions ST. Additionally, the dicing operation may be performed from the rear surface S2 side to the upper surface S1 side of the N-type semiconductor substrate 10. In the case of performing a first dicing step from the window plate 13 to part of the N-type semiconductor substrate 10 and then a second dicing step from the rest of the N-type semiconductor substrate 10 to the supporting film 32, in the side surfaces of the N-type semiconductor substrate 10 are formed stepped portions ST as shown in FIG. 21. Meanwhile, in the case where the first dicing step has been completed within the window plate 13, in the side surfaces of the window plate 13 are formed stepped portions ST as shown in FIG. 22. In FIG. 21 and FIG. 22, the N-type semiconductor substrate 10 side is raised higher than the window plate 13 side with respect to the stepped portions ST. FIG. 23 is a cross-sectional view showing a first exemplary variation of the back illuminated photodiode 1 shown in FIG. 1. In the back illuminated photodiode la, the shape of the N+-type highly-doped impurity semiconductor layer 21 differs from that in the back illuminated photodiode 1 shown in FIG. 1. The other arrangements of the back illuminated photodiode la are the same as those of the back illuminated photodiode 1. That is, in the back illuminated photodiode 1 shown in FIG. 1, the N+-type highly-doped impurity semiconductor layer 21 is formed in the entire surface layer on the rear surface S2 side of the N-type semiconductor substrate 10 at an approximately uniform thickness, while in the back illuminated photodiode la, the N+-type highly-doped impurity semiconductor layer 21 is formed in such a manner that the portion provided in the surface layer on the rear surface S2 side within the outer edge portion 14 has a thickness greater than that of the other portions. Also, in the back illuminated photodiode 1a, the N+-type highly-doped impurity semiconductor layer 21 provided in the bottom surface S3 portion of the recessed portion 12 can function as an accumulation layer. Also, even if there may be crystal defects in the outer edge portion 14, the N+-type highly-doped impurity semiconductor layer 21, which is provided in the surface layer on the rear surface S2 side within the outer edge portion 14, can suppress dark current and/or noise due to the crystal defects. FIG. 24 is a cross-sectional view showing a second exemplary variation of the back illuminated photodiode 1 shown in FIG. 1. In the back illuminated photodiode 1b, the shape of the N+-type highly-doped impurity semiconductor layer 21 differs from that in the back illuminated photodiode 1 shown in FIG. 1. The other arrangements of the back illuminated photodiode 1b are the same as those of the back illuminated photodiode 1. That is, in the back illuminated photodiode 1 shown in FIG. 1, the N+-type highly-doped impurity semiconductor layer 21 is formed in the entire surface layer on the rear surface S2 side of the N-type semiconductor substrate 10, while in the back illuminated photodiode 1b, the N+-type highly-doped impurity semiconductor layer 21 is formed only in the recessed portion 12 within the surface layer on the rear surface S2 side of the N-type semiconductor substrate 10. Also, in the back illuminated photodiode 1b, the N+-type highly-doped impurity semiconductor layer 21 provided in the bottom surface S3 portion of the recessed portion 12 can function as an accumulation layer. FIG. 25 is a perspective view showing a third exemplary variation of the back illuminated photodiode 1 shown in FIG. 1. The back illuminated photodiode 1c differs from the back illuminated photodiode 1 shown in FIG. 1 in that chamfered portions 13 a are formed in the window plate 13. The other arrangements of the back illuminated photodiode 1c are the same as those of the back illuminated photodiode 1. As can be seen from FIG. 25, the window plate 13 has a square cross-sectional shape in a plane perpendicular to the thickness direction thereof, at the four corners of the square being formed chamfered portions 13a. The chamfered portions 13a each have a fan shape with a center angle of 90° centering on each corner of the square in the cross-section. Additionally, the chamfered portions 13a are not restricted to have a fan shape in the cross-section, but may have a rectangular shape. In the back illuminated photodiode 1c, the chamfered portions 13a are thus formed at the corners of the window plate 13, that is, at the positions where two dicing lines intersect with each other in a dicing operation, which prevents chipping in the dicing operation. The positional relationship between the window plate 13 and dicing lines will here be described with reference to FIG. 26. FIG. 26 is a plan view showing the appearance of the wafer of the back illuminated photodiode 1 shown in FIG. 1 before dicing (e.g. the wafer in a state shown in FIG. 16) when viewed from the side of the window plate 13. In this plan view, the portions where recessed portions 12 are formed are indicated by the dashed lines L2. It can be found that the recessed portions 12 are arranged in a grid pattern at a constant spacing in the wafer before dicing. Also, the dicing lines in a dicing operation are indicated by the alternate long and short dashed lines L3. The dicing lines are specified in the vertical direction or the horizontal direction in the figure, and run through the center of the space between adjacent recessed portions 12. Each area surrounded by the dicing lines corresponds to each back illuminated photodiode 1 after dicing. As can be seen from FIG. 26, the corners of the window plate 13 in each back illuminated photodiode 1 after dicing correspond to the positions P where two dicing lines intersect with each other. Since the positions in the N-type semiconductor substrate 10 corresponding to the positions P, that is, the four corners of the rear surface S2 receive stress in a concentrated manner in a dicing operation, there is a possibility of chipping. On the contrary, in the back illuminated photodiode 1c shown in FIG. 25, at the corners of the window plate 13 are formed chamfered portions 13a, whereby the dicing of the window plate 13 at the positions P where dicing lines intersect with each other is avoided. This relaxes stress to be applied to the four corners of the rear surface S2 of the N-type semiconductor substrate 10, which prevents chipping in the back illuminated photodiode 1c in a dicing operation. FIG. 27 is a plan view showing the appearance of the wafer of the back illuminated photodiode 1c shown in FIG. 25 before dicing when viewed from the side of the window plate 13. As shown in this plan view, at the positions P where dicing lines intersect with each other are formed cylindrical hole portions 13b. The hole portions 13b are formed in and penetrate through each window plate 13. The chamfered portions 13a derive from these hole portions 13b. That is, each hole portion 13b is to be divided into quarters by a dicing operation to be chamfered portions 13a in the back illuminated photodiode 1c. Additionally, in the manufacturing process for the back illuminated photodiode 1c, it is only required to bond a window plate 13 with hole portions 13b formed preliminarily at predetermined positions to the rear surface S2 of the N-type semiconductor substrate 10 so that the positions P where dicing lines intersect with each other are aligned with the hole portions 13b. It is also noted that the hole portions 13b are not restricted to have a cylindrical shape, but may have a prismatic shape. FIG. 28 is a cross-sectional view showing a second embodiment of a back illuminated photodetector according to the present invention. The back illuminated photodiode 2 comprises an N-type semiconductor substrate 20, a P+-type impurity semiconductor region 11, a recessed portion 12, and a window plate 13. In the surface layer on the upper surface S1 side of the N-type semiconductor substrate 20 is partially formed the P+-type impurity semiconductor region 11. In the rear surface S2 of the N-type semiconductor substrate 20 and in an area opposite the P+-type impurity semiconductor region 11 is formed the recessed portion 12. Also, the window plate 13 is bonded to the outer edge portion 14 of the recessed portion 12 via a resin layer 15. The back illuminated photodiode 2 also comprises an N-type highly-doped impurity semiconductor region 28, insulating films 23 and 24, an anode electrode 25, and a cathode electrode 26. The N+-type highly-doped impurity semiconductor region 28 is formed in such a manner as to be exposed at the entire side surfaces S4 of the N-type semiconductor substrate 20. The N+-type highly-doped impurity semiconductor region 28 also reaches the entire rear surface S2 of the N-type semiconductor substrate 20. Therefore, the portion 20a within the N-type semiconductor substrate 20, in which neither the P+-type impurity semiconductor region 11 nor the N+-type highly-doped impurity semiconductor region 28 is formed, is surrounded entirely by the N+-type highly-doped impurity semiconductor region 28 from the side surface S4 sides and the rear surface S2 side of the N-type semiconductor substrate 20. An exemplary method of forming the N+-type highly-doped impurity semiconductor region 28 will here be described with reference to FIG. 29 to FIG. 31. First, there is prepared an N-type semiconductor substrate 20. In the N-type semiconductor substrate 20, an N+-type highly-doped impurity semiconductor layer 41 is diffused from the rear surface S2 with a part on the upper surface S1 side remaining. The remaining part on the upper surface S1 side is an N-type impurity semiconductor layer 42 having an impurity concentration lower than that of the N+-type highly-doped impurity semiconductor layer 41 (FIG: 29). Next, N-type impurities are diffused at a high concentration from the upper surface S1 side to form N+-type highly-doped impurity semiconductor regions 43 (FIG. 30). Then, the N-type impurities are diffused further deeply so that the N+-type highly-doped impurity semiconductor regions 43 reach the N+-type highly-doped impurity semiconductor layer 41 (FIG. 31). There is thus formed an N+-type highly-doped impurity semiconductor region 28 composed of the N+-type highly-doped impurity semiconductor layer 41 and the N+-type highly-doped impurity semiconductor regions 43. Additionally, in FIG. 31, the areas where a P+-type impurity semiconductor region 11 and a recessed portion 12 are to be formed are indicated, respectively, by the dashed lines L4 and L5. In accordance with the method, the manufacturing process for the N+-type highly-doped impurity semiconductor region 28 and therefore for the entire back illuminated photodiode 2 is simplified. Returning to FIG. 28, on the upper surface S1 and the rear surface S2 of the N-type semiconductor substrate 20 are formed, respectively, the insulating films 23 and 24. Also, in the insulating film 23 are formed openings 23a and 23b, one opening 23a being provided within the range of the P+-type impurity semiconductor region 11, while the other opening 23b being provided within the range of the N+-type highly-doped impurity semiconductor region 28. On the insulating film 23 and in the areas including the openings 23a and 23b are formed, respectively, the anode electrode 25 and the cathode electrode 26. The electrodes 25 and 26 are provided in such a manner as to fill the respective openings 23a and 23b. Thus, the anode electrode 25 is connected directly to the P+-type impurity semiconductor region 11 through the opening 23a, while the cathode electrode 26 is connected directly to the N+-type highly-doped impurity semiconductor-region 28 through the opening 23b. The back illuminated photodiode 2 further comprises a passivating film 31, a supporting film 32, filling electrodes 33a and 33b, UBMs 34a and 34b, and bumps 35a and 35b. The passivating film 31 is provided on the upper surface S1 of the N-type semiconductor substrate 20 in such a manner as to cover the insulating film 23, anode electrode 25, and cathode electrode 26. On the passivating film 31 is formed the supporting film 32. Also, the filling electrodes 33a and 33b penetrate through the passivating film 31 and the supporting film 32 to extend, respectively, from the anode electrode. 25 and the cathode electrode 26 to the surface of the supporting film 32. On the exposed portions of the filling electrodes 33a and 33b at the surface of the supporting film 32 are formed the UBMs 34a and 34b. On the surfaces of-the UBMs 34a and 34b on the opposite side of the filling electrodes 33a and 33b are formed the bumps 35a and 35b. The effect of the back illuminated photodiode 2 will here be described. In the back illuminated photodiode 2, the window plate 13 is bonded to the outer edge portion 14 of the N-type semiconductor substrate 20. This eliminates the use of an external package such as a ceramic package, whereby it is possible to obtain a chip-sized back illuminated photodiode 2. Accordingly, there is achieved a back illuminated photodiode 2 having a sufficiently small package. Further, in the back illuminated photodiode 2, the surface of the window plate 13 functions as an incident plane for to-be-detected light. Since the surface of the window plate 13 can be flattened more easily than resin, it is possible to suppress the scattering of to-be-detected light at the incident plane. There is thus achieved a back illuminated photodiode 2 capable of detecting light at a high sensitivity. Also, in the back illuminated photodiode 2, the N+-type highly-doped impurity semiconductor region 28 is formed in such a manner as to be exposed at the entire side surfaces S4 of the N-type semiconductor substrate 20. Thus, the N+-type highly-doped impurity semiconductor region 28 can suppress dark current and/or noise generated in the vicinity of the side surfaces S4 of the N-type semiconductor substrate 20. Although the side surfaces S4 correspond to dicing lines whereby there is a possibility of causing crystal defects in a dicing operation, the N+-type highly-doped impurity semiconductor region 28 can also suppress dark current and/or noise due to the crystal defects. Therefore, in accordance with the back illuminated photodiode 2, it is possible to obtain a-detected signal at a high S/N ratio. In addition, the portion 20a within the N-type semiconductor substrate 20 is surrounded entirely by the N+-type highly-doped impurity semiconductor region 28 from the side surface S4 sides and the rear surface S2 side of the N-type semiconductor substrate 20. There is thus achieved a PIN structure in which the surrounded portion 20a is employed as an I-layer. Therefore, the back illuminated photodiode 2 achieves a sensitivity increase due to such a PIN structure whereby the depletion layer is thickened to increase the length through which light is absorbed, and a high-speed response due to the thus thickened depletion layer whereby the thickness of the electric double layer is increased to reduce the capacitance thereof. FIG. 32 is a plan view showing a third embodiment of a back illuminated photodetector according to the present invention. The back illuminated photodiode array 3 is composed of a total of sixty-four back illuminated photodiodes that are arranged in an eight-by-eight grid pattern. The arrangement pitch of these photodiodes is 1 mm, for example. FIG. 32 shows the appearance of the back illuminated photodiode array 3 when viewed from the rear surface side. The rear surface of each photodiode is covered with a window plate, as is the case with the back illuminated photodiode 1 shown in FIG. 1. Additionally, in FIG. 32, the portions where recessed portions are formed are indicated by the dashed lines L6. FIG. 33 is a cross-sectional view of the back illuminated photodiode array 3 shown in FIG. 32 along the line XX-XX. In the cross-sectional view are shown two photodiodes P1 and P2 among the sixty-four photodiodes shown in FIG. 32. As shown in FIG. 33, the back illuminated photodiode array 3 comprises an N-type semiconductor substrate 50, a P+-type impurity semiconductor region 51, a recessed portion 52, and a window plate 53. In the surface layer on the upper surface S1 side of the N-type semiconductor substrate 50 are formed a plurality of the P+-type impurity semiconductor regions 51. The P+-type impurity semiconductor regions 51 are provided, respectively, for the photodiodes P1 and P2. The area of each P+-type impurity semiconductor region 51 is 0.75×0.75 mm2, for example. In the rear surface S2 of the N-type semiconductor substrate 50 and in an area opposite the P+-type impurity semiconductor region 51 is formed the recessed portion 52. Here is formed a plurality of the recessed portions 52 being provided with a plurality of the P+-type impurity semiconductor regions 51. In each of the photodiodes P1 and P2 are provided a pair of a P+-type impurity semiconductor region 51 and a recessed portion 52. Also, the window plate 53 is bonded to the outer edge portions 54 of the recessed portions 52 through resin layers 55. The back illuminated photodiode array 3 also comprises an N+-type highly-doped impurity semiconductor layer 61, N+-type highly-doped impurity semiconductor regions 62, insulating films 63 and 64, anode electrodes 65, and cathode electrodes 66. The N+-type highly-doped impurity semiconductor layer 61 is formed in the entire surface layer on the rear surface S2 side of the N-type semiconductor substrate 50. The N+-type highly-doped impurity semiconductor regions 62 are formed in the surface layer on the upper surface S1 side of the N-type semiconductor substrate 50. The N+-type highly-doped impurity semiconductor regions 62 are preferably provided in such a manner as to surround the P+-type impurity semiconductor regions 51 constituting the respective photodiodes. On the upper surface S1 and the rear surface S2 of the N-type semiconductor substrate 50 are formed, respectively, the insulating films 63 and 64. In the insulating film 63 are formed openings 63a and 63b, some openings 63a being provided within the range of the P+-type impurity semiconductor regions 51, while the other openings 63b being provided within the range of the N+-type highly-doped impurity semiconductor regions 62. On the insulating film 63 and in the areas including the openings 63a and 63b are formed, respectively, the anode electrodes 65 and the cathode electrodes 66. In each of the photodiodes P1 and P2 are provided a pair of an anode electrode 65 and a cathode electrode 66. The electrodes 65 and 66 are also provided in such a manner as to fill the respective openings 63a and 63b. Thus, the anode electrodes 65 are connected directly to the P+-type impurity semiconductor regions 51 through the respective openings 63a, while the cathode electrodes 66 are connected directly to the N+-type highly-doped impurity semiconductor regions 62 through the respective openings 63b. The back illuminated photodiode array 3 further comprises a passivating film 71, a supporting film 72, filling electrodes 73a and 73b, UBMs 74a and 74b, and bumps 75a and 75b. The passivating film 71 is provided on the upper surface S1 of the N-type semiconductor substrate 50 in such a manner as to cover the insulating film 63, anode electrodes 65, and cathode electrodes 66. On the passivating film 71 is formed the supporting film 72. Also, the filling electrodes 73a and 73b penetrate through the passivating film 71 and the supporting film 72 to extend, respectively, from the anode electrodes 65 and the cathode electrodes 66 to the surface of the supporting film 72. On the exposed portions of the filling electrodes 73a and 73b at the surface of the supporting film 72 are formed the UBMs 74a and 74b. On the surfaces of the UBMs 74a and 74b on the opposite side of the filling electrodes 73a and 73b are formed the bumps 75a and 75b. The effect of the back illuminated photodiode array 3 will here be described. In the back illuminated photodiode array 3, the window plate 53 is bonded to the outer edge portions 54 of the N-type semiconductor substrate 50. This eliminates the use of an external package such as a ceramic package, whereby it is possible to obtain a chip-sized back illuminated photodiode array 3 without extra portions around the array. Accordingly, there is achieved a back illuminated photodiode array 3 having a sufficiently small package. Further, in the back illuminated photodiode array 3, the surface of the window plate 53 functions as an incident plane for to-be-detected light. Since the surface of the window plate 53 can be flattened more easily than resin, it is possible to suppress the scattering of to-be-detected light at the incident plane. There is thus achieved a back illuminated photodiode array 3 capable of detecting light at a high sensitivity. There is also constructed a plurality of photodiodes by forming a plurality of P+-type impurity semiconductor regions 51 in a plurality of areas in the surface layer on the upper surface S1 side of the N-type semiconductor substrate 50, and by forming a plurality of recessed portions 52 in the rear surface S2 and in areas opposite the respective P+-type impurity semiconductor regions 51. Therefore, the back illuminated photodiode array 3 can suitably be used for an image sensor, etc., in which each photodiode represents one pixel. FIG. 34 is a cross-sectional view showing an exemplary variation of the back illuminated photodiode array 3 shown in FIG. 33. The back illuminated photodiode array 3a differs from the back illuminated photodiode array 3 shown in FIG. 33 in that resin layers 55 are provided only on some outer edge portions 54. The other arrangements of the back illuminated photodiode array 3a are the same as those of the back illuminated photodiode array 3. That is, in the cross-sectional view of FIG. 34, resin layers 55 are provided only between the outer edge portions 54 on both ends and the window plate 53, while no resin layer 55 between the central outer edge portion 54 and the window plate 53 is provided. This is achieved by dividing the sixty-four recessed portions indicated by the dashed lines L6 in the plan view of FIG. 32 into groups composed of four (two-by-two) proximal recessed portions, and then by providing resin layers 55 only between the outer edge portions 54 on the periphery of each group and the window plate 53. Thus, providing resin layers 55 only on some outer edge portions 54 allows the process for bonding the window plate 53 and the outer edge portions 54 and therefore the manufacturing process for the entire back illuminated photodiode array 3 to be simplified. FIG. 35 is a cross-sectional view showing a fourth embodiment of a back illuminated photodetector according to the present invention. The back illuminated photodiode 4 comprises an N-type semiconductor substrate 10, a P+-type impurity semiconductor region 11, a recessed portion 12, and a window plate 13. In the surface layer on the upper surface S1 side of the N-type semiconductor substrate 10 is partially formed the P+-type impurity semiconductor region 11. In the rear surface S2 of the N-type semiconductor substrate 20 and in an area opposite the P+-type impurity semiconductor region 11 is formed the recessed portion 12. Also, the window plate 13 is bonded to the outer edge portion 14 of the recessed portion 12. In the present embodiment, the window plate 13 is made of an optically transparent material and is bonded to the outer edge portion 14 by anodic bonding. As an optically transparent material of the window plate 13, glass containing alkali metal such as Pyrex (registered trademark) glass or kovar glass is preferably used. For example, borosilicate glass containing alkali metal such as #7740 manufactured by Corning Inc. is suitable for a material of the window plate 13. #7740 manufactured by Corning Inc., has a thermal expansion coefficient of 3.4×10−6/° C., which approximately corresponds to the thermal expansion coefficient (3×10−6/° C.) of silicon. Also, the thickness of the window plate 13 is preferably 0.5 mm or more but 1 mm or less. The back illuminated photodiode 4 also comprises an N+-type highly-doped impurity semiconductor layer 21, an N+-type highly-doped impurity semiconductor region 22, insulating films 23 and 24, an anode electrode 25, and a cathode electrode 26. The N+-type highly-doped impurity semiconductor layer 21 is formed in the entire surface layer on the rear surface S2 side of the N-type semiconductor substrate 10. The N+-type highly-doped impurity semiconductor region 22 is formed in the surface layer on the upper surface S1 side of the N-type semiconductor substrate 10 at a predetermined distance from the P+-type impurity semiconductor region 11. The insulating films 23 and 24 are formed, respectively, on the upper surface S1 and the rear surface S2 of the N-type semiconductor substrate 10. In the insulating film 23 are formed openings 23a and 23b. In the present embodiment, the insulating film 24 is formed only on the recessed portion 12, and not on the outer edge portion 14 that functions as a bond part for the window plate 13. On the insulating film 23 and in the areas including the openings 23a and 23b are formed, respectively, the anode electrode 25 and the cathode electrode 26. The electrodes 25 and 26 are provided in such a manner as to fill the respective openings 23 a and 23b. Thus, the anode elect rode 25 is connected directly to the P+-type impurity semiconductor region 11 through thee opening 23 a, while the cathode electrode 26 is connected directly to the N-type highly-doped impurity semi conductor region 22 through the opening 23b. The back illuminated photodiode 4 further comprises a passivating film 31, a supporting film 32, filling electrodes 33a and 33b, UBMs 34a and 34b, and bumps 35a and-35b. The passivating film 31 is provided on the upper surface S1 of the N-type semiconductor substrate 20 in such a manner as to cover the insulating film 23, anode electrode 25, and cathode electrode 26. On the passivating film 31 is formed the supporting film 32. Also, the filling electrodes 33a and 33b penetrate through the passivating film 31 and the supporting film 32 to extend, respectively, from the anode electrode 25 and the cathode electrode 26 to the surface of the supporting film 32. On the exposed portions of the filling electrodes 33a and 33b at the surface of the supporting film 32 are formed the UBMs 34a and 34b. On the surfaces of the UBMs 34a and 34b on the opposite side of the filling electrodes 33a and 33b are formed the bumps 35a and 35b. The effect of the back illuminated photo diode 4 will here be described. In the back illuminated photodiode 4, the window plate 13 is bonded to the outer edge portion 14 of the N-type semiconductor substrate 10. This eliminates the use of an external package such as a ceramic package, whereby it is possible to obtain a chip-sized back illuminated photodiode 4. Accordingly, there is achieved a back illuminated photodiode 4 having a sufficiently small package. Further, in the back illuminated photodiode 4, the surface of the window plate 13 functions as an incident plane for to-be-detected light. Since the surface of the window plate 13 can be flattened more easily than resin, it is possible to suppress the scattering of to-be-detected light at the incident plane. There is thus achieved a back illuminated photodiode 4 capable of detecting light at a high sensitivity. Further, the window plate 13 made of glass is bonded to the outer edge portion 14 by anodic bonding. This allows the window plate 13 and the outer edge portion 14 to be bonded solidly at the interface therebetween. In addition, the anodic bonding can seal the rear surface S2 of the N-type semiconductor substrate 10 hermetically, resulting in a further improvement in reliability for the back illuminated photodiode 4. Further, performing anodic bonding under a dry inert gas atmosphere such as dry nitrogen gas or under a vacuum atmosphere results in still a further improvement in reliability. Since the window plate 13 is bonded to the outer edge portion 14 by anodic bonding, the back illuminated photodiode 4 can suitably be used also in the case of UV light to be detected. That is, in the case of bonding the window plate 13 to the outer edge portion 14 using resin, there is a possibility that gas may be generated from the resin (degassing reaction) by irradiation of UV light. In this case, the gas may be attached to the window plate 13 and/or the recessed; portion 12 to be solidified, resulting in a possibility of prevention of to-be-detected light incidence and thereby sensitivity reduction of the back illuminated photodiode 4. On the contrary, in the back illuminated photodiode 4, since the window plate 13 is bonded to the outer edge portion 14 by anodic bonding, there is no possibility of sensitivity reduction due to degassing reaction even in the case of UV light to be detected. Also, in the case of using glass containing alkali metal such as Pyrex glass or kovar glass as an optically transparent material of the window plate 13, the window plate 13 can be bonded to the outer edge portion 14 more solidly. An exemplary method for manufacturing the back illuminated photodiode 4 shown in FIG. 35 will here be described with reference to FIG. 36 to FIG. 46. There is prepared an N-type semiconductor substrate 10. In the N-type semiconductor substrate 10 are then formed N+-type highly-doped impurity semiconductor regions 22, P+-type impurity semiconductor regions 11, and recessed portions 12, and on the upper surface S1 and the rear surface S2 are formed, respectively, insulating films 23 and 24. The steps so far are the same as the manufacturing method shown in FIG. 3 to FIG. 6, FIG. 7, and FIG. 8 (FIG. 36). In the present manufacturing method, the insulating film 24 on the outer edge portions 14 is further removed by etching (FIG. 37). Next, while a window plate 13 made of glass is in contact with the outer edge portions 14, the window plate 13 is bonded to the outer edge portions 14 by anodic bonding (window plate bonding step). The anodic bonding is to be performed at a temperature of 150 to 500° C., at a voltage of about 200 to 1000V, and under an ambient atmosphere, N2 atmosphere, or vacuum atmosphere, for example (FIG. 38). Next, contact holes are formed in the insulating film 23, and after aluminum is deposited on the upper surface S1, a predetermined pattern is made to form anode electrodes 25 and cathode electrodes 26 (FIG. 39). A passivating film 31 is deposited on the upper surface S1 of the N-type semiconductor substrate 10, on which the anode electrodes 25 and the cathode electrodes 26 are formed, by a plasma-CVD method. Also, through-holes 3 la are formed in portions corresponding to bumps 35a and 35b within the passivating film 31 (FIG. 40). Further, a supporting film 32 is formed on the upper surface S1, and through-holes 32a are formed in the portions corresponding to the through-holes 31a in the passivating film 31 (FIG. 41). Next, a conductive material 33 is deposited on the upper surface S1 in such a manner as to fill the through-holes 31 a and 32a. On the anode electrodes 25 and the cathode electrodes 26 are provided intermediate metals (not shown in the figure) for improving the bonding to the conductive material 33 (FIG. 42). Further, the surface of the conductive material 33 is polished to remove the conductive material 33 deposited on the supporting film 32. Thus, filling electrodes 33a and 33b are formed (FIG. 43). Additionally, instead of filling the through-holes, a thin film electrode (having a thickness of about 0.5 to 10 μm, for example, and preferably about hum) may be formed in such a manner as to cover the sidewalls of the through-holes 31a and 32a, although not shown in the figure. In this case, it is possible to omit the polishing step. In addition, UBMs 34a and 34b are formed, respectively, on the filling electrodes 33a and 33b on the upper surface S1 by electroless plating. Further, bumps 35a and 35b are formed on the UBMs 34a and 34b by printing, a ball-mounting method, or a transfer method (FIG. 44). Finally, in order to obtain individually separated back illuminated photodiodes 4, dicing is performed along the alternate long and short dashed lines L1 shown in FIG. 45 (dicing step). Thus, the wafer shown in FIG. 45 is to be separated individually to obtain back illuminated photodiodes 4 (FIG. 46). In accordance with the manufacturing method shown in FIG. 36 to FIG. 46, the window plate 13 is bonded to the outer edge portions 14 of the N-type semiconductor substrate 10 in the window plate bonding step (refer to FIG. 38). This eliminates the use of an external package such as a ceramic package, whereby it is possible to obtain a chip-sized back illuminated photodiode 4. In accordance with the present manufacturing method, it is therefore possible to achieve a back illuminated photodiode 4 having a sufficiently small package. Since this also eliminates the use of a step of packing a back illuminated photodiode 4 into a ceramic package, etc., the manufacturing process for the entire back illuminated photodiode 4 is simplified. Further, the window plate 13 is bonded to the outer edge portion 14 by anodic bonding. This allows the window plate 13 and the outer edge portion 14 to be bonded solidly at the interface therebetween. In addition, the anodic bonding can seal the rear surface S2 of the N-type semiconductor substrate 10 hermetically, resulting in a further improvement in reliability for the back illuminated photodiode 4. Also, since the insulating film 24 on the outer edge portions 14 is removed in the step shown in FIG. 37, the strength of the anodic bonding between the window plate 13 and the outer edge portions 14 is increased. Additionally, the insulating film 24 on the outer edge portions 14 shall not necessarily be removed, and that even if the insulating film 24 on the outer edge portions 14 may be formed, the window plate 13 can be bonded to the outer edge portions 14 by anodic bonding. However, in this case, the insulating film 24 on the outer edge portions 14 preferably has a small thickness (e.g. 0.1 μm or less). In addition, in the case of performing anodic bonding under a dry inert gas atmosphere such as dry N2 gas or under a vacuum atmosphere in the window plate bonding step, the areas between the recessed portions 12 and the window plate 13 are to be sealed with N2 or evacuated. Therefore, the reliability for the back illuminated photodiode 4 will further be improved in this case. FIG. 47 is a cross-sectional view showing a fifth embodiment of a back illuminated photodetector according to the present invention. The back illuminated photodiode 5 comprises an N-type semiconductor substrate 10, a P+-type impurity semiconductor region 11, a recessed portion 12, and a window plate 13. In the surface layer on the upper surface S1 side of the N-type semiconductor substrate 10 is partially formed the P+-type impurity semiconductor region 11. In the rear surface S2 of the N-type semiconductor substrate 10 and in an area opposite the P+-type impurity semiconductor region 11 is formed the recessed portion 12. Also, the window plate 13 is bonded to the outer edge portion 14 of the recessed portion 12. In the present embodiment, the window plate 13 is made of quartz and is bonded to the outer edge portion 14 by anodic bonding. In addition, the window plate 13 and the outer edge portion 14 are bonded to each other via a Pyrex glass 16 provided therebetween. The Pyrex glass 16 contains alkali metal and is formed on the window plate 13. More specifically, the Pyrex glass 16 is formed preliminarily on the window plate 13 and at the position corresponding to the outer edge portion 14. The thickness of the Pyrex glass 16 is about 0.1 to 10 μm, for example. Additionally, the glass between the window plate 13 and the outer edge portion 14 is not restricted to Pyrex glass, but may be one containing alkali metal. The back illuminated photodiode 5 also comprises an N-type highly-doped impurity semiconductor layer 21, an N+-type highly-doped impurity semiconductor region 22, insulating films 23 and 24, an anode electrode 25, and a cathode electrode 26. The N+-type highly-doped impurity semiconductor layer 21 is formed in the entire surface layer on the rear surface S2 side of the N-type semiconductor substrate 10. The N+-type highly-doped impurity semiconductor region 22 is formed in the surface layer on the upper surface S1 side of the N-type semiconductor substrate 10 at a predetermined distance from the P+-type impurity semiconductor region 11. The insulating films 23 and 24 are formed, respectively, on the upper surface S1 and the rear surface S2 of the N-type semiconductor substrate 10. In the insulating film 23 are formed openings 23a and 23b. On the insulating film 23 and in the areas including the openings 23a and 23b are formed, respectively, the anode electrode 25 and the cathode electrode 26. The back illuminated, photodiode 5 further comprises a passivating film 31, a supporting film 32, filling electrodes 33a and 33b, UBMs 34a and 34b, and bumps 35a and 35b. The passivating film 31 is provided on the upper surface S1 of the N-type semiconductor substrate 10 in such a manner as to cover the insulating film 23, anode electrode 25, and cathode electrode 26. On the passivating film 31 is formed the supporting film 32. Also, the filling electrodes 33a and 33b penetrate through the passivating film 31 and the supporting film 32 to extend, respectively, from the anode electrode 25 and the cathode electrode 26 to the surface of the supporting film 32. On the exposed portions of the filling electrodes 33a and 33b at the surface of the supporting film 32 are formed the UBMs 34a and 34b. On the surfaces of the UBMs 34a and 34b on the opposite side of the filling electrodes 33a and 33b are formed the bumps 35a and 35b. The effect of the back illuminated photodiode 5 will here be described. In the back illuminated photodiode 5, the window plate 13 is bonded to the outer edge portion 14 of the N-type semiconductor substrate 10. This eliminates the use of an external package such as a ceramic package, whereby it is possible to obtain a chip-sized back illuminated photodiode 5. Accordingly, there is achieved a back illuminated photodiode 5 having a sufficiently small package. Further, in the back illuminated photodiode 5, the surface of the window plate 13 functions as an incident plane for to-be-detected light. Since the surface of the window plate 13 can be flattened more easily than resin, it is possible to suppress the scattering of to-be-detected light at the incident plane. There is thus achieved a back illuminated photodiode 5 capable of detecting light at a high sensitivity. In addition, as a glass of the window plate 13 quartz is used. Quartz has a transmissivity for visible light especially higher than that of kovar glass or Pyrex, which contributes significantly to increasing the sensitivity of the back illuminated photodiode 5. Further, since quartz has a extremely high transmissivity also for UV light, the back illuminated photodiode 5 can detect light at a high sensitivity even in the case of UV light to be detected. Also, providing a glass containing alkali metal between the window plate 13 and the outer edge portion 14 allows for favorable anodic bonding between the window plate 13 made of quartz not containing alkali metal and the outer edge portion 14. In addition, the anodic bonding can hermetically seal the rear surface S2 of the N-type semiconductor substrate 10, resulting in a further improvement in reliability for the back illuminated photodiode 5. Further, performing anodic bonding under a dry inert gas atmosphere such as dry nitrogen gas or under a vacuum atmosphere results in still a further improvement in reliability. An exemplary method for manufacturing the back illuminated photodiode 5 shown in FIG. 47 will here be described with reference to FIG. 48 to FIG. 57. There is prepared an N-type semiconductor substrate 10. In the N-type semiconductor substrate 10 are then formed N+-type highly-doped impurity semiconductor regions 22, P+-type impurity semiconductor regions 11, and recessed portions 12, and on the upper surface S1 and the rear surface S2 are formed, respectively, insulating films 23 and 24. The steps so far are the same as the manufacturing method shown in FIG. 3 to FIG. 6, FIG. 7, and FIG. 8 (FIG. 48). Next, while the window plate 13 made of quartz is in contact with the outer edge portions 14, the window plate 13 is bonded to the outer edge portions 14 by anodic bonding (window plate bonding step). The bonding is to be performed via Pyrex glasses 16 which are formed preliminarily by vapor deposition or sputtering, etc., at the positions within the window plate 13 corresponding to the outer edge portions 14. In order to form the Pyrex glasses 16 only at the positions within the window plate 13 corresponding to the outer edge portions 14, after forming a Pyrex glass 16 on the entire window plate 13, it is only required to perform patterning so that only the Pyrex glass 16 formed at the positions within the window plate 13 corresponding to the outer edge portions 14 remains (FIG. 49). Additionally, instead of vapor deposition or sputtering, the Pyrex glasses 16 for connecting the window plate 13 and the outer edge portions 14 may be achieved by preparing a plate-like glass formed preliminarily in a shape corresponding to the outer edge portions 14, and then providing it between the window plate 13 and the outer edge portions 14. Also, after aluminum is deposited on the upper surface S1, a predetermined pattern is made to form anode electrodes 25 and cathode electrodes 26 (FIG 50). Next, a passivating film 31 is deposited on the upper surface S1 of the N-type semiconductor substrate 10, on which the anode electrodes 25 and the cathode electrodes 26 are formed, by a plasma-CVD method or the like. Also, through-holes 31 a are formed in portions corresponding to bumps 35a and 35b within the passivating film 31 (FIG. 51). Further, a supporting film 32 is formed on the upper surface S1, and through-holes 32a are formed in the portions corresponding to the through-holes 31 a in the passivating film 31 (FIG. 52). Also, a conductive material 33 is deposited on the upper surface S1 in such a manner as to fill the through-holes 31 a and 32a. On the anode electrodes 25 and the cathode electrodes 26 are provided intermediate metals (not shown in the figure) for improving the bonding to the conductive material 33 (FIG. 53). Next, the surface of the conductive material 33 is polished to remove the conductive material 33 deposited on the supporting film 32. Thus, filling electrodes 33a and 33b are formed (FIG. 54). Additionally, instead of filling the through holes, a thin film electrode (having a thickness of about 0.5 to 10 μm, for example, and preferably about 1 μm) may be formed in such a manner as to cover the sidewalls of the through-holes 31a and 32a, although not shown in the figure. In this case, it is possible to omit the polishing step. In addition, UBMs 34a and 34b are formed, respectively, on the filling electrodes 33a and 33b on the upper surface S1 by electroless plating. Further, bumps 35a and 35b are formed on the UBMs 34a and 34b by printing or a ball-mounting method (FIG. 55). Finally, in order to obtain individually separated back illuminated photodiodes 5, dicing is performed along the alternate long and short dashed lines L1 shown in FIG. 56 (dicing step). Thus, the wafer shown in FIG. 56 is to be separated individually to obtain back illuminated photodiodes 5 (FIG. 57). In accordance with the manufacturing method shown in FIG. 48 to FIG. 57, the window plate 13 is bonded to the outer edge portions 14 of the N-type semiconductor substrate 10 in the window plate bonding step (refer to FIG. 49). This eliminates the use of an external package such as a ceramic package, whereby it is possible to obtain a chip-sized back illuminated photodiode 5. In accordance with the present manufacturing method, it is therefore possible to achieve a back illuminated photodiode 5 having a sufficiently small package. Since this also eliminates the use of a step of packing a back illuminated photodiode 5 into a ceramic package, etc., the manufacturing process for the entire back illuminated photodiode 5 is simplified. In addition, as a glass of the window plate 13 quartz is used. Quartz has a transmissivity for visible light especially higher than that of kovar glass or Pyrex, which significantly contributes to increasing the sensitivity of the back illuminated photodiode 5. Further, since quartz has an extremely high transmissivity also for the wavelength of UV light, it is possible, in accordance with the present manufacturing method, to obtain a back illuminated photodiode 5 capable of detecting light at a high sensitivity even in the case of UV light to be detected. Also, providing a glass containing alkali metal between the window plate 13 and the outer edge portion 14 allows for favorable anodic bonding between the window plate 13 made of quartz not containing alkali metal and the outer edge portion 14. In addition, providing a metal layer between the window plate 13 and the outer edge portion 14 instead of a glass containing alkali metal may allow the same effect to be achieved. FIG. 58 is a cross-sectional view showing a sixth embodiment of a back illuminated photodetector according to the present invention. The back illuminated photodiode 6 comprises an N-type semiconductor substrate 10, a P+-type impurity semiconductor region 11, a recessed portion 12, and a window plate 13. In the surface layer on the upper surface S1 side of the N-type semiconductor substrate 10 is partially formed the P+-type impurity semiconductor region 11. In the rear surface S2 of the N-type semiconductor substrate 10 and in an area opposite the P+-type unpurity semiconductor region 1-1 is formed the recessed portion 12. Also, the window plate 13 is bonded to the outer edge portion 14 of the recessed portion 12. In the present embodiment, the bonding between the window plate 13 and the outer edge portion 14 is preformed via metal layers 17a, 17b and an intermediate metal layer 18. That is, between the window plate 13 and the outer edge portion 14 are provided the metal layer 17a, intermediate metal layer 18, and metal layer 17b in this order from the outer edge portion 14 side. As a metal of the metal layers 17a and 17b, for example, Al, Cu, Au, Ni, Ti, Pt, W, In, Sn, etc., or an laminated film or alloy of some of these metals can be used. Also, as a metal of the intermediate metal layer 18, for example, a metal solder made of Sn, SnPb, SnAg, AuSn, Al or In, etc., can be used. The back illuminated photodiode 6 also comprises an N-type highly-doped impurity semiconductor layer 21, an N+-type highly-doped impurity semiconductor region 22, insulating films 23 and 24, an anode electrode 25, and a cathode electrode 26. The R-type highly-doped impurity semiconductor layer 21 is formed in the entire surface layer on the rear surface S2 side of the N-type semiconductor substrate 10. The N+-type highly-doped impurity semiconductor region 22 is formed in the surface layer on the upper surface S1 side of the N-type semiconductor substrate 10 at a predetermined distance from the P+-type impurity semiconductor region 11. The insulating films 23 and 24 are formed, respectively, on the upper surface S1 and the rear surface S2 of the N-type semiconductor substrate 10. In the insulating film 23 are formed openings 23a and 23b. On the insulating film 23 and in the areas including the openings 23a and 23b are formed, respectively, the anode electrode 25 and the cathode electrode 26. The back illuminated photodiode 6 further comprises a passivating film 31, a supporting film 32, filling electrodes 33a and 33b, UBMs 34a and 34b, and bumps 35a and 35b. The passivating film 31 is provided on the upper surface S1 of the N-type semiconductor substrate 10 in such a manner as to cover the insulating film 23, anode electrode 25, and cathode electrode 26. On the passivating film 31 is formed the supporting film 32. Also, the filling electrodes 33a and 33b penetrate through the passivating film 31 and the supporting film 32 to extend, respectively, from the anode electrode 25 and the cathode electrode 26 to the surface of the supporting film 32. On the exposed portions of the filling electrodes 33a and 33b at the surface of the supporting film 32 are formed the UBMs 34a and 34b. On the surfaces of the UBMs 34a and 34b on the opposite side of the filling electrodes 33a and 33b are formed the bumps 35a and 35b. The effect of the back illuminated photodiode 6 will here be described. In the back illuminated photodiode 6, the window plate 13 is bonded to the outer edge portion- 14 of the N-type semiconductor substrate 10. This eliminates the use of an external package such as a ceramic package, whereby it is possible to obtain a chip-sized back illuminated photodiode 6. Accordingly, there is achieved a back illuminated photodiode 6 having a sufficiently small package. Further, in the back illuminated photodiode 6, the surface of the window plate 13 functions as an incident plane for to-be-detected light. Since the surface of the window plate 13 can be flattened more easily than resin, it is possible to suppress the scattering of to-be-detected light at the incident plane. There is thus achieved a back illuminated photodiode 6 capable of detecting light at a high sensitivity. In addition, between the window plate and the outer edge portion 14 are provided the metal layers 17a, 17b and the intermediate metal layer 18. This allows the window plate 13 and the outer edge portion 14 to be bonded solidly by metal bonding. In addition, the metal bonding can hermetically seal the rear surface S2 of the N-type semiconductor substrate 10, resulting in a further improvement in reliability for the back illuminated photodiode 6. Further, performing metal bonding under a dry inert gas atmosphere such as dry nitrogen gas or under a vacuum atmosphere results in still a further improvement in reliability. Additionally, the metal layers 17a and 17b may be bonded directly to each other without providing an intermediate metal layer 18. Since the window plate 13 is bonded to the outer edge portion 14 by metal bonding, the back illuminated photodiode 6 can suitably be used also in the case of UV light to be detected. An exemplary method for manufacturing the back illuminated photodiode 6 shown in FIG. 58 will here be described with reference to FIG. 59 to FIG. 68. There is prepared an N-type semiconductor substrate 10. In the N-type semiconductor substrate 10 are then formed N+-type highly-doped impurity semiconductor regions 22, P+-type impurity semiconductor regions 11, and recessed portions 12, and on the upper surface S1 and the rear surface S2 are formed, respectively, insulating films 23 and 24. The steps so far are the same as the manufacturing method shown in FIG. 3 to FIG. 6, FIG. 7, and FIG. 8. Contact holes for electrodes are also formed in the insulating film 23 (FIG. 59). Next, after aluminum is deposited on the upper surface S1, a predetermined pattern is made to form anode electrodes 25 and cathode electrodes 26. On the outer edge portions 14 are further formed metal layers 17a (FIG. 60). In addition, a passivating film 31 is deposited on the upper surface S1 of the N-type semiconductor substrate 10, on which the anode electrodes 25 and the cathode electrodes 26 are formed, by a plasma-CVD method or the like. Also, through-holes 331a are formed in portions corresponding to bumps 35a and 35b within the passivating film 31 (FIG. 61). Additionally, the metal layers 17a may be formed after the passivating film 31. Next, a supporting film 32 is formed on the upper surface S1, and through-holes 32a are formed in the portions corresponding to the through-holes 31a in the passivating film 31 (FIG. 62). Also, a conductive material 33 is deposited on the-upper surface S1 in such a manner as to fill the through-holes 31 a and 32a. On the anode electrodes 25 and the cathode electrodes 26 are provided intermediate metals (not shown in the figure) for improving the bonding to the conductive material 33 (FIG. 63). Further, the surface of the conductive material 33 is polished to remove the conductive material 33 deposited on the supporting film 32. Thus, filling electrodes 33a and 33b are formed (FIG. 64). Additionally, instead of filling the through-holes, a thin film electrode (having a thickness of about 0.5 to 10 cm, for example, and preferably about 1 μm) may be formed in such a manner as to cover the sidewalls of the through-holes 31 a and 32a, although not shown in the figure. In this case, it is possible to omit the polishing step. Next, while the window plate 13 is in contact with the outer edge portions 14 with the metal layers 17a formed thereon, the window plate 13 is bonded to the outer edge portions 14 (window plate bonding step). The bonding is to be performed by preliminarily forming metal layers 17b at the positions within the window plate 13 corresponding to the outer edge portions 14, and then by metal bonding the metal layers 17a on the outer edge portions 14 and the metal layers 17b on the window plate 13 to each other via intermediate metal layers 18. Additionally, the metal bonding is preferably performed under a dry inert gas atmosphere such as dry N2 gas or under a vacuum atmosphere (FIG. 65). In addition, UBMs 34a and 34b are formed on the filling electrodes 33a and 33b on the upper surface S1 by electroless plating. Further, bumps 35a and 35b are formed on the UBMs 34a and 34b by printing or a ball-mounting method, etc. (FIG. 66). Finally, in order to obtain individually separated back illuminated photodiodes 6, dicing is performed along the alternate long and short dashed lines L1 shown in FIG. 67 (dicing step). Thus, the wafer shown in FIG. 67 is to be separated individually to obtain back illuminated photodiodes 6 (FIG. 68). In accordance with the manufacturing method shown in FIG. 59 to FIG. 68, the window plate 13 is bonded to the outer edge portions 14 of the N-type semiconductor substrate 10 in the window plate bonding step (refer to FIG. 65). This eliminates the use of an external package such as a ceramic package, whereby it is possible to obtain a chip-sized back illuminated photodiode 6. In accordance with the present manufacturing method, it is therefore possible to achieve a back illuminated photodiode 6 having a sufficiently small package. Since this also eliminates the use of a step of packing a back illuminated photodiode 6 into a ceramic package, etc., the manufacturing process for the entire back illuminated photodiode 6 is simplified. Further, the window plate 13 is bonded to the outer edge portion 14 via the metal layers 17a and 17b, which are formed, respectively, on the outer edge portion 14 and the window plate 13. This allows the window plate 13 and the outer edge portion 14 to be bonded solidly by metal bonding. In addition, the metal bonding can hermetically seal the rear surface S2 of the N-type semiconductor substrate 10, resulting in a further improvement in reliability for the back illuminated photodiode 6. The back illuminated photodetector according to the present invention is not restricted to the above-described embodiments, and various modifications may be made. For example, in the back illuminated photodiode 1 shown in FIG. 1, a P-type semiconductor substrate may be used instead of the N-type semiconductor substrate 10. In this case, the impurity semiconductor region 11 has N-type conductivity, while the highly-doped impurity semiconductor layer 21 and the highly-doped impurity semiconductor region 22 have P-type conductivity. Although in FIG. 12 an example of depositing a conductive material 33 made of Cu is shown, Ni may be used instead of Cu to perform electroless plating of Ni directly on the surface of the anode electrodes 25 and the cathode electrodes 26 that are exposed from the through-holes 31a and 32a. In this case, it is possible to omit the step of polishing the surface of the conductive material 33 illustrated in FIG. 13. Although in FIG. 15 an example of forming UBMs 34a and 34b as well as bumps 35a and 35b on the filling electrodes 33a and 33b is shown, there is also a method of employing the filling electrodes 33a and 33b themselves as bumps. That is, 02, etc., is used to dry etch the surface of the supporting film 32 with the through-holes 32a being filled with the filling electrodes 33a and 33b (refer to FIG. 14). Thus, since the filling electrodes 33a and 33b partially protrude from the surface of the supporting film 32, the protruding portions can be used as bumps. In this case, it is also not necessary to form UBMs 34a and 34b. Alternatively, as a conductive material for forming the filling electrodes 33a and 33b, a conductive resin may be used. This allows the operation of filling the through-holes with electrodes by printing, etc., to be completed in a short time. Although in FIG. 25 an arrangement that chamfered portions 13a are formed at the four corners of the window plate 13 is shown, it is only required that at least one corner of the window plate 13 is formed into a chamfered portion 13a. Also, in this case, it is possible to reduce the possibility of chipping relative to the case where no chamfered portion 13a is provided. Also, in FIG. 29, as the N-type semiconductor substrate 20, as a bonded wafer in which an N+-type highly-doped impurity semiconductor region and an N-type impurity semiconductor region having an impurity concentration lower than that of the N+-type highly-doped impurity semiconductor region are bonded to each other may be used. In this case, the N-type impurity semiconductor region is to be provided on the upper surface S1 side, while the N+-type highly-doped impurity-semiconductor layer on the rear surface S2 side of the N-type semiconductor substrate 20. Further, the window plate bonding step shown in FIG. 38 may be performed after the step of forming a passivating film 31 (refer to FIG. 40). Alternatively, the window plate bonding step may be performed after the step of polishing the surface of the conductive material 33 (refer to FIG. 43). In this case, since it is possible to perform anodic bonding with the thinned portions in the N-type semiconductor substrate 10 being protected by the supporting film 32, it is possible to prevent the N-type semiconductor substrate 10 from being physically damaged in an anodic bonding operation. Although in the window plate bonding step shown in FIG. 49, the anodic bonding is performed with the insulating film 24 being formed in the entire rear surface S2 of the N-type semiconductor substrate 10, the anodic boding may be performed with the outer edge portions 14 of the N-type semiconductor substrate 10 being exposed by removing the insulating film 24 on the outer edge portions 14. In this case, the strength of the bonding between the window plate 13 and the outer edge portions 14 will be further improved. Also, the window plate bonding step shown in FIG. 49 may be performed after the step of forming a passivating film 31 (refer to FIG. 51). Alternatively, the window plate bonding step may be performed after the step of polishing the surface of the conductive material 33 (refer to FIG. 54). In this case, since it is possible to perform anodic bonding with the thinned portions in the N-type semiconductor substrate 10 being protected by the supporting film 32, it is possible to prevent the N-type semiconductor substrate 10 from being physically damaged in an anodic bonding operation. Although in FIG. 49, the Pyrex glasses 16 are formed only at the positions within the window plate 13 corresponding to the outer edge portions 14, a Pyrex glass 16, having a small thickness, may be formed on the entire window plate 13 because it never blocks optical transmission. Also, the window plate bonding step shown in FIG. 65 may be performed immediately after the step of forming metal layers 17a on the outer edge portions 14 (refer to FIG. 60). INDUSTRIAL APPLICABILITY In accordance with the present invention, it is possible to achieve a back illuminated photodetector having a sufficiently small package as well as being capable of suppressing the scattering of to-be-detected light and method for manufacturing the same.

<SOH> BACKGROUND ART <EOH>In such a conventional back illuminated photodiode 100 as shown in FIG. 69 , in the superficial surface layer of an N-type silicon substrate 101 are formed a P + -type highly-doped impurity semiconductor region 102 and an N + -type highly-doped impurity semiconductor region 103 . The P + -type highly-doped impurity semiconductor region 102 and the N + -type highly-doped impurity semiconductor region 103 are connected, respectively, with an anode electrode 104 and a cathode electrode 105 . On the electrodes 104 and 105 are formed bump electrodes 106 made from solder. Also, the N-type silicon substrate 101 is thinned in the portion corresponding to the P + -type highly-doped impurity semiconductor region 102 from the rear surface side thereof. The thinned portion functions as an incident part for to-be-detected light. As shown in FIG. 69 , the back illuminated back illuminated photodiode 100 is packed into a ceramic package 107 by flip-chip bonding. That is, the bump electrodes 106 of the back illuminated photodiode 100 are connected to solder pads 109 provided on a bottom wiring 108 of the ceramic package 107 . The bottom wiring 108 is connected to output terminal pins 110 through wire bonding. Also, on the surface of the ceramic package 107 is seam-welded a window frame 111 using brazing material 112 . In the window frame 1 l is formed an opening at the position corresponding to the thinned portion of the back illuminated photodiode 100 , and in the opening is provided a transparent window member 113 such as kovar glass for transmitting to-be-detected light. Patent Document 1: Japanese Published Unexamined Patent Application No. H09-219421

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a cross-sectional view showing a first embodiment of a back illuminated photodetector according to the present invention. FIG. 2 is a perspective view of the back illuminated photodiode 1 shown in FIG. 1 . FIG. 3 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 4 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 5 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 6 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 7 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 8 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 9 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 10 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG 1 . FIG. 11 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 12 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 13 is a step chart showing a method for manufacturing the back illuminated photodiode. 1 shown in FIG. 1 . FIG. 14 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 15 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 16 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 17 is a step chart showing a method for manufacturing the back illuminated photodiode 1 shown in FIG. 1 . FIG. 18 is a view illustrating an exemplary variation of the dicing step shown in FIG. 16 . FIG. 19 is a: cross-sectional view showing an exemplary structure of a back illuminated photodiode obtained through the dicing step illustrated in FIG. 18 . FIG. 20 is a cross-sectional view showing- an exemplary structure of a back illuminated photodiode obtained through the dicing step illustrated in FIG. 18 . FIG. 21 is a cross-sectional view showing an exemplary structure of a back illuminated photodiode obtained through the dicing step illustrated in FIG. 18 . FIG. 22 is a cross-sectional view showing an exemplary structure of a back illuminated photodiode obtained through the dicing step illustrated in FIG. 18 . FIG. 23 is a cross-sectional view showing a first exemplary variation of the back illuminated photodiode 1 shown in FIG. 1 . FIG. 24 is a cross-sectional view showing a second exemplary variation of the back illuminated photodiode 1 shown in FIG. 1 . FIG. 25 is a perspective view showing a third exemplary variation of the back illuminated photodiode 1 shown in FIG. 1 . FIG. 26 is a plan view showing the appearance of the wafer of the back illuminated photodiode 1 shown in FIG. 1 before dicing when viewed from the side of the window plate 13 . FIG. 27 is a plan view showing the appearance of the wafer of the back illuminated photodiode 1 c shown in FIG. 25 before dicing when viewed from the side of the window plate 13 . FIG. 28 is a cross-sectional view showing a second embodiment of a back illuminated photodetector according to the present invention. FIG. 29 is a view illustrating an exemplary method of forming the N + -type highly-doped impurity semiconductor region 28 shown in FIG. 28 . FIG. 30 is a view illustrating an exemplary method of forming the N + -type highly-doped impurity semiconductor region 28 shown in FIG. 28 . FIG. 31 is a view illustrating an exemplary method of forming the N + -type highly-doped impurity semiconductor region 28 shown in FIG. 28 . FIG. 32 is a plan view showing a third embodiment of a back illuminated photodetector according to the present invention. FIG. 33 is a cross-sectional view of the back illuminated photodiode array 3 shown in FIG. 32 along the line XX-XX.: FIG. 34 is a cross-sectional view showing an exemplary variation of the back illuminated photodiode array 3 shown in FIG. 33 . FIG. 35 is a cross-sectional view showing a fourth embodiment of a back illuminated photodetector according to the present invention. FIG. 36 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG 35 . FIG. 37 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG 35 . FIG. 38 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35 . FIG. 39 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35 . FIG. 40 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35 . FIG. 41 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35 . FIG. 42 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35 . FIG. 43 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35 . FIG. 44 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35 . FIG. 45 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35 . FIG. 46 is a step chart showing a method for manufacturing the back illuminated photodiode 4 shown in FIG. 35 . FIG. 47 is a cross-sectional view showing a fifth embodiment of a back illuminated photodetector according to the present invention. FIG. 48 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47 . FIG. 49 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47 . FIG. 50 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47 . FIG. 51 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47 . FIG. 52 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47 . FIG. 53 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47 . FIG. 54 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47 . FIG. 55 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47 . FIG. 56 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47 . FIG. 57 is a step chart showing a method for manufacturing the back illuminated photodiode 5 shown in FIG. 47 . FIG. 58 is a cross-sectional view showing a sixth embodiment of a back illuminated photodetector according to the present invention. FIG. 59 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58 . FIG. 60 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58 . FIG. 61 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58 . FIG. 62 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58 . FIG. 63 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58 . FIG. 64 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58 . FIG. 65 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58 . FIG. 66 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58 . FIG. 67 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58 . FIG. 68 is a step chart showing a method for manufacturing the back illuminated photodiode 6 shown in FIG. 58 . FIG. 69 is a cross-sectional view of a conventional back illuminated photodiode. detailed-description description="Detailed Description" end="lead"?

20060712

20090714

20061214

61774.0

H01L27148

BUDD, PAUL A

BACKSIDE-ILLUMINATED PHOTODETECTOR

UNDISCOUNTED

ACCEPTED

H01L

ACCEPTED

Image sensor and method for fabricating the same

An image sensor includes a substrate in which photoelectric elements have been formed, and an array of optical path conversion elements formed at a light so that the optical path converted light may be incident on the substrate, wherein each of the optical path conversion elements has different tangent line gradients on the corresponding parts of incident surfaces according to distances from the center of the image sensor in order to compensate for differences of incident angles of incident light according to the distances from the center of the image sensor. In addition, a method for fabricating the image sensor fabricates the optical path conversion elements according to a photolithography process using a gray scale mask, combinations of the photolithography process and a reactive ion etching process, or combinations of the photolithography process, the reactive ion etching process, and an UV-molding process.

1-18. (canceled) 19. The image sensor comprising: a substrate in which an array of photoelectric elements is formed; and an array of optical path conversion elements for converting optical paths of incident light formed at a light incident side of the substrate so that the optical path converted light may be incident on the substrate, each optical path conversion element being formed to match with each photoelectric element, wherein the optical path conversion elements are selected from the group consisting of aspheric micro lenses and aspheric micro reflecting mirrors, the aspheric micro lenses and aspheric micro reflecting mirror having different tangent line gradient values on individual parts of an incident surface of the same optical path conversion element to condense incident light to the photoelectric element, and the incident surface of each optical path conversion element has a tangent line gradient value to convert the optical path of light incident slantingly on a peripheral area of the image sensor at a larger inclination angle as the peripheral area is away from the center of the image sensor to be identical with the optical path of light incident vertically on a central area of the image sensor to counterbalance the inclination angle of light incident on the peripheral area of the image sensor, tangent line gradient values of corresponding parts of the incident surfaces of the optical path conversion elements at an identical distance from the respective matching photoelectric elements being different from one another according to distances between the corresponding parts and the center of the image sensor. 20. The image sensor of claim 19, wherein the centers of the optical path conversion elements are offset from the centers of the matching photoelectric elements according to the distances from the center of the image sensor. 21. The image sensor of claim 19, wherein, when the single image sensor is divided into a plurality of regions according to the distances from its center, the optical path conversion elements in the same region have the identical tangent line gradient value on the corresponding parts of the incident surfaces, but the optical path conversion elements in the different regions have different tangent line gradient values on the corresponding parts of the incident surfaces according to the distances from the center of the image sensor. 22. The image sensor of claim 19, which comprises both the aspheric micro lens type optical path conversion elements and the aspheric micro reflecting mirror type optical path conversion elements. 23. The image sensor of claim 22, wherein the centers of the optical path conversion elements are offset from the centers of the matching photoelectric elements according to the distances from the center of the image sensor. 24. The image sensor of claim 22, wherein, when the single image sensor is divided into a plurality of regions according to the distances from its center, the optical path conversion elements in the same region have the identical tangent line gradient value on the corresponding parts of the incident surfaces, but the optical path conversion elements in the different regions have different tangent line gradient values on the corresponding parts of the incident surfaces according to the distances from the center of the image sensor. 25. The image sensor of claim 19, wherein, when it is presumed that a refraction index of a layer contacting the incident surface of the aspheric micro lens is ‘n1’ the inclination angle between light incident on the incident surface of the aspheric micro lens and the optical axis is ‘φ1’, a refraction index of the aspheric micro lens is ‘n2’, and an angle of refracted light to the optical axis for light incident to one point on the incident surface of the aspheric micro lens to be refracted by the aspheric micro lens and condensed to the photoelectric element is ‘φ2’, a tangent line gradient α at the point on the incident surface of the aspheric micro lens is represented by following formula: α = tan - 1 ⁡ ( n 1 ⁢ sin ⁢ ⁢ ϕ 1 - n 2 ⁢ sin ⁢ ⁢ ϕ 2 n 1 ⁢ cos ⁢ ⁢ ϕ 1 - n 2 ⁢ cos ⁢ ⁢ ϕ 2 ) . 26. The image sensor of claim 25, wherein the centers of the optical path conversion elements are offset from the centers of the matching photoelectric elements according to the distances from the center of the image sensor. 27. The image sensor of claim 25, wherein, when the single image sensor is divided into a plurality of regions according to the distances from its center, the optical path conversion elements in the same region have the identical tangent line gradient value on the corresponding parts of the incident surfaces, but the optical path conversion elements in the different regions have different tangent line gradient values on the corresponding parts of the incident surfaces according to the distances from the center of the image sensor. 28. The image sensor of claim 19, wherein, when it is presumed that the inclination angle between light incident on the incident surface of the aspheric micro reflecting mirror and the optical axis is ‘φ3’, and an angle of reflected light to the optical axis for light incident to one point on the incident surface of the aspheric micro reflecting mirror to be reflected by the aspheric micro reflecting mirror and condensed to the photoelectric element is ‘φ4’, a tangent line gradient β at the point on the incident surface of the aspheric micro reflecting mirror is represented by following formula: β = 90 ⁢ ° + ϕ 3 + ϕ 4 2 . 29. The image sensor of claim 28, wherein the centers of the optical path conversion elements are offset from the centers of the matching photoelectric elements according to the distances from the center of the image sensor. 30. The image sensor of claim 28, wherein, when the single image sensor is divided into a plurality of regions according to the distances from its center, the optical path conversion elements in the same region have the identical tangent line gradient value on the corresponding parts of the incident surfaces, but the optical path conversion elements in the different regions have different tangent line gradient values on the corresponding parts of the incident surfaces according to the distances from the center of the image sensor.

CROSS-REFERENCE TO RELATED PATENT APPLICATION This application claims the benefit of Korean Patent Application No. 2003-0049859, filed on Jul. 21, 2003, in the Korean Intellectual Property Office and International Application No. PCT/KR2004/000729, filed on Mar. 30, 2004, the disclosures of which are incorporated herein in their entirety by reference. FIELD OF THE INVENTION The present invention relates to an image sensor and a method for fabricating the same, and more particularly to, an image sensor and a method for fabricating the same, which can make intensive and homogeneous light sensed in every position of the image sensor. DESCRIPTION OF THE RELATED ART An image sensor such as a CCD or CMOS has been used for various products including a digital camera, a digital camcorder, a CCTV, etc. The image sensor is used together with lenses in order to improve performance of the products. There have been increasing demands of consumers on high performance and miniaturization of the image sensor. Thus, researches have been made to develop a high performance miniaturized image sensor. FIG. 1 illustrates a basic structure of a conventional image sensor, which does not have an array of micro lenses 5. Referring to FIG. 1, an electric circuit including photoelectric elements 1 is formed on a substrate 3 of the image sensor. When light passing through a lens system 6 is incident on the substrate 3, the photoelectric elements 1 sense the light and convert the light into an electric signal, to capture images. A color image sensor includes color filters 2. The color filters 2 transmit a specific wavelength of light. Photodiodes are generally used as the photoelectric elements 1. The substrate 3 may include a variety of composite layers. In order to simplify explanations of the invention, the substrate 3 is presumed to have a silicon chip layer 3a and a color filter layer 3b. Here, the photoelectric elements 1 are formed on the silicon chip layer 3a and the color filters 2 are formed on the color filter layer 3b. Sensitivity of the image sensor is very dependent upon an amount of light incident on the photoelectric elements 1 for sensing light. However, in the image sensor of FIG. 1, an amount of light sensed by photoelectric elements 1 having small area is not much, which reduces optical efficiency. Accordingly, micro lenses 5 are used to condense light to the photoelectric elements 1. As a result, the amount of sensed light is increased, to improve optical efficiency of the image sensor. FIG. 2 illustrates a basic structure of a conventional image sensor including an array of micro lenses 5. According to high miniaturization and integration of the image sensor, the micro lenses 5 have been gradually recognized as essential elements for improving performance of the image sensor. Nevertheless, image sensors, which do not include micro lenses, are also useful in the low priced image sensor market. FIG. 3 illustrates one example of a system using an image sensor 8 (for example, digital camera). As illustrated in FIG. 3, the system using the image sensor 8 includes the image sensor 8, a lens system 6 having single or plural lenses, and a protective glass 7 for protecting the image sensor 8. FIG. 4 illustrates low optical efficiency of peripheral pixels of the image sensor of FIG. 2. The most important factor of the system using the image sensor 8 is whether the photoelectric elements 1 of the image sensor 8 can efficiently sense incident light. In the central area 8a of the image sensor 8, light is incident on the image sensor along an optical axis, passes through the micro lenses 5 and the color filters 2, and is efficiently sensed by the photoelectric elements 1. Conversely, in the peripheral areas 8b and 8c of the image sensor 8, light slanted to the optical axis is incident on the image sensor 8, passes through the micro lenses 5 and the color filters 2, and is incident on the photoelectric elements 1. Here, the amount of light is smaller in the peripheral areas 8b and 8c than the central area 8a. That is, the amount of sensed light is very different in the central area 8a and the peripheral areas 8b and 8c of the image sensor 8. Therefore, images captured in the peripheral areas 8b and 8c are more darkened than those in the central area 8a. In the worst case, images may not be captured in the peripheral areas 8b and 8c. Accordingly, a lot of researches have been made to efficiently condense light passing through the micro lenses 5 to the photoelectric elements 1 without loss. As the first method for efficiently condensing light, a large size lens system 6 for reducing an angle of light incident on the image sensor was used to improve optical efficiency. However, this requires many lenses to be used for aberration correction and thus increases a size of the whole system. It runs against the miniaturization tendency of the system. The second to fourth methods will be explained with reference to FIGS. 5 to 7. FIG. 5 illustrates another example of the conventional image sensor. As shown in FIG. 5, micro lenses 5 are arranged on different planes according to distances from the center of the image sensor. Such an image sensor has been disclosed in U.S. Pat. No. 6,556,349. This method is very efficient to correct spherical aberrations generated by a lens system 6. However, as compared with FIG. 4, an angle of light refracted by the micro lenses 5 is the same in the peripheral areas, but distances between the micro lenses 5 and the photoelectric elements 1 are increased. Thus, light is condensed separately from the photoelectric elements 1. FIG. 6 illustrates yet another example of the conventional image sensor. As depicted in FIG. 6, micro lenses 5 of different sizes are arranged according to distances from the center of the image sensor. Such an image sensor has been disclosed in Korean Unexamined Patent Publication 2003-0010148 and U.S. Pat. No. 6,556,349. This method increases a fill factor in the area in which light is incident on the surface of the image sensor at a large angle to an optical axis, and decreases the fill factor in the area in which light is incident at a small angle to the optical axis, to equalize amounts of light sensed by every photoelectric element 1. However, a large size micro lens 5 has a greater radius of curvature than a small size micro lens 5. In addition, a focal distance of the large size micro lens 5 is increased, to restrict refraction. Accordingly, light condensed by the large size micro lens 5 forms a focus farther than the small size micro lens 5, and is condensed separately from the photoelectric elements 1. FIG. 7 illustrates yet another example of the conventional image sensor. As illustrated in FIG. 7, micro lenses 5 are arranged in deviated positions from photoelectric elements 1 according to distances from the center of the image sensor. Such an image sensor has been disclosed in U.S. Pat. Nos. 6,518,640 and 6,008,511. In order to prevent light from being condensed outside the photoelectric elements 1 as shown in the methods of FIGS. 5 and 6, the method of FIG. 7 moves the micro lenses 5, to condense light to the photoelectric elements 1. However, when light is incident at a relatively large angle, it is intercepted by the other structures on a substrate 3. Therefore, an amount of sensed light is reduced. Moreover, intervals between the micro lenses 5 are different in the central area and the peripheral area of the image sensor, which complicates the fabrication process. That is, the conventional methods for improving optical efficiency stick to resultant phenomena, instead of seeking countermeasures on the basis of basic principles, and thus make little improvements in optical efficiency. DISCLOSURE OF THE INVENTION An object of the present invention is to change a structure of an image sensor to prevent brightness and resolution of captured images from being reduced because amounts of light sensed by photoelectric elements are small in some positions in the image sensor. That is, the object of the present invention is to improve efficiency of the image sensor by making very intensive and homogeneous light sensed in every position in the image sensor, when light from a lens system passes through a color filter layer of a substrate and is sensed by the photoelectric elements. The present invention takes notice of radical reasons of problems of the conventional image sensor, and solves the problems to raise efficiency of the image sensor. The conventional methods stick to resultant phenomena rather than radical countermeasures, and thus rarely improve efficiency of the image sensor. However, the present invention can considerably improve efficiency of the image sensor. For this, the present invention is based on two very simple principles. The first principle can be obtained from consideration of problems of the conventional image sensor that efficiency is bad. The optical efficiency of the conventional image sensor is reduced because light is slantingly incident on micro lenses. Accordingly, the present invention makes light incident on the micro lenses at a right angle, or makes the micro lenses themselves perform this function (aspheric micro lenses). It is very meaningful that light is incident at a right angle. It implies that light is incident at a right angle on the micro lenses of peripheral pixels of the image sensor as well as the micro lenses of central pixels. The second principle relates to a way of embodying the first principle, namely a way for making light incident on the surface of the image sensor at a right angle. Here, the present invention uses the Snell's law, a refraction law for controlling refractions when light passes through the interface between different media, and also uses the reflection law. An optical path of light is changed due to refraction or reflection. Here, let's presume that the optical path of light slantingly incident on the peripheral pixels of the image sensor is changed by a refraction or reflection element and then light is incident on the micro lenses at a right angle. Because light is incident on the micro lenses at a right angle, an angle of light refracted or reflected by the refraction or reflection element can be regarded as a fixed value. Therefore, we can consider that an inclination angle of light incident on the refraction or reflection element and a gradient value of an incident surface of the refraction or reflection element are mutually dependent variables. That is, when the inclination angle of light is changed, the gradient value of the incident surface has to be changed, to keep refracted or reflected light parallel to an optical axis. It implies that the present invention can make refracted or reflected light parallel to the optical axis by using optical path conversion elements which have different tangent line gradients on the corresponding parts of the incident surfaces according to distances between the corresponding parts and the center of the image sensor. The present invention originates from these very simple but important radical principles, which will later be explained in more detail with reference to FIGS. 8 to 10 and FIGS. 14 to 16. In order to achieve the above-described object of the invention, there is provided an image sensor comprising: a substrate in which an array of photoelectric elements is formed; and an array of optical path conversion elements for converting optical paths of incident light formed at a light incident side of the substrate so that the optical path converted light may be incident on the substrate, each optical path conversion element being formed to match with each photoelectric element, wherein an incident surface of each optical path conversion element has a tangent line gradient value to convert the optical path of light incident slantingly on a peripheral area of the image sensor at a larger inclination angle as the peripheral area is away from the center of the image sensor to be identical with the optical path of light incident vertically on a central area of the image sensor to counterbalance the inclination angle of light incident on the peripheral area of the image sensor, the tangent line gradient values of corresponding parts of the incident surfaces of the optical path conversion elements at an identical distance from the respective matching photoelectric elements being different from one another according to distances between the corresponding parts and the center of the image sensor. Preferably, the optical path conversion elements are micro prisms or micro reflecting mirrors having different incident surface gradients according to the distances from the center of the image sensor. Here, the single image sensor can include both the micro prism type optical path conversion elements and the micro reflecting mirror type optical path conversion elements. In addition, the single optical path conversion element can include combinations of a plurality of micro prisms. The micro prism type optical path conversion elements and the flat surface micro reflecting mirror type optical path conversion elements convert the optical path of light to be parallel to the optical axis. Preferably, the image sensor includes micro lenses, and the micro lenses are positioned in the optical path of light converted by the optical path conversion elements, for condensing light to the photoelectric elements. Preferable, the optical path conversion elements are aspheric micro lenses or aspheric micro reflecting mirrors. The single image sensor can include both the aspheric micro lens type optical path conversion elements and the aspheric micro reflecting mirror type optical path conversion elements. Preferably, the optical path conversion elements are so positioned that the centers of the optical path conversion elements are offset from the centers of the photoelectric elements according to the distances from the center of the image sensor. Preferably, when the image sensor is divided into a plurality of regions according to the distances from its center, the optical path conversion elements in the same region have the identical tangent line gradient value on the corresponding parts of the incident surfaces, but the optical path conversion elements in the different regions have different tangent line gradient values on the corresponding parts of the incident surfaces according to the distances between the corresponding parts and the center of the image sensor. According to another aspect of the invention, there is provided a method for fabricating an image sensor in which optical path conversion elements are formed according to a photolithography process using a gray scale mask, combinations of the photolithography process and a reactive ion etching process, or combinations of the photolithography process, the reactive ion etching process, and an UV-molding process. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 illustrates a basic structure of a conventional image sensor, which does not have an array of micro lenses; FIG. 2 illustrates a basic structure of a conventional image sensor including an array of micro lenses; FIG. 3 illustrates one example of a system using an image sensor; FIG. 4 illustrates low optical efficiency of peripheral pixels of the image sensor of FIG. 2; FIG. 5 illustrates another example of a conventional image sensor wherein micro lenses are arranged on different planes according to distances from the center of the image sensor; FIG. 6 illustrates yet another example of a conventional image sensor wherein micro lenses of different sizes are arranged according to distances from the center of the image sensor; FIG. 7 illustrates yet another example of a conventional image sensor wherein micro lenses are arranged in deviated positions from photoelectric elements according to distances from the center of the image sensor; FIG. 8 is a concept view showing that a prism can vary an optical path of light; FIG. 9 illustrates the refraction law of light, especially light passing through the prism of FIG. 8; FIG. 10 illustrates relations between an inclination angle and a gradient value of an incident surface for making light refracted by the prism parallel to an optical axis; FIGS. 11a and 11b illustrate image sensors including an array of micro prisms as optical path conversion elements in accordance with one embodiment of the present invention, wherein FIG. 1a shows the image sensor including a single array of micro prisms, and FIG. 11b shows the image sensor including a double array of micro prisms; FIG. 12 illustrates an image sensor including an array of micro prisms and an array of micro lenses as optical path, conversion elements in accordance with another embodiment of the present invention; FIG. 13 illustrates an image sensor including an array of aspheric micro lenses in accordance with yet another embodiment of the present invention; FIG. 14 is a concept view showing that a reflecting mirror can vary an optical path of light; FIG. 15 illustrates the reflection law of light, especially light reflected by the reflecting mirror of FIG. 14; FIG. 16 illustrates relations between an inclination angle and a gradient of an incident surface for making light reflected by the reflecting mirror parallel to an optical axis; FIG. 17 illustrates an image sensor including an array of micro reflecting mirrors as optical path conversion elements in accordance with yet another embodiment of the present invention; FIG. 18 illustrates an image sensor including an array of micro reflecting mirrors and an array of micro lenses as optical path conversion elements in accordance with yet another embodiment of the present invention; FIG. 19 illustrates an image sensor including an array of aspheric micro reflecting mirrors in accordance with yet another embodiment of the present invention; FIGS. 20a to 20c respectively illustrate processes for fabricating an image sensor in accordance with various embodiments of the present invention; FIGS. 21a and 21b illustrate simulation results for the image sensor including the array of micro lenses in FIG. 2, wherein FIG. 21a shows an optical path of light, and FIG. 21b shows distribution of light intensity in photoelectric element; and FIGS. 22a and 22b illustrate simulation results for the image sensor including the array of micro prisms and the array of micro lenses in FIG. 12, wherein FIG. 22a shows an optical path of light, and FIG. 22b shows distribution of light intensity in photoelectric element. BEST MODE FOR CARRYING OUT THE INVENTION An image sensor and a method for fabricating the same in accordance with preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings. FIG. 8 is a concept view showing that a prism 10 can vary an optical path of light. As illustrated in FIG. 8, the micro prism 10 converts the optical path of light to be parallel to an optical axis in order to prevent reduction of optical efficiency due to light slantingly incident on peripheral pixels of an image sensor. The relations between an inclination angle of light incident on the surface of the prism 10, an angle of refracted light and a gradient value of an incident surface of the prism 10 will now be explained with reference to FIG. 9. FIG. 9 illustrates the refraction law of light, especially light passing through the prism 8 of FIG. 8. FIG. 9 shows a refraction path of light when light is incident on an interface between different media having a gradient of ‘α’. When it is presumed that an angle of incident light to a normal line of the interface is ‘θ1’, an angle of refracted light to the normal line of the interface is ‘θ2’, a refraction index of the medium in the incident side is ‘n1’ and a refraction index of the medium in the refraction side is ‘n2’, the Snell's law is represented by following formula (1): n1 sin θ1=n2 sin θ2 (1) Here, when it is presumed that the gradient of the interface is ‘α’, an inclination angle of incident light to the optical axis is ‘φ1’ and an angle of refracted light to the optical axis is ‘φ2’, and they are introduced to formula (1), we can obtain following formula (2): tan ⁢ ⁢ α = n 1 ⁢ sin ⁢ ⁢ ϕ 1 - n 2 ⁢ sin ⁢ ⁢ ϕ 2 n 1 ⁢ cos ⁢ ⁢ ϕ 1 - n 2 ⁢ cos ⁢ ⁢ ϕ 2 ( 2 ) In case that light is vertically refracted (φ2=0) through the surface of the prism 10, the gradient α of the incident surface of the prism 10 is represented by following formula (3) with regard to the inclination angle φ1 of incident light and the refraction indexes n1 and n2 of the media: α = tan - 1 ⁡ ( n 1 ⁢ sin ⁢ ⁢ ϕ 1 n 1 ⁢ cos ⁢ ⁢ ϕ 1 - n 2 ) ( 3 ) FIG. 10 illustrates relations between the inclination angle and the gradient value of the incident surface for making light refracted by the prism 8 parallel to the optical axis. FIG. 10 shows the gradient α of the incident surface of the prism 10 according to the inclination angle φ1 of light incident on the incident surface of the prism 10 for making refracted light parallel to the optical axis, when the refraction index of the medium in the incident side is ‘1’ and the refraction index of the medium in the refraction side is ‘1.5’. Here, two points must be noted. First, as the inclination angle φ1 increases, that is, in the peripheral pixels of the image sensor, the gradient of the incident surface of the prism 10 increases in the negative direction, which will later be explained with reference to FIG. 11a. Second, when the refraction index of the prism 10 is larger than that of the medium in the incident side, the gradient of the incident surface of the prism 10 has a negative value, and reversely, when the refraction index of the prism 10 is smaller than that of the medium in the incident side, the gradient of the incident surface of the prism 10 has a positive value, which will later be explained with reference to FIG. 11b. FIGS. 11a and 11b illustrate image sensors including an array of micro prisms 10 as optical path conversion elements in accordance with one embodiment of the present invention. Here, FIG. 11a shows the image sensor including a single array of micro prisms 10, and FIG. 11b shows the image sensor including a double array of micro prisms 10a and 10b. FIGS. 11a and 11b show that the array of micro prisms 10 having different incident surface gradients can make light incident at different angles on each pixel refracted parallel to an optical axis. This method equalizes angles of light incident on photoelectric elements 1 of the image sensor, and thus equalizes amounts of light sensed in each position of the image sensor. The structure of FIG. 11a includes an air layer and a prism layer. The prism layer has a higher refraction index than the air layer, and thus the incident surface of the prism 10 faces the right side. Conversely, as shown in FIG. 11b, when the second micro prism 10b contacting the air layer has a higher refraction index than the first micro prism 10a, the incident surface of the first micro prism 10a faces the left side. The second micro prism 10b can be formed in various shapes to refract light. Here, FIG. 11b exemplifies the flat layer type second micro prism 10b formed on the first micro prism 10a. The incident surface of the first micro prism 10a has a gradient to the right angle surface to the optical axis, and the incident surface of the second micro prism 10b is at right angles to the optical axis. FIG. 12 illustrates an image sensor including an array of micro prisms 10 and an array of micro lenses 5 as optical path conversion elements in accordance with another embodiment of the present invention. As depicted in FIG. 12, the image sensor uses both the array of micro prisms 10 and the array of micro lenses 5. Here, the array of micro prisms 10 convert an optical path of light to be parallel to an optical axis, and the array of micro lenses 5 condense light to photoelectric elements 1. Accordingly, the method of FIG. 12 more efficiently senses light than the methods of FIGS. 11a and 11b, and equalizes amounts of light sensed in each position. That is, the image sensors of FIGS. 11a to 12 are fabricated by additionally arranging micro prisms on the general image sensor, to improve optical efficiency. In addition, the image sensor of the invention can be easily fabricated by using gray scale masks of FIGS. 20a to 20c discussed later. The method of FIG. 13 can advantageously improve optical efficiency as much as that of FIG. 12 according to a single process for fabricating aspheric micro lenses. FIG. 13 illustrates the image sensor including the array of aspheric micro lenses 11 in accordance with yet another embodiment of the present invention. As illustrated in FIG. 13, tangent lines to the corresponding parts of the incident surfaces have different gradients according to distances between the corresponding parts and the center of the image sensor, and thus aspheric micro lenses 11 in different shapes are arranged to convert optical paths of slantingly incident light and condense light to photoelectric elements 1. That is, the aspheric micro lens and aspheric micro reflecting mirror have different tangent line gradient values on individual parts of the incident surface of the same optical path conversion element to condense incident light to the photoelectric element. Therefore, the aspheric micro lenses 11 perform functions of micro prisms 10 as optical path conversion elements as well as functions of micro lenses 5 as condensers. Differently from the micro prisms 10, tangent line gradients are different at each point on the incident surface of one aspheric micro lens 11. The tangent line gradients at each point can be calculated by formula (2). FIGS. 8 to 13 show that we can improve optical efficiency of the image sensor by using the refraction law. The reflection law has the same effects as discussed later. FIG. 14 is a concept view showing that a reflecting mirror 12 can vary an optical path of light. Relations between an inclination angle of light incident on the surface of the reflecting mirror 12, an angle of reflected light and a gradient of an incident surface of the reflecting mirror 12 will now be described with reference to FIG. 15. FIG. 15 illustrates the reflection law of light, especially light incident on the reflecting mirror 12 of FIG. 14. FIG. 15 shows an angle of reflected light when light is incident on the incident surface having a gradient of β. When it is presumed that an angle of incident light to a normal line of the incident surface is ‘θ3’ and an angle of reflected light to a normal line of incident surface is ‘θ4’, the reflection law is represented by formula (4): θ3=θ4 (4) Here, when it is presumed that the gradient of the incident surface is ‘β’, an inclination angle of incident light to an optical axis is ‘φ3’ and an angle of reflected light to the optical axis is ‘φ4’, and they are introduced to formula (4), we can obtain following formula (5): β = 90 ⁢ ° + ϕ 3 + ϕ 4 2 ( 5 ) The gradient β of the reflecting mirror 12 for making light reflected by the reflecting mirror 12 parallel to the optical axis (φ4=0) is represented by following formula (6) with regard to the gradient φ3 of incident light: β = 90 ⁢ ° + ϕ 3 2 ( 6 ) FIG. 16 illustrates relations between the inclination angle and the gradient value of the incident surface for making light reflected by the reflecting mirror 12 parallel to the optical axis. Here, as the inclination angle increases, that is, in the peripheral pixels of the image sensor, the gradient of the incident surface of the reflecting mirror 12 increases, which will later be explained with reference to FIG. 17. FIG. 17 illustrates an image sensor including an array of micro reflecting mirrors 12 as optical path conversion elements in accordance with yet another embodiment of the present invention. The method of FIG. 17 reflects light incident at different angles on each pixel to be parallel to an optical axis by using the array of micro reflecting mirrors 12 having different incident surface gradients. This method equalizes angles of light incident on photoelectric elements 1, and thus equalizes amounts of light sensed in each position of the image sensor. FIG. 18 illustrates an image sensor including an array of micro reflecting mirrors 12 and an array of micro lenses 5 as optical path conversion elements in accordance with yet another embodiment of the present invention. As shown in FIG. 18, the image sensor uses both the array of micro reflecting mirrors 12 and the array of micro lenses 5. Here, the array of micro reflecting mirrors 12 convert an optical path of light to be parallel to an optical axis, and the array of micro lenses 5 condense light to photoelectric elements 1. Accordingly, the method of FIG. 18 more efficiently senses light than the method of FIG. 17, and equalizes amounts of light sensed in each position. FIG. 19 illustrates an image sensor including an array of aspheric micro reflecting mirrors 13 in accordance with yet another embodiment of the present invention. Referring to FIG. 19, tangent lines to the corresponding parts of incident surfaces have different gradients according to angles of light incident on the surface of the image sensor, namely distances of each pixel from the center of the image sensor, and thus aspheric micro reflecting mirrors 13 in different shapes are arranged to convert optical paths of slantingly-incident light and condense light to photoelectric elements 1. That is, the aspheric micro reflecting mirrors 13 perform the functions of the optical path conversion element as well as the condenser. Differently from the flat surface micro reflecting mirrors 12, tangent line gradients are different at each point on the incident surface of one aspheric micro reflecting mirror 13. The tangent line gradients at each point can be calculated by formula (5). As discussed earlier, the image sensor of the invention includes optical path conversion elements having different tangent line gradients on the corresponding parts of incident surfaces according to distances between the corresponding parts and the center of the image sensor. It is therefore required to fabricate fine structures having various tangent line gradients. It is very difficult to fabricate the fine structures according to a single process using a conventional MEMS process. However, as shown in FIGS. 20a to 20c, the fine structures having various tangent line gradients can be easily fabricated according to a photolithography process using a gray scale mask, a reactive ion etching process and an UV-molding process. FIG. 20a illustrates a process for fabricating an image sensor in accordance with yet another embodiment of the present invention. As illustrated in FIG. 20a, a photoresist 15 is coated on a substrate 3 of the image sensor, and exposed to ultraviolet rays through a gray scale mask 14. Thereafter, the photoresist 15 exposed to the ultraviolet rays is removed, to obtain photoresist fine structures 15a having various tangent line gradients. FIG. 20b illustrates a process for fabricating an image sensor in accordance with yet another embodiment of the present invention. As shown in FIG. 20b, fine structures 16a having different tangent line gradients are fabricated on a substrate 3 of the image sensor according to the photolithography process and the reactive ion etching process. First, a material for the reactive ion etching process is positioned on the substrate 3. A photoresist 15 is coated on the resulting structure, and exposed to ultraviolet rays through a gray scale mask 14, to obtain photoresist fine structures 15a. The fine structures 16a having different tangent line gradients are fabricated on the substrate 3 by etching the fine structures 15a according to the reactive ion etching process. FIG. 20c illustrates a process for fabricating an image sensor in accordance with yet another embodiment of the present invention. As depicted in FIG. 20c, the image sensor is fabricated according to the UV-molding process. A photoresist 15 is coated on an ultraviolet transparent material 17 for the reactive ion etching process. A mold 17a on which fine structures have been formed is fabricated according to the photolithography process using the gray scale mask and the reactive ion etching process. A photopolymer 18 is applied on a substrate 3, and then the UV-molding process is performed thereon by using the mold 17a, to obtain fine structures 18a having various tangent line gradients. The process for fabricating the image sensor of FIG. 12 according to the method of FIG. 20c will now be explained. First, the micro lenses 5 are molded on the substrate 3 according to the process of FIG. 20c. The photopolymer is applied on the resulting structure, and then the flat layer and the micro prisms 10 are molded at the same time by using the mold 17a on which concave micro prism patterns 10 have been formed. It is also possible to sequentially mold the flat layer by using a flat surface mold, and the micro prisms 10 by using the mold 17a on which the concave micro prism patterns 10 have been formed. However, this method may not be preferable in the number of processes. The process for fabricating the image sensor of FIG. 17 according to the method of FIG. 20c will now be described. A variety of processes can be used to fabricate the micro reflecting mirror 12 of FIG. 17. For example, fine structures having triangular sections are micro molded according to the UV-molding process, similarly to FIG. 11a. The outside surface of the slanting right side of the micro reflecting mirror 12 of FIG. 17 is coated. The inside surface of the slanting right side is used as a reflecting surface (incident surface of reflecting mirror 12). In this case, a refraction index of the fine structure is preferably almost identical to a refraction index of an air layer. Otherwise, differences between the refraction indexes of the fine structure and the air layer must be taken into consideration. FIGS. 21a and 21b illustrate simulation results for the image sensor including the array of micro lenses 5 in FIG. 2. Here, FIG. 21a shows the optical path of light, and FIG. 21b shows distribution of light intensity in the photoelectric element 1. For simulations, it is presumed that the size of cells of the image sensor is 5 μm×5 μm the size of photodiodes is 2 μm×2 μm the thickness of a circuit part surrounding the photodiode is 1 μm, and the thickness from the micro lenses 5 to the photodiodes is 8 μm. Referring to FIGS. 21a and 21b, if the array of micro prisms 10 does not exist and the inclination angle of light is 0 or 10°, the focus is formed on the photodiodes and thus the photodiodes can sense light. However, if the array of micro prisms 10 does not exist and the inclination angle of light is 20 or 30°, the photodiodes cannot sense light. Even if the inclination angle of light is 10°, the photodiodes having small area cannot sense a lot of light. FIGS. 22a and 22b illustrate simulation results for the image sensor including the array of micro prisms 10 and the array of micro lenses 5 in FIG. 12. Here, FIG. 22a shows the optical path of light, and FIG. 22b shows distribution of light intensity in the photoelectric element 1. As shown in FIGS. 22a and 22b, if the array of micro prisms 10 and the array of micro lenses 5 exist and an incident angle of light is 0, 10, 20 or 30°, the focus is formed on the photodiodes and thus the photodiodes can sense light. On the Basis of an amount of light sensed by the photodiodes at an inclination angle of 0°, when the micro prism arrangements 10 do not exist and exist, condensation efficiency is 92% and 93% respectively at an incident angle of 10°; 0% and 90% respectively at an inclination angle of 20°; and 0% and 76% respectively at an incident angle of 30°. Accordingly, even when the inclination angle of light incident on the image sensor is large, the micro prisms 10 can make the photodiodes of the image sensor efficiently sense light. Although the preferred embodiments of the present invention have been described, it is understood that the present invention should not be limited to these preferred embodiments but various changes and modifications can be made by one skilled in the art within the spirit and scope of the present invention as hereinafter claimed.

<SOH> FIELD OF THE INVENTION <EOH>The present invention relates to an image sensor and a method for fabricating the same, and more particularly to, an image sensor and a method for fabricating the same, which can make intensive and homogeneous light sensed in every position of the image sensor.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 illustrates a basic structure of a conventional image sensor, which does not have an array of micro lenses; FIG. 2 illustrates a basic structure of a conventional image sensor including an array of micro lenses; FIG. 3 illustrates one example of a system using an image sensor; FIG. 4 illustrates low optical efficiency of peripheral pixels of the image sensor of FIG. 2 ; FIG. 5 illustrates another example of a conventional image sensor wherein micro lenses are arranged on different planes according to distances from the center of the image sensor; FIG. 6 illustrates yet another example of a conventional image sensor wherein micro lenses of different sizes are arranged according to distances from the center of the image sensor; FIG. 7 illustrates yet another example of a conventional image sensor wherein micro lenses are arranged in deviated positions from photoelectric elements according to distances from the center of the image sensor; FIG. 8 is a concept view showing that a prism can vary an optical path of light; FIG. 9 illustrates the refraction law of light, especially light passing through the prism of FIG. 8 ; FIG. 10 illustrates relations between an inclination angle and a gradient value of an incident surface for making light refracted by the prism parallel to an optical axis; FIGS. 11 a and 11 b illustrate image sensors including an array of micro prisms as optical path conversion elements in accordance with one embodiment of the present invention, wherein FIG. 1 a shows the image sensor including a single array of micro prisms, and FIG. 11 b shows the image sensor including a double array of micro prisms; FIG. 12 illustrates an image sensor including an array of micro prisms and an array of micro lenses as optical path, conversion elements in accordance with another embodiment of the present invention; FIG. 13 illustrates an image sensor including an array of aspheric micro lenses in accordance with yet another embodiment of the present invention; FIG. 14 is a concept view showing that a reflecting mirror can vary an optical path of light; FIG. 15 illustrates the reflection law of light, especially light reflected by the reflecting mirror of FIG. 14 ; FIG. 16 illustrates relations between an inclination angle and a gradient of an incident surface for making light reflected by the reflecting mirror parallel to an optical axis; FIG. 17 illustrates an image sensor including an array of micro reflecting mirrors as optical path conversion elements in accordance with yet another embodiment of the present invention; FIG. 18 illustrates an image sensor including an array of micro reflecting mirrors and an array of micro lenses as optical path conversion elements in accordance with yet another embodiment of the present invention; FIG. 19 illustrates an image sensor including an array of aspheric micro reflecting mirrors in accordance with yet another embodiment of the present invention; FIGS. 20 a to 20 c respectively illustrate processes for fabricating an image sensor in accordance with various embodiments of the present invention; FIGS. 21 a and 21 b illustrate simulation results for the image sensor including the array of micro lenses in FIG. 2 , wherein FIG. 21 a shows an optical path of light, and FIG. 21 b shows distribution of light intensity in photoelectric element; and FIGS. 22 a and 22 b illustrate simulation results for the image sensor including the array of micro prisms and the array of micro lenses in FIG. 12 , wherein FIG. 22 a shows an optical path of light, and FIG. 22 b shows distribution of light intensity in photoelectric element. detailed-description description="Detailed Description" end="lead"?

20060123

20070807

20070308

70075.0

G02B2608

PYO, KEVIN K

IMAGE SENSOR AND METHOD FOR FABRICATING THE SAME

SMALL

ACCEPTED

G02B

ACCEPTED

N-'2-(2-pyridinyl) ethylbenzamide compounds and their use as fungicides

Compound of general formula (I): Process for preparing this compound. Fungicidal composition comprising a compound of general formula (I). Method for treating plants by applying a compound of general formula (I) or a composition comprising it.

1. A compound of general formula (I): in which: n is 1, 2 or 3; X is the same or different and is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carboxy group, a carbamoyl group, a N-hydroxycarbamoyl group, a carbamate group, a (hydroxyimino)-C1-C6-alkyl group, a C1-C8-alkyl, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-C8-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C2-C8-alkenyloxy, a C2-C8-halogenoalkenyloxy having 1 to 5 halogen atoms, a C3-C8-alkynyloxy, a C3-C8-halogenoalkynyloxy having 1 to 5 halogen atoms, a C3-C8-cycloalkyl, a C3-C8-halogenocycloalkyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyl, a C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbamoyl, a di-C1-C8-alkylcarbamoyl, a (N-C1-C8-alkyl)oxycarbamoyl, a C1-C8-alkoxycarbamoyl, a (N—C1-C8-alkyl)-C1-C8-alkoxycarbamoyl, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyloxy, a C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a C1-C8-alkylcarbonylamino, a C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, a C1-C8-alkylaminocarbonyloxy, a di-C1-C8-alkylaminocarbonyloxy, a C1-C8-alkyloxycarbonyloxy, a C1-C8-alkylsulphenyl, a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphonyl, a C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, a (C1-C6-alkoxyimino)-C1-C6-alkyl, a (C1-C6-alkenyloxyimino)-C1-C6-alkyl, a (C1-C6-alkynyloxyimino)-C1-C6-alkyl, a (benzyloxyimino)-C1-C6-alkyl, a benzyloxy, a benzylsulfanyl, a benzylamino, a phenoxy, a phenylsulfanyl or a phenylamino; R1 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carboxy group, a carbamoyl group, a N-hydroxycarbamoyl group, a carbamate group, a (hydroxyimino)-C1-C6-alkyl group, a C1-C8-alkyl, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-C8-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C2-C8-alkenyloxy, a C2-C8-halogenoalkenyloxy having 1 to 5 halogen atoms, a C3-C8-alkynyloxy, a C3-C8-halogenoalkynyloxy having 1 to 5 halogen atoms, a C3-C8-cycloalkyl, a C3-C8-halogenocycloalkyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyl, a C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbamoyl, a di-C1-C8-alkylcarbamoyl, a N—C1-C8-alkyloxycarbamoyl, a C1-C8-alkoxycarbamoyl, a N—C1-C8-alkyl-C1-C8-alkoxycarbamoyl, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyloxy, a C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a C1-C8-alkylcarbonylamino, a C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, a C1-C8-alkylaminocarbonyloxy, a di-C1-C8-alkylaminocarbonyloxy, a C1-C8-alkyloxycarbonyloxy, a C1-C8-alkylsulphenyl, a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphonyl, a C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, a (C1-C6-alkoxyimino)-C1-C6-alkyl, a (C1-C6-alkenyloxyimino)-C1-C6-alkyl, a (C1-C6-alkynyloxyimino)-C1-C6-alkyl, a (benzyloxyimino)-C1-C6-alkyl, a benzyloxy, a benzylsulfanyl optionally substituted with 1 to 5 halogen atoms, a benzylamino, a phenoxy, a phenylsulfanyl optionally substituted with 1 to 5 halogen atoms or a phenylamino; with the proviso that X and R1 are not both a hydrogen atom; R2 and R3 are the same or different and are a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6-alkyl, a C1-C6-halogenoalkyl having 1 to 5 halogen atoms, a C2-C6-alkenyl, a C1-C6-alkoxy, a C1-C6-alkylsulfanyl, a C1-C6-alkylsulfenyl, a C1-C6-alkylsulfinyl, a C1-C6-alkoxycarbonyl, a C1-C6-alkylcarbonyloxy or a C1-C6-alkylcarbonylamino; or R2 and R3 may together form a 3-, 4-, 5- or 6-membered carbocycle; R4 and R5 are the same or different and are a hydrogen atom, a halogen atom, a cyano group, a C1-C6-alkyl or a C1-C6-halogenoalkyl having 1 to 5 halogen atoms; or R4 and R5 may together form a 3-, 4-, 5- or 6-membered carbocycle; R6 is a hydrogen atom, a cyano group, a formyl group, a hydroxy group, a C1-C6-alkyl, a C1-C6-halogenoalkyl having 1 to 5 halogen atoms, a C1-C6-alkoxy, a C1-C6-halogenoalkoxy having 1 to 5 halogen atoms, a C3-C6-cycloalkyl, a C3-C6-halogenocycloalkyl having 1 to 5 halogen atoms, a C2-C6-alkenyl, a C2-C6-alkynyl, a C1-C6-alkoxy-C1-C6-alkyl, a C1-C6-cyanoalkyl, a C1-C6-aminoalkyl, a C1-C6-alkylamino-C1-C6-alkyl, a di-C1-C6-alkylamino-C1-C6-alkyl, a C1-C6-alkylcarbonyl, a C1-C6-halogenalkylcarbonyl having 1 to 5 halogen atoms, a C1-C6-alkyloxycarbonyl, a C1-C6-benzyloxycarbonyl, a C1-C6-alkoxy-C1-C6-alkylcarbonyl, a C1-C6-alkylsulfonyl or a C1-C6-halogenoalkylsulfonyl having 1 to 5 halogen atoms; p is 1, 2, 3 or 4; Y is the same or different and is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carboxy group, a C1-C8-alkyl, a C1-C8-halogenoalkyl having 1 to 5 halogen atoms, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-C8-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkoxy-C2-C8-alkenyl, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyloxy, a C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a C1-C8-alkylsulphenyl, a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphonyl, a C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms or a C1-C8-alkylsulfonamide; and R7 is a halogen atom, a nitro group, a cyano group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carboxy group, a C1-C8-alkyl, a C1-C8-halogenoalkyl having 1 to 5 halogen atoms, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-C8-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkoxy-C2-C8-alkenyl, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyloxy, a C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a C1-C8-alkylsulphenyl, a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphonyl, a C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms or a C1-C8-alkylsulfonamide; as well as its salts, N-oxydes, metallic and metalloidic complexes. 2. A compound according to claim 1, characterised in that R1 is a hydrogen atom or a halogen atom. 3. A compound according to claim 1, characterised in that n is 1 or 2. 4. A compound according to claim 1, characterised in that X is a halogen atom or a C1-C8-alkyl. 5. A compound according to claim 1, characterised in that the 2-pyridyl is substituted by X in 3- and/or in 5-position. 6. A compound according to claim 1, characterised in that R7 is a halogen atom, a C1-C8-alkyl or a C1-C8-halogenoalkyl having 1 to 5 halogen atoms. 7. A compound according to claim 1, characterised in that p is 1 or 2. 8. A compound according to claim 7, characterised in that p is 1. 9. A compound according to claim 1, characterised in that Y is a hydrogen atom, a halogen atom or a C1-C8-alkyl. 10. A compound according to claim 9, characterised in that Y is a hydrogen atom. 11. A compound according to claim 1, characterised in that the phenyl is substituted by Y preferentially first in para position. 12. A process (A) for the preparation of compound of general formula (Ia) wherein: R1, R2, R7, X, Y, n and p are as defined in claim 1; R3 is a C1-C6alkyl; which comprises a first step according to reaction scheme A-1: in which: R8 is a C1-C6alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; U is a leaving group chosen as being a halogen, a C1-C6 alkylsulfonate or a C1-C6haloalkylsulfonate; comprising the arylation of a cyanoacetate derivative of general formula (III) by a pyridine derivative of general formula (II), to provide a 2-(pyridyl)cyanoacetate derivative of general formula (IV), in the presence of a base, at a temperature of from 0° C. to 200° C.; a second step according to reaction scheme A-2: in which: R3 is a hydrogen atom; R8 is a C1-C6alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; comprising a basic hydrolysis, an acidic hydrolysis or a displacement by an halide of a compound of general formula (IV) in the same or a different pot to provide, upon heating at a temperature of from 40° C. to reflux, a 2-pyridylacetonitrile derivative of general formula (Va); a third step according to reaction scheme A-3: in which: R3 is a C1-C6alkyl; W is a halogen atom, a C1-C6 alkylsulfonate, a C1-C6 haloalkylsulfonate or a 4-methyl-phenylsulfonate, comprising the alkylation of a compound of general formula (Va) by a reagent of general formula (XVII) to provide a compound of general formula (Vb); a fourth step according to reaction scheme A-4: in which: R3 is a hydrogen atom or a C1-C6alkyl; L1 is a leaving group chosen as being a —OR8 group or a —OCOR8 group, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; PG represents a protecting group which may be a —COOR8 group or —COR8 group, R8 being a C1-C6alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; comprising the reduction, by hydrogenation or by an hydride donor, of a compound of general formula (Va) or (Vb), in the presence of a catalyst and in the presence of a compound of general formula (VI) to produce a compound of general formula (VII), at a temperature of from 0° C. to 150° C. and under a pressure of from 1 bar and 100 bar; a fifth step according to reaction scheme A-5: in which: R3 is a C1-C6alkyl; PG represents a protecting group which may be a —COOR8 group or —COR8 group, R8 being a C1-C6alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; comprising a deprotection reaction, in an acidic or in a basic medium, of a compound of general formula (VII) to provide an amine derivative of general formula (VIIIa) or one of its salt; a sixth step according to reaction scheme A-6: in which: R3 is a C1-C6alkyl; L2 is a leaving group chosen as being a halogen atom, a hydroxyl group, an OR8 group, an OCOR8, R8 being a C1-C6alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; or a group of formula comprising a coupling reaction of an amine derivative of general formula (VIIIa) or one of its salt, with a carboxylic acid derivative of formula (IX) to provide a compound of general formula (Ia). 13. A process (B) for the preparation of compound of general formula (Ia) wherein: R1, R2, R7, X, Y, n and p are as defined in claim 1; R3 is a C1-C6alkyl; which comprises a first step according to reaction scheme B-1: in which: R8 is a C1-C6alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; U is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate or a C1-C6haloalkylsulfonate; comprising the arylation of a cyanoacetate derivative of general formula (III) by a pyridine derivative of general formula (II) to provide a 2-pyridylcyanoacetate derivative of general formula (IV); a second step according to reaction scheme B-2: in which: R8 is a C1-C6alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; comprising a basic hydrolysis, an acidic hydrolysis or a displacement by an halide of a compound of general formula (IV) in the same or a different pot to provide, upon heating at a temperature of from 40° C. to reflux, a 2-pyridylacetonitrile derivative of general formula (Va); a third step according to reaction schemeB-3: in which: R3 is a C1-C6alkyl; W is a halogen atom, a C1-C6 alkylsulfonate, a C1-C6 haloalkylsulfonate or a 4-methyl-phenylsulfonate, comprising the alkylation of a compound of general formula (Va) by a reagent of general formula (XVII) to provide a compound of general formula (Vb); a fourth step according to reaction scheme B-4: in which: R3 is a C1-C6alkyl; L3is a leaving group chosen as being —OCOR8, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; —OCHO, —SCSN(Me)2 or a group of formula comprising the reduction by hydrogenation or by an hydride of a compound of general formula (Va) or a compound of general formula (Vb) in the presence of a catalyst and in the presence of a compound of general formula (IX) to produce a compound of general formula (Ia), at a temperature of from 0° C. to 150° C. and under a pressure of from 1 bar and 100 bar. 14. A process (C) for the preparation of compound of general formula (Ia) wherein R1, R2, R3, R7, X, Y, n and p are as defined in claim 1; which comprises a first step according to reaction scheme C-1: in which: U is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate or a C1-C6haloalkylsulfonate; comprising the arylation of a compound of general formula (IIIb) by a pyridine derivative of general formula (II) to provide a 2-pyridylacetonitrile derivative of general formula (Vb), in the presence of a base and at a at temperature of from −100° C. to 200° C.; a second step according to reaction scheme C-2: in which: L1 is a leaving group chosen as being a —OR8 group or a —OCOR8 group, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; PG represents a protecting group which may be a —COOR8 group or —COR8 group, R8 being a C1-C6alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; comprising the reduction, by hydrogenation or by an hydride donor, of a compound of general formula (Va) or (Vb), in the presence of a compound of general formula (VI) to produce a compound of general formula (VII); a third step according to reaction scheme C-3: in which: PG represents a protecting group which may be a —COOR8 group or —COR8 group, R8 being a C1-C6alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; comprising a deprotection reaction, in an acidic or in a basic medium, of a compound of general formula (VII) to provide an amine derivative of general formula (VIIIa) or one of its salt; a fourth step according to reaction scheme C-4: in which: L4 is a leaving group chosen as being a halogen atom, a hydroxyl group, —OCHO, —SCSN(Me)2, an OR8 group, an OCOR8, R8 being a C1-C6alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; or a group of formula comprising a coupling reaction of an amine derivative of general formula (VIIIa) or one of its salt, with a carboxylic acid derivative of formula (IX) to provide a compound of general formula (Ia). 15. A process (D) for the preparation of compound of general formula (Ia) wherein: R1, R2, R7, X, Y, n and p are as defined in claim 1; R3 is a C1-C6alkyl; which comprises a first step according to reaction scheme D-1: in which: R3 is a hdyrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6-alkyl, a C1-C6-halogenalkyl having 1 to 5 halogen atoms, a C2-C6-alkenyl, a C1-C6-alkoxy, a C1-C6-alkylsulfanyl, a C1-C6-alkylsulfenyl, a C1-C6-alkylsulfinyl, a C1-C6-alkoxycarbonyl, a C1-C6-alkylcarbonyloxy or a C1-C6-alkylcarbonylamino; or R2 and R3 may together form a 3-, 4-, 5- or 6-membered carbocycle; U is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate or a C1-C6haloalkylsulfonate; comprising the arylation of a compound of general formula (IIIb) by a pyridine derivative of general formula (II) to provide a 2-pyridylacetonitrile derivative of general formula (Vb), in the presence of a base and at a at temperature of from −100° C. to 200° C.; a second step according to reaction scheme D-2: in which: R3 is a C1-C6alkyl; L3 is a leaving group chosen as being —OCOR8, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; —OCHO, —SCSN(Me)2 or a group of formula comprising the reduction by hydrogenation or by an hydride donor a compound of general formula (Va) or a compound of general formula (Vb) in the presence of a compound of general formula (IX) to provide a compound of general formula (Ia). 16. A process (E) for the preparation of compound of general formula (Ia) wherein: R1, R2, R3, R7, X, Y, n and p are as defined in claim 1; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R5 is a C1-C6alkyl or a C1-C6haloalkyl; -L4 is a leaving group chosen as being a halogen atom, a hydroxyl group, —OCHO, —SCSN(Me)2, an OR8 group, an OCOR8, R8 being a C1-C6alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; or a group of formula which comprises a first step according to reaction scheme E-1: in which: R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; U is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate or a C1-C6haloalkylsulfonate; comprising the arylation of a compound of general formula (X) by a pyridine derivative of general formula (II) to provide a compound of general formula (XI); a second step according to reaction scheme E-2: in which: R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; comprising the conversion of a compound of general formula (XI) into a compound of general formula (XIII) by addition of a compound of general formula R5-M, in which R5 is a C1-C6alkyl or a C1-C6haloalkyl and M is a metal specie; a third step according to reaction scheme E-3: in which: R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R5 is a C1-C6alkyl or a C1-C6haloalkyl; W is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate, a C1-C6haloalkylsulfonate or a 4-methyl-phenylsulfonate; comprising the activation of a compound of general formula (XIII) by converting it intoa compound of general formula (XIV); a fourth step according to reaction scheme E-4: in which: R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R5 is a C1-C6alkyl or a C1-C6haloalkyl; W is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate, a C1-C6 haloalkylsulfonate or a 4-methyl-phenylsulfonate; comprising the substitution of a compound of general formula (XIV) by a phtalimide derivative or one of its salt to provide a compound of general formula (XVa); a fifth step according to reaction scheme E-5: in which: R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R5 is a C1-C6alkyl or a C1-C6haloalkyl; comprising the de-protection of a compound of general formula (XVa) by reacting it with hydrazine hydrate or a hydrazine salt to provide an amine derivative of general formula (VIIIc) or one of its salt; a sixth step according to reaction scheme E-6: in which: R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R5 is a C1-C6alkyl or a C1-C6haloalkyl; -L4 is a leaving group chosen as being a halogen atom, a hydroxyl group, —OCHO, —SCSN(Me)2, an OR8 group, an OCOR8, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; or a group of formula comprising a coupling reaction of an amine derivative of general formula (VIIIb) or one of its salt, with a carboxylic acid derivative of formula (IX) to provide a compound of general formula (Ia). 17. A process (F) for the preparation of compound of general formula (Ia) wherein: R1, R7, X, Y, n and p are as defined in claim 1; R2, R4 and R5 are independently from each other chosen as being a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; which comprises a first step according to reaction scheme F-1: in which: U is a leaving group chosen as being a halogen atom a C1-C6 alkylsulfonate or a C1-C6haloalkylsulfonate; R2, R4 and R5 are independently from each other chosen as being a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; M is a metal or a metalloid specie; comprising a coupling reaction of a pyridine derivative of general formula (II) with a vinylic specie of general formula (XVI), at a temperature of from 0° C. to 200° C., to provide a compound of general formula (XVII); a second step according to reaction scheme F-2: in which: R2, R4 and R5 are independently from each other chosen as being a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; comprising the addition of a phtalimide or one of its salt on a compound of general formula (XVII) to provide a compound of general formula (XVb); a third step according to reaction scheme F-3: in which: R2, R4 and R5 are independently from each other chosen as being a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; comprising the de-protection of a compound of general formula (XVb) with hydrazine hydrate or an hydrazine salt, to provide an amine derivative of general formula (VIIId) or one of its salts; a fourth step according to reaction scheme F-4: in which: R2, R4 and R5 are independently from each other chosen as being a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; L4 is a leaving group chosen as being a halogen atom, a hydroxyl group, —OCHO, —SCSN(Me)2, an OR8 group, an OCOR8, R8 being a C1-C6alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; or a group of formula comprising a coupling reaction of an amine derivative of general formula (VIIIb) or one of its salt, with a carboxylic acid derivative of formula (IX) to provide a compound of general formula (Ia). 18. A process according to claim 12 which further comprises a step according to reaction scheme G: in which: n is 1, 2 or 3; X is the same or different and is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carboxy group, a carbamoyl group, a N-hydroxycarbamoyl group, a carbamate group, a (hydroxyimino)-C1-C6-alkyl group, a C1-C8-alkyl, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-C8-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C2-C8-alkenyloxy, a C2-C8-halogenoalkenyloxy having 1 to 5 halogen atoms, a C3-C8-alkynyloxy, a C3-C8-halogenoalkynyloxy having 1 to 5 halogen atoms, a C3-C8-cycloalkyl, a C3-C8-halogenocycloalkyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyl, a C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbamoyl, a di-C1-C8-alkylcarbamoyl, a (N—C1-C8-alkyl)oxycarbamoyl, a C1-C8-alkoxycarbamoyl, a (N—C1-C8-alkyl)-C1-C8-alkoxycarbamoyl, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyloxy, a C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a C1-C8-alkylcarbonylamino, a C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, a C1-8-alkylaminocarbonyloxy, a di-C1-C8-alkylaminocarbonyloxy, a C1-C8-alkyloxycarbonyloxy, a C1-C8-alkylsulphenyl, a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphonyl, a C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, a (C1-C6-alkoxyimino)-C1-C6-alkyl, a (C1-C6-alkenyloxyimino)-C1-C6-alkyl, a (C1-C6-alkynyloxyimino)-C1-C6-alkyl, a (benzyloxyimino)-C1-C6-alkyl, a benzyloxy, a benzylsulfanyl, a benzylamino, a phenoxy, a phenylsulfanyl or a phenylamino; R1 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carboxy group, a carbamoyl group, a N-hydroxycarbamoyl group, a carbamate group, a (hydroxyimino)-C1-C6-alkyl group, a C1-C8-alkyl, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-C8-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C2-C8-alkenyloxy, a C2-C8-halogenoalkenyloxy having 1 to 5 halogen atoms, a C3-C8-alkynyloxy, a C3-C8-halogenoalkynyloxy having 1 to 5 halogen atoms, a C3-C8-cycloalkyl, a C3-C8-halogenocycloalkyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyl, a C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbamoyl, a di-C1-C8-alkylcarbamoyl, a N—C1-C8-alkyloxycarbamoyl, a C1-C8-alkoxycarbamoyl, a N—C1-C8-alkyl-C1-C8-alkoxycarbamoyl, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyloxy, a C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a C1-C8-alkylcarbonylamino, a C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, a C1-C8-alkylaminocarbonyloxy, a di-C1-C8-alkylaminocarbonyloxy, a C1-C8-alkyloxycarbonyloxy, a C1-C8-alkylsulphenyl, a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphonyl, a C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, a (C1-C6-alkoxyimino)-C1-C6-alkyl, a (C1-C6-alkenyloxyimino)-C1-C6-alkyl, a (C1-C6-alkynyloxyimino)-C1-C6-alkyl, a (benzyloxyimino)-C1-C6-alkyl, a benzyloxy, a benzylsulfanyl optionally substituted with 1 to 5 halogen atoms, a benzylamino, a phenoxy, a phenylsulfanyl optionally substituted with 1 to 5 halogen atoms or a phenylamino; with the proviso that X and R1 are not both a hydrogen atom; R2 and R3 are the same or different and are a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6-alkyl, a C1-C6-halogenoalkyl having 1 to 5 halogen atoms, a C2-C6-alkenyl, a C1-C6-alkoxy, a C1-C6-alkylsulfanyl, a C1-C6-alkylsulfenyl, a C1-C6-alkylsulfinyl, a C1-C6-alkoxycarbonyl, a C1-C6-alkylcarbonyloxy or a C1-C6-alkylcarbonylamino; or R2 and R3 may together form a 3-, 4-, 5- or 6-membered carbocycle; R4 and R5 are the same or different and are a hydrogen atom, a halogen atom, a cyano group, a C1-C6-alkyl or a C1-C6-halogenoalkyl having 1 to 5 halogen atoms; or R4 and R5 may together form a 3-, 4-, 5- or 6-membered carbocycle; R6 is a hydrogen atom, a cyano group, a formyl group, a hydroxy group, a C1-C6-alkyl, a C1-C6-halogenoalkyl having 1 to 5 halogen atoms, a C1-C6-alkoxy, a C1-C6-halogenoalkoxy having 1 to 5 halogen atoms, a C3-C6-cycloalkyl, a C3-C6-halogenocycloalkyl having 1 to 5 halogen atoms, a C2-C6-alkenyl, a C2-C6-alkynyl, a C1-C6-alkoxy-C1-C6-alkyl, a C1-C6-cyanoalkyl, a C1-C6-aminoalkyl, a C1-C6-alkylamino-C1-C6-alkyl, a di-C1-C6-alkylamino-C1-C6-alkyl, a C1-C6-alkylcarbonyl, a C1-C6-halogenalkylcarbonyl having 1 to 5 halogen atoms, a C1-C6-alkyloxycarbonyl, a C1-C6-benzyloxycarbonyl, a C1-C6-alkoxy-C1-C6-alkylcarbonyl, a C1-C6-alkylsulfonyl or a C1-C6-halogenoalkylsulfonyl having 1 to 5 halogen atoms; p is 1, 2, 3 or 4; Y is the same or different and is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carboxy group, a C1-C8-alkyl, a C1-C8-halogenoalkyl having 1 to 5 halogen atoms, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-C8-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkoxy-C2-C8-alkenyl, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyloxy, a C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a C1-C8-alkylsulphenyl, a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphonyl, a C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms or a C1-C8-alkylsulfonamide; and R7 is a halogen atom, a nitro group, a cyano group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carboxy group, a C1-C8-alkyl, a C1-C8-halogenoalkyl having 1 to 5 halogen atoms, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-C8-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkoxy-C2-C8-alkenyl, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyloxy, a C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a C1-C8-alkylsulphenyl a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphonyl, a C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms or a C1-C8-alkylsulfonamide; as well as its salts, N-oxydes, metallic and metalloidic complexes; L5 is a leaving group chosen as being a halogen atom, a 4-methyl phenylsulfonyloxy, a methylsulfonyloxy; comprising the reaction of a compound of general formula (Ia) with a compound of general formula (XVI) to provide a compound of general formula (Ib). 19. A process for the preparation of a fungicidal compound which comprises a first step according to reaction scheme H-1: in which in the foregoing scheme and all of the schemes below, R1, R2, R3, R7, X, Y, n and p are as defined in claim 1; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; U is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate or a C1-C6haloalkylsulfonate; comprising the arylation of a compound of general formula (X) by a pyridine derivative of general formula (II) to provide a compound of general formula (XI), in the presence of a base, at a temperature of from 0° C. to 200° C.; a second step according to reaction scheme H-2: in which: R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R is a hydrogen atom, a C1-C6alkyl, a C1-C6haloalkyl, a C1-C6 alkoxy or a C3-C7 cycloalkyl; comprising the reaction of a compound of general formula (XI) with an amine of formula R6—NH2 to provide an imine derivative of general formula (XII); a third step according to scheme H-3: in which: R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R6 is a hydrogen atom, a C1-C6alkyl, a C1-C6haloalkyl, a C1-C6 alkoxy or a C3-C7 cycloalkyl; comprising the reduction of an imine derivative of general formula (XII) by hydrogenation or by an hydride donor, in the same or a different pot to provide an amine derivative of general formula (VIIIb) or one of its salt; a fourth step according to reaction scheme H-4: in which: R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R6 is a hydrogen atom, a C1-C6alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy or a C3-C7 cycloalkyl; L4 is a leaving group chosen as being a halogen atom, a hydroxyl group, —OCHO, —SCSN(Me)2, an OR8 group, an OCOR8, R8 being a C1-C6alkyl a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; or a group of formula comprising a coupling reaction of an amine derivative of general formula (VIIIb) or one of its salt, with a carboxylic acid derivative of formula (IX) to provide a compound of general formula (I). 20. Fungicidal composition comprising an effective amount of a compound according to claim 1 and an agriculturally acceptable support. 21. Method for preventively or curatively combating the phytopathogenic fungi of crops, characterised in that an effective and non-phytotoxic amount of a composition according to claim 20 is applied to the plant seeds or to the plant leaves and/or to the fruits of the plants or to the soil in which the plants are growing or in which it is desired to grow them.

The present invention relates to novel N-[2-(2-pyridinyl)ethyl]benzamide derivatives, their process of preparation, their use as fungicides, particularly in the form of fungicidal compositions, and methods for the control of phytopathogenic fungi of plants using these compounds or their compositions. The international patent application WO 01/11965 discloses a broad family of fungicidal compounds in which the 2-pyridyl group is substituted by at least one halogenoalkyl group. It is always of high-interest in agriculture to use novel pesticidal compounds in order to avoid or to fight the development of resistant strains to the active ingredients used by the farmer. It is also of high-interest to use novel compounds being more active than those already known, with the aim of decreasing the amounts of active material to be used by the farmer, whilst at the same time maintaining an effectiveness at least equivalent to the already known compounds. We have now found a new family of compounds which possess the above mentioned characteristics. Accordingly, the present invention relates to N-[2-(2-pyridinyl)ethyl]benzamide derivative of general formula (I): in which: n is 1, 2 or 3; X is the same or different and is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carboxy group, a carbamoyl group, a N-hydroxycarbamoyl group, a carbamate group, a (hydroxyimino)-C1-C6-alkyl group, a C1-C8-alkyl, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-CS-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C2-C8-alkenyloxy, a C2-C8-halogenoalkenyloxy having 1 to 5 halogen atoms, a C3-C8-alkynyloxy, a C3-C8-halogenoalkynyloxy having 1 to 5 halogen atoms, a C3-C8-cycloalkyl, a C3-C8-halogenocycloalkyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyl, a C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbamoyl, a di-C1-C8-alkylcarbamoyl, a (N—C1-C8-alkyl)oxycarbamoyl, a C1-C8-alkoxycarbamoyl, a (N—C1-C8-alkyl)-C1-C8-alkoxycarbamoyl, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyloxy, a C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a C1-C8-alkylcarbonylamino, a C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, a C1-C8-alkylaminocarbonyloxy, a di-C1-C8-alkylaminocarbonyloxy, a C1-C8-alkyloxycarbonyloxy, a C1-C8-alkylsulphenyl, a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphonyl, a C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, a (C1-C6-alkoxyimino)-C1-C6-alkyl, a (C1-C6-alkenyloxyimino)-C1-C6-alkyl, a (C1-C6-alkynyloxyimino)-C1-C6-alkyl, a (benzyloxyimino)-C1-C6-alkyl, a benzyloxy, a benzylsulfanyl, a benzylamino, a phenoxy, a phenylsulfanyl or a phenylamino; R1 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carboxy group, a carbamoyl group, a N-hydroxycarbamoyl group, a carbamate group, a (hydroxyimino)-C1-C6-alkyl group, a C1-C8-alkyl, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-C8-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C2-C8-alkenyloxy, a C2-C8-halogenoalkenyloxy having 1 to 5 halogen atoms, a C3-C8-alkynyloxy, a C3-C8-halogenoalkynyloxy having 1 to 5 halogen atoms, a C3-C8-cycloalkyl, a C3-C8-halogenocycloalkyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyl, a C1-C8-halogenoalkylcarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbamoyl, a di-C1-C8-alkylcarbamoyl, a N—C1-C8-alkyloxycarbamoyl, a C1-C8-alkoxycarbamoyl, a N—C1-C8-alkyl-C1-C8-alkoxycarbamoyl, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyloxy, a C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a C1-C8-alkylcarbonylamino, a C1-C8-halogenoalkylcarbonylamino having 1 to 5 halogen atoms, a C1-C8-alkylaminocarbonyloxy, a di-C1-C8-alkylaminocarbonyloxy, a C1-C8-alkyloxycarbonyloxy, a C1-C8-alkylsulphenyl, a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphonyl, a C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms, a (C1-C6-alkoxyimino)-C1-C6-alkyl, a (C1-C6-alkenyloxyimino)-C1-C6-alkyl, a (C1-C6-alkynyloxyimino)-C1-C6-alklyl, a (benzyloxyimino)-C1-C6-alkyl, a benzyloxy, a benzylsulfanyl optionally substituted with 1 to 5 halogen atoms, a benzylamino, a phenoxy, a phenylsulfanyl optionally substituted with 1 to 5 halogen atoms or a phenylamino; with the proviso that X and R1 are not both a hydrogen atom; R2 and R3 are the same or different and are a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a C1-C6-alkyl, a C1-C6-halogenoalkyl having 1 to 5 halogen atoms, a C2-C6-alkenyl, a C1-C6-alkoxy, a C1-C6-alkylsulfanyl, a C1-C6-alkylsulfenyl, a C1-C6-alkylsulfinyl, a C1-C6-alkoxycarbonyl, a C1-C6-alkylcarbonyloxy or a C1-C6-alkylcarbonylamino; or R2 and R3 may together form a 3-, 4-, 5- or 6-membered carbocycle; R4 and R5 are the same or different and are a hydrogen atom, a halogen atom, a cyano group, a C1-C6-alkyl or a C1-C6-halogenoalkyl having 1 to 5 halogen atoms; or R4 and R5 may together form a 3-, 4-, 5- or 6-membered carbocycle; R6 is a hydrogen atom, a cyano group, a formyl group, a hydroxy group, a C1-C6-alkyl, a C1-C6-halogenoalkyl having 1 to 5 halogen atoms, a C1-C6-alkoxy, a C1-C6-halogenoalkoxy having 1 to 5 halogen atoms, a C3-C6-cycloalkyl, a C3-C6-halogenocycloalkyl having 1 to 5 halogen atoms, a C2-C6-alkenyl, a C2-C6-alkynyl, a C1-C6-alkoxy-C1-C6-alkyl, a C1-C6-cyanoalkyl, a C1-C6-aminoalkyl, a C1-C6-alkylamino-C1-C6-alkyl, a di-C1-C6-alkylamino-C1-C6-alkyl, a C1-C6-alkylcarbonyl, a C1-C6-halogenalkylcarbonyl having 1 to 5 halogen atoms, a C1-C6-alkyloxycarbonyl, a C1-C6-benzyloxycarbonyl, a C1-C6-alkoxy-C1-C6-alkylcarbonyl, a C1-C6-alkylsulfonyl or a C1-C6-halogenoalkylsulfonyl having 1 to 5 halogen atoms; p is 1, 2, 3 or 4; Y is the same or different and is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carboxy group, a C1-C8-alkyl, a C1-C8-halogenoalkyl having 1 to 5 halogen atoms, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-C8-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkoxy-C2-C8-alkenyl, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyloxy, a C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a C1-C8-alkylsulphenyl, a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphonyl, a C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms or a C1-C8-alkylsulfonamide; and R7 is a halogen atom, a nitro group, a cyano group, an amino group, a sulfanyl group, a pentafluoro-λ6-sulfanyl group, a formyl group, a formyloxy group, a formylamino group, a carboxy group, a C1-C8-alkyl, a C1-C8-halogenoalkyl having 1 to 5 halogen atoms, a C2-C8-alkenyl, a C2-C8-alkynyl, a C1-C8-alkylamino, a di-C1-C8-alkylamino, a C1-C8-alkoxy, a C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, a C1-C8-alkoxy-C2-C8-alkenyl, a C1-C8-alkylsulfanyl, a C1-C8-halogenoalkylsulfanyl having 1 to 5 halogen atoms, a C1-C8-alkoxycarbonyl, a C1-C8-halogenoalkoxycarbonyl having 1 to 5 halogen atoms, a C1-C8-alkylcarbonyloxy, a C1-C8-halogenoalkylcarbonyloxy having 1 to 5 halogen atoms, a C1-C8-alkylsulphenyl, a C1-C8-halogenoalkylsulphenyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphinyl, a C1-C8-halogenoalkylsulphinyl having 1 to 5 halogen atoms, a C1-C8-alkylsulphonyl, a C1-C8-halogenoalkylsulphonyl having 1 to 5 halogen atoms or a C1-C8-alkylsulfonamide; as well as its salts, N-oxydes, metallic and metalloidic complexes. In the context of the present invention: halogen means fluorine, bromine, chlorine or iodine. carboxy means —C(═O)OH; carbonyl means —C(═O)—; carbamoyl means —C(═O)NH2; N-hydroxycarbamoyl means —C(═O)NHOH; an alkyl group, an alkenyl group, and an alkynyl group as well as moieties containing these terms, can be linear or branched. In the context of the present invention, it has also to be understood that in the case of di-substituted amino and of di-substituted carbamoyl radicals, the two substituents may form together with the nitrogen atom bearing them a saturated heterocyclic ring containing 3 to 7 atoms. Any of the compound of the present invention can exist in one or more optical or chiral isomer forms depending on the number of asymmetric centres in the compound. The invention thus relates equally to all the optical isomers and to their racemic or scalemic mixtures (the term “scalemic” denotes a mixture of enantiomers in different proportions), and to the mixtures of all the possible stereoisomers, in all proportions. The diastereoisomers and/or the optical isomers can be separated according to the methods which are known per se by the man ordinary skilled in the art. Any of the compound of the present invention can also exist in one or more geometric isomer forms depending on the number of double bonds in the compound. The invention thus relates equally to all geometric isomers and to all possible mixtures, in all proportions. The geometric isomers can be separated according to general methods, which are known per se by the man ordinary skilled in the art. Any of the compound of general formula (I) wherein R1 represents a hydroxy or sulfanyl group, and/or X represents a hydroxy, sulfanyl or amino group, may be found in its tautomeric form resulting of the shift of the proton of said hydroxy, sulfanyl or amino group. Such tautomeric forms of such compounds are also part of the present invention. More generally speaking, all tautomeric forms of compounds of general formula (I) wherein R1 represents a hydroxy or sulfanyl group, and/or X represents a hydroxy, sulfanyl or amino group, as well as the tautomeric forms of the compounds which can optionally be used as intermediates in the preparation processes, and which will be defined in the description of these processes, are also part of the present invention. According to the present invention, the 2-pyridyl is substituted in 6-position by R1 and may be substituted in any other position by (X)n, in which X and n are as defined above. Preferably, the present invention relates to N-[2-(2-pyridinyl)ethyl]benzamide derivative of general formula (I) in which the different characteristics may be chosen alone or in combination as being: as regards R1, R1 is a hydrogen atom or a halogen atom; as regards n, n is 1 or 2; as regards X, X is a halogen atom or a C1-C8-alkyl; as regards the positions in which the 2-pyridyl moiety is substituted by X, the 2-pyridyl moiety is substituted by X in 3- and/or in 5-position. According to the present invention, the phenyl is substituted in ortho position by R7 and may be substituted in any other position by (Y)p, in which Y and p are as defined above. Preferably, the present invention relates to N-[2-(2-pyridinyl)ethyl]benzamide derivative of general formula (I) in which the different characteristics may be chosen alone or in combination as being: as regards R7, R7 is a halogen atom, a C1-C8-alkyl or a C1-C8-halogenoalkyl having 1 to 5 halogen atoms; as regards p, p is 1 or 2. More preferably, p is 1. as regards Y, Y is a hydrogen atom, a halogen atom or a C1-C8-alkyl. More preferably Y is a hydrogen atom; as regards the positions in which the phenyl moiety is substituted by Y, the phenyl moiety is substituted by Y preferentially first in para position. The present invention also relates to a process for the preparation of the compound of general formula (I). Thus, according to a further aspect of the present invention there is provided a process (A) for the preparation of compound of general formula (Ia) wherein: R1, R2, R7, X, Y, n and p are as defined above; R3 is a C1-C6alkyl; which comprises a first step according to reaction scheme A-1: in which: R1, R2, X and n are as defined above; R8 is a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; U is a leaving group chosen as being a halogen, a C1-C6 alkylsulfonate or a C1-C6 haloalkylsulfonate; comprising the arylation of a cyanoacetate derivative of general formula (III) by a pyridine derivative of general formula (II), to provide a 2-(pyridyl)cyanoacetate derivative of general formula (IV), in the presence of a base, at a temperature of from 0° C. to 200° C.; a second step according to reaction scheme A-2: in which: R1, R2, X, n are as defined above; R3 is a hydrogen atom; R8 is a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; comprising a basic hydrolysis, an acidic hydrolysis or a displacement by an halide of a compound of general formula (IV) in the same or a different pot to provide, upon heating at a temperature of from 40° C. to reflux, a 2-pyridylacetonitrile derivative of general formula (Va); a third step according to reaction scheme A-3: in which: R1, R2, X, n are as defined above; R3 is a C1-C6 alkyl; W is a halogen atom, a C1-C6 alkylsulfonate, a C1-C6 haloalkylsulfonate or a 4-methyl-phenylsulfonate, comprising the alkylation of a compound of general formula (Va) by a reagent of general formula (XVII) to provide a compound of general formula (Vb); a fourth step according to reaction scheme A-4: in which: R1, R2, X, n are as defined above; R3 is a hydrogen atom or a C1-C6alkyl; L1 is a leaving group chosen as being a —OR8 group or a —OCOR8 group, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; PG represents a protecting group which may be a —COOR8 group or —COR8 group; R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; comprising the reduction, by hydrogenation or by an hydride donor, of a compound of general formula (Va) or (Vb), in the presence of a catalyst and in the presence of a compound of general formula (VI) to produce a compound of general formula (VII), at a temperature of from 0° C. to 150° C. and under a pressure of from 1 bar and 100 bar; a fifth step according to reaction scheme A-5: in which: R1, R2, X, n are as defined above; p1 R3 is a C1-C6alkyl; PG represents a protecting group which may be a —COOR8 group or —COR8 group, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; comprising a deprotection reaction, in an acidic or in a basic medium, of a compound of general formula (VII) to provide an amine derivative of general formula (VIIIa) or one of its salt; a sixth step according to reaction scheme A-6: in which: R1, R2, R7, X, Y, n and p are as defined above; R3 is a C1-C6 alkyl; L2 is a leaving group chosen as being a halogen atom, a hydroxyl group, an OR8 group, an OCOR8, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; or a group of formula comprising a coupling reaction of an amine derivative of general formula (VIIIa) or one of its salt, with a carboxylic acid derivative of formula (IX) to provide a compound of general formula (Ia). The first step (step A-1) of the process A according to the present invention is conducted in the presence of a base. Preferably, the base will be chosen as being an inorganic or an organic base. Suitable examples of such bases may for example be alkaline earth metal or alkali metal hydrides, hydroxides, amides, alcoholates, carbonates or hydrogen carbonates, acetates or tertiary amines. The first step (step A-1) of the process A according to the present invention is conducted at a temperature of from 0° C. to 200° C. Preferably, first step (step A-1) is conducted at a temperature of from 0° C. to 120° C., more preferably at a temperature of from 0° C. to 80° C. The first step (step A-1) of the process A according to the present invention may be conducted in the presence of a solvent. Preferably, the solvent is chosen as being water, an organic solvent or a mixture of both. Suitable organic solvents may for example be aliphatic, alicyclic or aromatic solvent. The first step (step A-1) of the process A according to the present invention may also be conducted in the presence of a catalyst. Preferably, the catalyst is chosen as being palladium salts or complexes. More preferably, the catalyst is chosen as being a palladium complex. Suitable palladium complex catalyst may for example be generated directly in the reaction mixture by separately adding to the reaction mixture a palladium salt and a complex ligand. Suitable ligands may for example be bulky phosphines or arsines ligands, such as (R)-(−)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine and its corresponding enantiomer, or a mixture of both; (R)-(−)-1[(S)-2-(dicyclohexylphosphino)ferrocenyl]hyldiphenylphosphine and its corresponding enantiomer, or a mixture of both; (R)-(−)-1[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-t-butylphosphine and its corresponding enantiomer, or a mixture of both; or (R)-(−)-1[(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine and its corresponding enantiomer, or a mixture of both. The fourth step (step A-4) of the process A according to the present invention is conducted in the presence of a hydride donor. Preferably, the hydride donor is chosen as being metal or metallloid hydrides such as LiAlH4, NaBH4, KBH4, B2H6. The fourth step (step A-4) of the process A according to the present invention is conducted in the presence of a catalyst. Preferably, the catalyst is chosen as being Co(II)-Chloride, Ni(II)-chloride, ammonia or one of its salt, Palladium on charcoal, Raney Nickel, Raney Cobalt or Platinum. The fourth step (step A-4) of the process A according to the present invention is conducted at a temperature of from 0° C. to 150° C. Preferably the temperature is of from 10° C. to 120° C. More prefereably, the temperature is of from 10° C. to 80° C. The fourth step (step A-4) of the process A according to the present invention is conducted under a pressure of from 1 bar to 100 bar. Preferably the pressure is of from 1 bar to 50 bar. The fourth step (step A-4) of the process A according to the present invention may be conducted in the presence of an organic solvent, of water or of a mixture thereof. Preferably, the solvent is chosen as being ether, alcohol, carboxylic acid, or a mixture thereof with water or pure water. The present invention also relates to another process for the preparation of the compound of general formula (I). Thus, according to a further aspect of the present invention there is provided a second process B for the preparation compound of general formula (Ia) wherein: R1, R2, R7, X, Y, n and p are as defined above; R3 is a C1-C6alkyl; which comprises a first step according to reaction scheme B-1: in which: R1, R2, X and n are as defined above; RS is a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; U is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate or a C1-C6 haloalkylsulfonate; comprising the arylation of a cyanoacetate derivative of general formula (III) by a pyridine derivative of general formula (II) to provide a 2-pyridylcyanoacetate derivative of general formula (IV); a second step according to reaction scheme B-2: in which: R1, R2, X and n are as defined above; R8 is a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; comprising a basic hydrolysis, an acidic hydrolysis or a displacement by an halide of a compound of general formula (IV) in the same or a different pot to provide, upon heating at a temperature of from 40° C. to reflux, a 2-pyridylacetonitrile derivative of general formula (Va); a third step according to reaction schemeB-3: in which: R1, R2, X, n are as defined above; R3 is a C1-C6alkyl; W is a halogen atom, a C1-C6 alkylsulfonate, a C1-C6 haloalkylsulfonate or a 4-methyl-phenylsulfonate, comprising the alkylation of a compound of general formula (Va) by a reagent of general formula (XVII) to provide a compound of general formula (Vb); a fourth step according to reaction scheme B-4: in which: R1, R2, R7, X, Y, n and p are as defined above; R3 is a C1-C6alkyl; L3 is a leaving group chosen as being —OCOR8, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; —OCHO, —SCSN(Me)2 or a group of formula comprising the reduction by hydrogenation or by an hydride of a compound of general formula (Va) or a compound of general formula (Vb) in the presence of a catalyst and in the presence of a compound of general formula (IX) to produce a compound of general formula (Ia), at a temperature of from 0° C. to 150° C. and under a pressure of from 1 bar and 100 bar. Compound of general formula (Ia) according to the present invention may be prepared according to the process B. The preferred conditions under which step B-1 of the process B is conducted are the same than the preferred conditions under which step A-1 of the above mentioned process A is conducted. The preferred conditions under which step B-2 of the process B is conducted are the same than the preferred conditions under which step A-2 of the above mentioned process A is conducted. The preferred conditions under which step B-3 of the process B is conducted are the same than the preferred conditions under which step A-3 of the above mentioned process A is conducted. The preferred conditions under which step B-4 of the process B is conducted are the same than the preferred conditions under which step A-4 of the above mentioned process A is conducted. The present invention also relates to another process for the preparation of the compound of general formula (I). Thus, according to a further aspect of the present invention there is provided a third process C for the preparation compound of general formula (Ia) wherein R1, R2, R3, R7, X, Y, n and p are as defined above; which comprises a first step according to reaction scheme C-1: in which: R1, R2, R3, X and n are as defined above; U is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate or a C1-C6haloalkylsulfonate; comprising the arylation of a compound of general formula (IIIb) by a pyridine derivative of general formula (II) to provide a 2-pyridylacetonitrile derivative of general formula (Vb), in the presence of a base and at a at temperature of from −100° C. to 200° C.; a second step according to reaction scheme C-2: in which: R1, R2, R3, X and n are as defined above; L1 is a leaving group chosen as being a —OR8 group or a —OCOR8 group, R8 being a C1-C6alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; PG represents a protecting group which may be a —COOR8 group or —COR8 group, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; comprising the reduction, by hydrogenation or by an hydride donor, of a compound of general formula (Va) or (Vb), in the presence of a compound of general formula (VI) to produce a compound of general formula (VII); a third step according to reaction scheme C-3: in which: R1, R2, R3, X and n are as defined above; PG represents a protecting group which may be a —COOR8 group or —COR8 group, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; comprising a deprotection reaction, in an acidic or in a basic medium, of a compound of general formula (VII) to provide an amine derivative of general formula (VIIIa) or one of its salt; a fourth step according to reaction scheme C-4: in which: R1, R2, R3, R7, X, Y, n and p are as defined above; L4 is a leaving group chosen as being a halogen atom, a hydroxyl group, —OCHO, —SCSN(Me)2, an ORS group, an OCOR8, R8 being a C1-C6 alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; or a group of formula comprising a coupling reaction of an amine derivative of general formula (VIIIa) or one of its salt, with a carboxylic acid derivative of formula (IX) to provide a compound of general formula (Ia). The first step (step C-1) of the process C according to the present invention is conducted at a temperature of from −100° C. to 200° C. Preferably, first step (step A-1) is conducted at a temperature of from −80° C. to 120° C., more preferably at a temperature of from −80° C. to 80° C. The first step (step C-1) of the process C according to the present invention is conducted in the presence of a base. Preferably, the base will be chosen as being an inorganic or an organic base. Suitable examples of such bases may for example be alkaline earth metal or alkali metal hydrides, hydroxides, amides, alcoholates, carbonates or hydrogen carbonates, acetates or tertiary amines. The first step (step C-1) of the process C according to the present invention may be conducted in the presence of a solvent. Preferably, the solvent is chosen as being water, an organic solvent or a mixture of both. Suitable organic solvents may for example be aliphatic, alicyclic or aromatic solvent. The first step (step C-1) of the process C according to the present invention may also be conducted in the presence of a catalyst. Preferably, the catalyst is chosen as being palladium salts or complexes. More preferably, the catalyst is chosen as being a palladium complex. Suitable palladium complex catalyst may for example be generated directly in the reaction mixture by separately adding to the reaction mixture a palladium salt and a complex ligand. Suitable ligands may for example be bulky phosphines or arsines ligands, such as (R)-(−)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine and its corresponding enantiomer, or a mixture of both; (R)-(−)-1[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldiphenylphosphine and its corresponding enantiomer, or a mixture of both; (R)-(−)-1[(S)-2-(diphenylphoshino)ferrocenyl]ethyldi-t-butylphosphine and its corresponding enantiomer, or a mixture of both; or (R)-(−)-1[(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine and its corresponding enantiomer, or a mixture of both. The preferred conditions under which step C-2 of the process C is conducted are the same than the preferred conditions under which step A-4 of the above mentioned process A is conducted. The preferred conditions under which step C-3 of the process C is conducted are the same than the preferred conditions under which step A-5 of the above mentioned process A is conducted. The preferred conditions under which step C-4 of the process C is conducted are the same than the preferred conditions under which step A-6 of the above mentioned process A is conducted. The present invention also relates to another process for the preparation of the compound of general formula (I). Thus, according to a further aspect of the present invention there is provided a fourth process D for the preparation of compound of general formula (Ia) wherein: R1, R2, R7, X, Y, n and p are as defined above; R3 is a C1-C6alkyl; which comprises a first step according to reaction scheme D-1: in which: R1, R2, R3, X and n are as defined above; U is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate or a C1-C6haloalkylsulfonate; comprising the arylation of a compound of general formula (IIIb) by a pyridine derivative of general formula (II) to provide a 2-pyridylacetonitrile derivative of general formula (Vb), in the presence of a base and at a at temperature of from −100° C. to 200° C.; a second step according to reaction scheme D-2: in which: R1, R2, R7, X, Y, n and p are as defined above; R3 is a C1-C6alkyl; L3 is a leaving group chosen as being —OCOR8, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; —OCHO, —SCSN(Me)2 or a group of formula comprising the reduction by hydrogenation or by an hydride donor a compound of general formula (Va) or a compound of general formula (Vb) in the presence of a compound of general formula (IX) to provide a compound of general formula (Ia). Compound of general formula (Ia) according to the present invention may be prepared according to the process D. The preferred conditions under which step D-1 of the process D is conducted are the same than the preferred conditions under which step C-1 of the above mentioned process C is conducted. The preferred conditions under which step D-2 of the process D is conducted are the same than the preferred conditions under which step A-4 of the above mentioned process A is conducted. The present invention also relates to a process for the preparation of the compound of general formula (I). Thus, according to a further aspect of the present invention there is provided a fifth process (E) for the preparation of compound of general formula (Ia) wherein: R1, R2, R3, R7, X, Y, n and p are as defined above; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R5 is a C1-C6 alkyl or a C1-C6 haloalkyl; L4 is a leaving group chosen as being a halogen atom, a hydroxyl group, —OCHO, —SCSN(Me)2, an OR8 group, an OCOR8, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; or a group of formula which comprises a first step according to reaction scheme E-1: in which: R1, R2, R3, X and n are as defined above; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; U is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate or a C1-C6haloalkylsulfonate; comprising the arylation of a compound of general formula (X) by a pyridine derivative of general formula (II) to provide a compound of general formula (XI); a second step according to reaction scheme E-2: in which: R1, R2, R3, X and n are as defined above; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; comprising the conversion of a compound of general formula (XI) into a compound of general formula (XIII) by addition of a compound of general formula R5-M, in which R5 is a C1-C6alkyl or a C1-C6haloalkyl and M is a metal specie; a third step according to reaction scheme E-3: in which: R1, R2, R3, X and n are as defined above; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R5 is a C1-C6alkyl or a C1-C6haloalkyl; W is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate, a C1-C6haloalkylsulfonate or a 4-methyl-phenylsulfonate; comprising the activation of a compound of general formula (XIII) by converting it intoa compound of general formula (XIV); a fourth step according to reaction scheme E-4: in which: R1, R2, R3, X and n are as defined above; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R5 is a C1-C6alkyl or a C1-C6haloalkyl; W is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate, a C1-C6haloalkylsulfonate or a 4-methyl-phenylsulfonate; comprising the substitution of a compound of general formula (XIV) by a phtalimide derivative or one of its salt to provide a compound of general formula (XVa); a fifth step according to reaction scheme E-5: in which: R1, R2, R3, X and n are as defined above; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R5 is a C1-C6alkyl or a C1-C6haloalkyl; comprising the de-protection of a compound of general formula (XVa) by reacting it with hydrazine hydrate or a hydrazine salt to provide an amine derivative of general formula (VIIIc) or one of its salt; a sixth step according to reaction scheme E-6: in which: R1, R2, R3, R7, X, Y, n and p are as defined above; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R5 is a C1-C6 alkyl or a C1-C6 haloalkyl; L4 is a leaving group chosen as being a halogen atom, a hydroxyl group, —OCHO, —SCSN(Me)2, an OR8 group, an OCOR8, R8 being a C1-C6 alkyl, a C1-C6 haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; or a group of formula comprising a coupling reaction of an amine derivative of general formula (VIIIb) or one of its salt, with a carboxylic acid derivative of formula (IX) to provide a compound of general formula (Ia). Compound of general formula (I) according to the present invention may be prepared according to the process E. The preferred conditions under which step E-6 of the process E is conducted are the same than the preferred conditions under which step A-6 of the above mentioned process A is conducted. The present invention also relates to another process for the preparation of the compound of general formula (I). Thus, according to a further aspect of the present invention there is provided a sixth process F for the preparation of compound of general formula (Ia) wherein: R1, R7, X, Y, n and p are as defined above; R2, R4 and R5 are independently from each other chosen as being a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; which comprises a first step according to reaction scheme F-1: in which: R1, X and n are as defined above; U is a leaving group chosen as being a halogen atom a C1-C6 alkylsulfonate or a C1-C6haloalkylsulfonate; R2, R4 and R5 are independently from each other chosen as being a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; M is a metal or a metalloid specie; comprising a coupling reaction of a pyridine derivative of general formula (II) with a vinylic specie of general formula (XVI), at a temperature of from 0° C. to 200° C., to provide a compound of general formula (XVII); a second step according to reaction scheme F-2: in which: R1, X and n are as defined above; R2, R4 and R5 are independently from each other chosen as being a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; comprising the addition of a phtalimide or one of its salt on a compound of general formula (XVII) to provide a compound of general formula (XVb); a third step according to reaction scheme F-3: in which: R1, X and n are as defined above; R2, R4 and R5 are independently from each other chosen as being a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; comprising the de-protection of a compound of general formula (XVb) with hydrazine hydrate or an hydrazine salt, to provide an amine derivative of general formula (VIIId) or one of its salts; a fourth step according to reaction scheme F-4: in which: R1, R7, X, Y, n and p are as defined above; R2, R4 and R5 are independently from each other chosen as being a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; L4 is a leaving group chosen as being a halogen atom, a hydroxyl group, —OCHO, —SCSN(Me)2, an OR8 group, an OCOR8, R8 being a C1-C6 alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; or a group of formula comprising a coupling reaction of an amine derivative of general formula (VIIIb) or one of its salt, with a carboxylic acid derivative of formula (IX) to provide a compound of general formula (Ia). The first step (step F-1) of the process F according to the present invention is conducted in the presence of a vinylic specie of general formula (XVI) in which M can be a metal or a metalloid specie. Preferably M is a tin derivative or a boron derivative. More preferably M is a tri-nbutyltin group. The first step (step F-1) of the process F according to the present invention is conducted at a temperature of from 0° C. to 200° C. Preferably, step G-1 is conducted at a temperature of from 60° C. to 160° C., more preferably at temperature of from 80° C. to 140° C. The first step (step F-1) of the process F according to the present invention may be conducted in the presence of a solvent. Preferably, the solvent is chosen as being water, an organic solvent or a mixture of both. Suitable organic solvents may for example be aliphatic, alicyclic or aromatic solvent. The first step (step F-1) of the process F according to the present invention may also be conducted in the presence of a catalyst. Preferably, the catalyst is chosen as being palladium salts or complexes. More preferably, the catalyst is chosen as being a palladium complex. Suitable palladium complex catalyst may for example be generated directly in the reaction mixture by separately adding to the reaction mixture a palladium salt and a complex ligand. Suitable ligands may for example be bulky phosphines or arsines ligands, such as (R)-(−)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine and its corresponding enantiomer, or a mixture of both; (R)-(−)-1[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldiphenylphosphine and its corresponding enantiomer, or a mixture of both; (R)-(−)-1[(S)-2-(diphenylphosphino)ferrocenyl]ethyldi-t-butylphosphine and its corresponding enantiomer, or a mixture of both; or (R)-(−)-1(S)-2-(diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine and its corresponding enantiomer, or a mixture of both. The first step (step F-1) of the process F according to the present invention may also be conducted in the presence of a base. Preferably, the base is chosen as being an inorganic or an organic base. Suitable examples of such bases may for example be alkaline earth metal or alkali metal hydrides, hydroxides, amides, alcoholates, carbonates or hydrogen carbonates, acetates or tertiary amines. The preferred conditions under which step F-3 of the process F is conducted are the same than the preferred conditions under which step E-5 of the above mentioned process E is conducted. The preferred conditions under which step F-4 of the process F is conducted are the same than the preferred conditions under which step A-6 of the above mentioned process A is conducted. Any of the above described processes A to F may optionally comprise a further step according to reaction scheme G: in which: R1, R2, R3, R4, R5, R6, R7, X, Y, n and p are as defined above; L5 is a leaving group chosen as being a halogen atom, a 4-methyl phenylsulfonyloxy, a methylsulfonyloxy; comprising the reaction of a compound of general formula (Ia) with a compound of general formula (XVI) to provide a compound of general formula (Ib). The present invention also relates to another process for the preparation of the compound of general formula (I). Thus, according to a further aspect of the present invention there is provided a seventh process H for the preparation of compound of general formula (I) as defined above, which comprises a first step according to reaction scheme H-1: in which: R1, R2, R3, X and n are as defined above; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; U is a leaving group chosen as being a halogen atom, a C1-C6 alkylsulfonate or a C1-C6haloalkylsulfonate; comprising the arylation of a compound of general formula (X) by a pyridine derivative of general formula (II) to provide a compound of general formula (XI), in the presence of a base, at a temperature of from 0° C. to 200° C.; a second step according to reaction scheme H-2: in which: R1, R2, R3, X and n are as defined above; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R6 is a hydrogen atom, a C1-C6alkyl, a C1-C6haloalkyl, a C1-C6alkoxy or a C3-C7 cycloalkyl; comprising the reaction of a compound of general formula (XI) with an amine of formula R6—NH2 to provide an imine derivative of general formula (XII); a third step according to scheme H-3: in which: R1, R2, R3, X and n are as defined above; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R6 is a hydrogen atom, a C1-C6alkyl, a C1-C6haloalkyl, a C1-C6alkoxy or a C3-C7 cycloalkyl; comprising the reduction of an imine derivative of general formula (XII) by hydrogenation or by an hydride donor, in the same or a different pot to provide an amine derivative of general formula (VIIIb) or one of its salt; a fourth step according to reaction scheme H-4: in which: R1, R2, R3, R7, X, Y, n and p are as defined above; R4 is a hydrogen atom, a C1-C6alkyl or a C1-C6haloalkyl; R6 is a hydrogen atom, a C1-C6alkyl, a C1-C6haloalkyl, a C1-C6alkoxy or a C3-C7 cycloalkyl; L4 is a leaving group chosen as being a halogen atom, a hydroxyl group, —OCHO, —SCSN(Me)2, an OR8 group, an OCOR8, R8 being a C1-C6 alkyl, a C1-C6haloalkyl, a benzyl, 4-methoxybenzyl or pentafluorophenyl; or a group of formula comprising a coupling reaction of an amine derivative of general formula (VIIIb) or one of its salt, with a carboxylic acid derivative of formula (IX) to provide a compound of general formula (I). Compound of general formula (I) according to the present invention may be prepared according to the process H. The preferred conditions under which step H-1 of the process H is conducted are the same than the preferred conditions under which step A-1 of the above mentioned process A is conducted. The third step (step H-3) of the process H according to the present invention is conducted in the presence of a hydride donor. Preferably, the hydride donor is chosen as being metal or metalloid hydrides such as LiAlH4, NaBH4, KBH4, B2H6. The compound according to the present invention can be prepared according to the general processes of preparation described above. It will nevertheless be understood that, on the basis of his general knowledge and of available publications, the skilled worker will be able to adapt this method according to the specifics of each of the compounds, which it is desired to synthesise. The present invention also relates to a fungicidal composition comprising an effective amount of an active material of general formula (I). Thus, according to the present invention, there is provided a fungicidal composition comprising, as an active ingredient, an effective amount of a compound of general formula (I) as defined above and an agriculturally acceptable support, carrier or filler. In the present specification, the term “support” denotes a natural or synthetic, organic or inorganic material with which the active material is combined to make it easier to apply, notably to the parts of the plant. This support is thus generally inert and should be agriculturally acceptable. The support may be a solid or a liquid. Examples of suitable supports include clays, natural or synthetic silicates, silica, resins, waxes, solid fertilisers, water, alcohols, in particular butanol, organic solvents, mineral and plant oils and derivatives thereof. Mixtures of such supports may also be used. The composition may also comprise additional components. In particular, the composition may further comprise a surfactant. The surfactant can be an emulsifier, a dispersing agent or a wetting agent of ionic or non-ionic type or a mixture of such surfactants. Mention may be made, for example, of polyacrylic acid salts, lignosulphonic acid salts, phenolsulphonic or naphthalenesulphonic acid salts, polycondensates of ethylene oxide with fatty alcohols or with fatty acids or with fatty amines, substituted phenols (in particular alkylphenols or arylphenols), salts of sulphosuccinic acid esters, taurine derivatives (in particular alkyl taurates), phosphoric esters of polyoxyethylated alcohols or phenols, fatty acid esters of polyols, and derivatives of the above compounds containing sulphate, sulphonate and phosphate functions. The presence of at least one surfactant is generally essential when the active material and/or the inert support are water-insoluble and when the vector agent for the application is water. Preferably, surfactant content may be comprised between 5% and 40% by weight of the composition. Optionally, additional components may also be included, e.g. protective colloids, adhesives, thickeners, thixotropic agents, penetration agents, stabilisers, sequestering agents. More generally, the active materials can be combined with any solid or liquid additive, which complies with the usual formulation techniques. In general, the composition according to the invention may contain from 0.05 to 99% (by weight) of active material, preferably 10 to 70% by weight. Compositions according to the present invention can be used in various forms such as aerosol dispenser, capsule suspension, cold fogging concentrate, dustable powder, emulsifiable concentrate, emulsion oil in water, emulsion water in oil, encapsulated granule, fine granule, flowable concentrate for seed treatment, gas (under pressure),gas generating product, granule, hot fogging concentrate, macrogranule, microgranule, oil dispersible powder, oil miscible flowable concentrate, oil miscible liquid, paste, plant rodlet, powder for dry seed treatment, seed coated with a pesticide, soluble concentrate, soluble powder, solution for seed treatment, suspension concentrate (flowable concentrate), ultra low volume (ulv) liquid, ultra low volume (ulv) suspension, water dispersible granules or tablets, water dispersible powder for slurry treatment, water soluble granules or tablets, water soluble powder for seed treatment and wettable powder. These compositions include not only compositions which are ready to be applied to the plant or seed to be treated by means of a suitable device, such as a spraying or dusting device, but also concentrated commercial compositions which must be diluted before application to the crop. The compounds of the invention can also be mixed with one or more insecticides, fungicides, bactericides, attractant acaricides or pheromones or other compounds with biological activity. The mixtures thus obtained have a broadened spectrum of activity. The mixtures with other fungicides are particularly advantageous. The fungicidal compositions of the present invention can be used to curatively or preventively control the phytopathogenic fungi of crops. Thus, according to a further aspect of the present invention, there is provided a method for curatively or preventively controlling the phytopathogenic fungi of crops characterized in that a fungicidal composition as hereinbefore defined is applied to the seed, the plant and/or to the fruit of the plant or to the soil in which the plant is growing or in which it is desired to grow. The composition as used against phytopathogenic fungi of crops comprises an effective and non-phytotoxic amount of an active material of general formula (I). The expression “effective and non-phytotoxic amount” means an amount of composition according to the invention which is sufficient to control or destroy the fungi present or liable to appear on the crops, and which does not entail any appreciable symptom of phytotoxicity for the said crops. Such an amount can vary within a wide range depending on the fungus to be controlled, the type of crop, the climatic conditions and the compounds included in the fungicidal composition according to the invention. This amount can be determined by systematic field trials, which are within the capabilities of a person skilled in the art. The method of treatment according to the present invention is useful to treat propagation material such as tubers or rhizomes, but also seeds, seedlings or seedlings pricking out and plants or plants pricking out. This method of treatment can also be useful to treat roots. The method of treatment according to the present invention can also be useful to treat the overground parts of the plant such as trunks, stems or stalks, leaves, flowers and fruits of the concerned plant. Among the plants that can be protected by the method according to the invention, mention may be made of cotton; flax; vine; fruit or vegetable crops such as Rosaceae sp. (for instance pip fruits such as apples and pears, but also stone fruits such as apricots, almonds and peaches), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceae sp., Actinidaceae sp., Lauraceae sp., Musaceae sp. (for instance banana trees and plantins), Rubiaceae sp., Theaceae sp., Sterculiceae sp., Rutaceae sp. (for instance lemons, oranges and grapefruits); leguminous crops such as Solanaceae sp. (for instance tomatoes), Liliaceae sp., Asteraceae sp. (for instance lettuces), Umbelliferae sp., Cruciferae sp., Chenopodiaceae sp., Cucurbitaceae sp., Papilionaceae sp. (for instance peas), Rosaceae sp. (for instance strawberries); big crops such as Graminae sp. (for instance maize, lawn or cereals such as wheat, rice, barley and triticale), Asteraceae sp. (for instance sunflower), Cruciferae sp. (for instance colza), Papilionaceae sp. (for instance soja), Solanaceae sp. (for instance potatoes), Chenopodiaceae sp. (for instance beetroots); horticultural and forest crops; as well as genetically modified homologues of these crops. Among the plants and the possible diseases of these plants protected by the method according to the present invention, mention may be made of: wheat, as regards controlling the following seed diseases: fusaria (Microdochium nivale and Fusarium roseum), stinking smut (Tilletia caries, Tilletia controversa or Tilletia indica), septoria disease (Septoria nodorum) and loose smut; wheat, as regards controlling the following diseases of the aerial parts of the plant: cereal eyespot (Tapesia yallundae, Tapesia acuiformis), take-all (Gaeumannomyces graminis), foot blight (F. culmorum, F. graminearum), black speck (Rhizoctonia cerealis), powdery mildew (Erysiphe graminis forma specie tritici), rusts (Puccinia striiformis and Puccinia recondita) and septoria diseases (Septoria tritici and Septoria nodorum); wheat and barley, as regards controlling bacterial and viral diseases, for example barley yellow mosaic; barley, as regards controlling the following seed diseases: net blotch (Pyrenophora graminea, Pyrenophora teres and Cochliobolus sativus), loose smut (Ustilago nuda) and fusaria (Microdochium nivale and Fusarium roseum); barley, as regards controlling the following diseases of the aerial parts of the plant: cereal eyespot (Tapesia yallundae), net blotch (Pyrenophora teres and Cochliobolus sativus), powdery mildew (Erysiphe graminis forma specie hordef), dwarf leaf rust (Puccinia hordei) and leaf blotch (Rhynchosporium secalis); potato, as regards controlling tuber diseases (in particular Helminthosporium solani, Phoma tuberosa, Rhizoctonia solani, Fusarium solani), mildew (Phytopthora infestans) and certain viruses (virus Y); potato, as regards controlling the following foliage diseases: early blight (Alternaria solani), mildew (Phytophthora infestans); cotton, as regards controlling the following diseases of young plants grown from seeds: damping-off and collar rot (Rhizoctonia solani, Fusarium oxysporum) and black root rot (Thielaviopsis basicola); protein yielding crops, for example peas, as regards controlling the following seed diseases: anthracnose (Ascochyta pisi, Mycosphaerella pinodes), fusaria (Fusarium oxysporum), grey mould (Botrytis cinerea) and mildew (Peronospora pisi); oil-bearing crops, for example rape, as regards controlling the following seed diseases: Phoma lingam, Alternaria brassicae and Sclerotinia sclerotiorum; corn, as regards controlling seed diseases: (Rhizopus sp., Penicillium sp., Trichoderma sp., Aspergillus sp., and Gibberella fujikuroi); flax, as regards controlling the seed disease: Alternaria linicola; forest trees, as regards controlling damping-off (Fusarium oxysporum, Rhizoctonia solani); rice, as regards controlling the following diseases of the aerial parts: blast disease (Magnaporthe grisea), bordered sheath spot (Rhizoctonia solani); leguminous crops, as regards controlling the following diseases of seeds or of young plants grown from seeds: damping-off and collar rot (Fusarium oxysporum, Fusarium roseum, Rhizoctonia solani, Pythium sp.); leguminous crops, as regards controlling the following diseases of the aerial parts: grey mould (Botrytis sp.), powdery mildews (in particular Erysiphe cichoracearum, Sphaerotheca fuliginea and Leveillula taurica), fusaria (Fusarium oxysporum, Fusarium roseum), leaf spot (Cladosporium sp.), alternaria leaf spot (Alternaria sp.), anthracnose (Colletotrichum sp.), septoria leaf spot (Septoria sp.), black speck (Rhizoctonia solani), mildews (for example Bremia lactucae, Peronospora sp., Pseudoperonospora sp., Phytophthora sp.); fruit trees, as regards diseases of the aerial parts: monilia disease (Monilia fructigenae, M. laxa), scab (Venturia inaequalis), powdery mildew (Podosphaera leucotricha); vine, as regards diseases of the foliage: in particular grey mould (Botrytis cinerea), powdery mildew (Uncinula necator), black rot (Guignardia biwelli) and mildew (Plasmopara viticola); beetroot, as regards the following diseases of the aerial parts: cercospora blight (Cercospora beticola), powdery mildew (Erysiphe beticola), leaf spot (Ramularia beticola). The fungicide composition according to the present invention may also be used against fungal diseases liable to grow on or inside timber. The term “timber” means all types of species of wood, and all types of working of this wood intended for construction, for example solid wood, high-density wood, laminated wood, and plywood. The method for treating timber according to the invention mainly consists in contacting one or more compounds of the present invention, or a composition according to the invention; this includes for example direct application, spraying, dipping, injection or any other suitable means. The dose of active material usually applied in the treatment according to the present invention is generally and advantageously between 10 and 800 g/ha, preferably between 50 and 300 g/ha for applications in foliar treatment. The dose of active substance applied is generally and advantageously between 2 and 200 g per 100 kg of seed, preferably between 3 and 150 g per 100 kg of seed in the case of seed treatment. It is clearly understood that the doses indicated above are given as illustrative examples of the invention. A person skilled in the art will know how to adapt the application doses according to the nature of the crop to be treated. The fungicidal composition according to the present invention may also be used in the treatment of genetically modified organisms with the compounds according to the invention or the agrochemical compositions according to the invention. Genetically modified plants are plants into whose genome a heterologous gene encoding a protein of interest has been stably integrated. The expression “heterologous gene encoding a protein of interest” essentially means genes which give the transformed plant new agronomic properties, or genes for improving the agronomic quality of the transformed plant. The compositions according to the present invention may also be used for the preparation of composition useful to curatively or preventively treat human and animal fungal diseases such as, for example, mycoses, dermatoses, trichophyton diseases and candidiases or diseases caused by Aspergillus spp., for example Aspergillus fumigatus. The aspects of the present invention will now be illustrated with reference to the following tables of compounds and examples. The following Table illustrates in a non-limiting manner examples of fungicidal compounds according to the present invention. In the following Examples, M+1 (or M−1) means the molecular ion peak, plus or minus 1 a.m.u. (atomic mass units) respectively, as observed in mass spectroscopy and M (ApcI+) means the molecular ion peak as it was found via positive atmospheric pressure chemical ionisation in mass spectroscopy. Compound no X1 X2 X3 R1 R2 R3 R4 R5 R6 R7 Y1 Y2 Y3 Y4 M (M + 1) 1 Cl H Cl H H H H H H CF3 H H H H — 363 2 Cl H Cl H H H H H H Cl H H H H — 329 3 Cl H Cl H H H H H H CH3 H H H H — 309 4 Cl H Cl H H H H H H Br H H H H — 374 5 Cl H Cl H H H H H H I H H H H — 421 6 H H Cl H H H H H H CF3 H H H H — 329 7 Cl H H H Me H H H H Cl H F H H 327 — 8 CH3 H Br H H H H H H CF3 H H H H — 388 9 CH3 H H H H H H H H CF3 H H H H — 309 10 Cl H F H H H H H H CF3 H H H H — 347 11 Cl H F H H H H H H Br H H H H — 358 12 F H F F H H H H H CF3 H H H H — 349 13 H H Cl F H H H H H CF3 H H H H — 347 14 CH3 H H H H H H H H I H H H H — 367 15 C(Me)═NOMe H Cl H H H H H H Cl H H H H — 366 16 C(Me)═NOMe H Cl H H H H H H I H H H H — 458 17 C(Me)═NOMe H Cl H H H H H H CF3 H H H H — 400 18 Br H CH3 H H H H H H CF3 H H H H — 387 19 Br H H H H H H H H CF3 H H H H — 374 20 Cl H H H H H H H H CF3 H H H H — 329 21 Cl H F H H H H H H I H H H H — 405 22 Cl H Cl Cl H H H H H I H H H H — 455 23 Cl H Cl Cl H H H H H CF3 H H H H — 397 24 Cl H H H H H H H H I H H H H — 387 25 CH═NOMe H Cl H H H H H H I H H H H — 444 26 CH═NOMe H Cl H H H H H H CF3 H H H H — 386 27 CH═NOEt H Cl H H H H H H I H H H H — 458 28 CH═NOEt H Cl H H H H H H CF3 H H H H — 400 29 Cl H F H H H H H H CHF2 H H H H — 329 30 CH═NOiPr H Cl H H H H H H CF3 H H H H — 414 31 CH═NOiPr H Cl H H H H H H I H H H H — 472 32 CH═NOiPr H Cl H H H H H H Br H H H H — 424 33 CH═NOiPr H Cl H H H H H H CHF2 H H H H — 396 34 Cl H Cl F H H H H H I H H H H — 439 35 H H Cl Cl H H H H H CF3 H H H H — 363 36 H H Cl Cl H H H H H I H H H H — 421 37 H H Cl Cl H H H H H Br H H H H — 375 38 Cl H Br H H H H H H CF3 H H H H — 407 39 Cl H H H H H H H H Br H H H H — 339 40 Cl H Br H H H H H H I H H H H — 465 41 H H Cl Cl H H H H H CHF2 H H H H — 345 42 F Me F F H H H H H CF3 H H H H — 363 43 F Me F F H H H H H I H H H H — 421 44 F Me F F H H H H H Br H H H H — 374 45 F H F F H H H H H I H H H H — 407 46 Cl H F H H H H H H CHF2 H H H H — 329 47 F H F F H H H H H Br H H H H — 359 48 F H F F H H H H H Cl H H H H — 315 49 F Me F F H H H H H Me H H H H — 309 50 Br H Cl H H H H H H CF3 H H H H — 406 51 Br H Cl H H H H H H I H H H H — 466 52 Br H Cl H H H H H H Br H H H H — 419 53 Cl H Cl Me H H H H H CF3 H H H H — 376 54 Cl H Cl Me H H H H H I H H H H — 434 55 Cl H Cl Me H H H H H Br H H H H — 386 56 H H Cl Me H H H H H CF3 H H H H — 343 57 Cl H Cl F H H H H H CF3 H H H H — 381 58 Cl H Cl F H H H H H Br H H H H — 391 59 Cl H Cl F H H H H H Cl H H H H — 347 60 Cl H Cl H Me H H H H CF3 H H H H 377 — 61 Cl H Cl H Me H H H H I H H H H 435 — 62 Cl H F F H H H H H CF3 H H H H — 365 63 Cl H F F H H H H H I H H H H — 423 64 F H F F H H H H H CHF2 H H H H — 331 65 Cl H H H Me H H H H I H H H H — 401 66 Cl H H H Me H H H H CF3 H H H H — 343 67 Cl H Cl H cPr H H H CF3 H H H H — 389 68 Cl H H H cPr H H H CF3 H H H H — 355 69 Cl H Cl pCl—Ph—CH2S H H H H H CF3 H H H H — 519 70 Cl H H H Me H H H H Cl Cl H F H 327 — EXAMPLES OF PROCESS FOR THE PREPARATION OF THE COMPOUND OF GENERAL FORMULA (I) Example of Process A Preparation of N-[2-(3,5-dichloro-2-pyridinyl)ethyl]-2-(iodo)benzamide (compound 5) Step 1: Preparation of ter-butyl cyano(3,5-dichloro-2-pyridinyl)acetate To 50 ml of dimethoxyethane was slowly added portionwise at 0° C., 8.8 g (0.22 mol) of sodium hydride (60% dispersion in mineral oil). To this suspension, was further added dropwise at 5° C, 17 g (0.12 mol) of ter-butyl cyanoacetate in 50 ml of dimethoxyethane. The suspension was stirred for 45 mn at room temperature. To the suspension were successively added 20 g (0.11 mol) of 2,3,5-trichloropyridine, 0.59 g (1.1 mmol) of (S)-(+)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyl-ter-butylphosphine, and 1,2 g (2.2 mmol) of bis(dibenzylideneacetone)palladium(0). The black mixture was heated at reflux for 5 hours. After cooling, the reaction mixture was poured into 100 ml of 1N hydrochloric acid. The aqueous phase was filtered on supersel and was extracted with ethyl acetate (3×200 ml). The organic phase was washed with brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give 38.5 g of the crude product as a brown oil. The crude product was purified by flash chromatography on silica gel (eluent: heptane/chloroforme: 6/4) to give ter-butyl cyano(3,5-dichloro-2-pyridinyl)acetate: 13 g (41%) as a yellow oil; mass spectrum: 287 (M+1). Step 2: Preparation of (3,5-dichloro-2-pyridinyl)acetonitrile To a solution of 12 g (0.042 mol) of ter-butyl cyano(3,5-dichloro-2-pyridinyl)acetate in 50 ml of a 25/1 mixture of dimethylsulfoxide/water, was added 1.2 g (0.021 mol) of sodium chloride. The mixture was stirred for 3 hours at 130° C. After cooling, the reaction mixture was poured into ice water. The aqueous phase was extracted with ethyl acetate (3×250 ml) and the organic phase was washed with brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give 8.2 g of die crude product as a brown oil. The crude product was purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate: 7/3) to give (3,5-dichloro-2-pyridinyl)acetonitrile: 5.9 g (76%) as an orange oil; mass spectrum: 185 (M−1). Step 3: Preparation of ter-butyl 2-(3,5-dichloro-2-pyridinyl)ethylcarbamate To a solution of 2.8 (0.015 mol) of (3,5-dichloro-2-pyridinyl)acetonitrile in 40 ml of methanol were rapidly added 3.9 g (0.0165 mol) of colbalt(II) chloride hexahydrate and 6.5 g (0.03 mol) of di-ter-butyl dicarbonate. The dark solution was cooled to −5° C. and 3.96 g (0.1 mol) of sodium borohydride was added portion-wise at 0° C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was neutralized by 1 N hydrochloric acid and methanol was remove under reduced pressure. The aqueous phase was reextracted by dichloromethane and the organic phase was washed with brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give 4 g of the crude product as a brown oil. The crude product was purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate: 5/1) to give ter-butyl 2-(3,5-dichloro-2-pyridinyl)ethylcarbamate: 2.0 g (46%) as a yellow oil; mass spectrum: 192 (M+1-101 (boc)). Step 4: Preparation of hydrochlorhide of 2-(3,5-dichloro-2-pyridinyl)ethanamine To a solution of 2.4 g (8.2 mmol) of ter-butyl 2-(3,5-dichloro-2-pyridinyl)ethyl carbamate in 100 ml of dichloromethane were added 5 ml of trifluoroacetique acid. The mixture was stirred 1 hour at room temperature. The solvent was evaporated under reduced pressure to give 4.7 g of a crude yellow oil. The crude oil was redissolved in 10 ml of ethyl ether and 5.2 ml of 2 N hydrochloric acid was added dropwise to precipitated the hydrochlorhide. The solid was collected by filtration, washed by ethyl ether and dried under vacuum to give 2-(3,5-dichloro-2-pyridinyl) ethanamine as its hydrochlorhide: 1.3 g (70%). Step 5: Preparation of N-[2-(3,5-dichloro-2-pyridinyl)ethyl]-2-(iodo)benzamide (compound 5) To a suspension of 60 mg (0.26 mmol) of the hydrochlorhide of 2-(3,5-dichloro-2-pyridinyl)ethanamine in 1 ml of dichloromethane was added successively 81 μl (0.58 mmol) of triethylamine and 85 mg (0.32 mmol) of 2-iodobenzoyl chloride. The mixture was stirred 18 hour at room temperature. The reaction mixture was poured into water and the pH brought to 4. The aqueous phase was extracted with ethyl acetate and the organic phase was washed with brine and dried over magnesium sulphate. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate: 8/2) to give N-[2-(3,5-dichloro-2-pyridinyl)ethyl]-2-(iodo)benzamide as a brown solid: 47 mg (43%); m.p.=133° C. The following compounds of formula (I) are prepared according to a process identical to the one used for the preparation of compound 5, and illustrate as well the present invention: 2, 3, 4, 13, 16, 17, 21, 22, 23, 25 and 26. Example of Process B Preparation of N-[2-(3,5-dichloro-2-pyridinyl)ethyl]-2-(trifluoromethyl)benzamide (compound 1) Step 1: Preparation of methyl cyano(3,5-dichloro-2-pyridinyl)acetate To 100 ml of 1-methyl-2-pyrrolidinone was slowly added portionwise at 0° C., 24.8 g (0.62 mol) of sodium hydride (60% dispersion in mineral oil). To this suspension, was further added dropwise at 5° C., 32.7 g (0.33 mol) of methyl cyanoacetate in 50 ml of 1-methyl-2-pyrrolidinone. The suspension was stirred for 30 mn at 5° C. To the cooled suspension were then rapidly added 70 g (0.3 mol) of 2-bromo-3,5-dichloropyridine and the mixture was heated at 130° C. for 5 hours. After cooling, the reaction mixture was poured into ice water. The aqueous phase was extracted with ethyl ether (3×300 ml) and the organic phase was washed with brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and crude product was recrystallized in methanol to give methyl cyano(3,5-dichloro-2-pyridinyl)acetate: 24.8 g (34%) as brown crystals; m.p.=109-110° C. Step 2: Preparation of (3,5-dichloro-2-pyridinyl)acetonitrile To a solution of 14.45 g (0.06 mol) of methyl cyano(3,5-dichloro-2-pyridinyl)acetate in 70 ml of a 25/1 mixture of dimethylsulfoxide/water, was added 1.75 g (0.03 mol) of sodium chloride. The mixture was stirred for 4 hours at 130° C. After cooling, the reaction mixture was poured into ice water. The aqueous phase was extracted with ethyl ether (3×250 ml) and the organic phase was washed with brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give 11.2 g of the crude product as a brown oil. The crude product was purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate: 7/3) to give (3,5-dichloro-2-pyridinyl)acetonitrile: 8.65 g (77%) as a yellow oil; mass spectrum: 185 (M−1). Step 3: Preparation of N-[2-(3,5-dichloro-2-pyridinyl)ethyl]-2-(trifluoromethyl)benzamide (compound 1) To a solution of 1 g (5.4 mmol) of (3,5-dichloro-2-pyridinyl)acetonitrile in 15 ml of methanol were rapidly added 1.3 g (5.9 mmol) of colbalt(II) chloride hexahydrate and 3.9 g (10.8 mmol) of 2-trifluoromethylbenzoic anhydride. The dark green solution was cooled to −5° C. and 1.4 g (37.4 mmol) of sodium borohydride was added portion-wise at 0° C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was neutralized by 1N hydrochloric acid and methanol was remove under reduced pressure. The aqueous phase was reextracted by ethyl acetate and the organic phase was washed with brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give 2.6 g of the crude product as a brown oil. The crude product was purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate: 7/3) to give N-[2-(3,5-dichloro-2-pyridinyl)ethyl]-2-(trifluoromethyl)benzamide: 0.80 g (41%) as white crystals; m.p.=118° C. The following compounds of formula (I) are prepared according to a process identical to the one used for the preparation of compound 1, and illustrate as well the present invention: 10, 11, 12 and 15. Example of Process C/D Preparation of N-[2-(3-chloro-2-pyridinyl)ethyl]-2-(trifluoromethyl)benzamide (compound 6) Step 1: Preparation of (3-chloro-2-pyridinyl)acetonitrile To a solution of 55.5 ml (0.138 mol) of 2.5 M butyl lithium in 400 ml of anhydrous tetrahydrofurane at −78° C., were added 6.22 g (0.153 mol) of acetonitrile. The reaction mixture was stirred 45 mn at −78° C. until formation of a suspension. To the resulting suspension, a solution of 3 g (0.02 mol) of 2,3-dichloropyridine in 50 ml of anhydrous tetrahydrofurane was slowly added at −78° C. and the reaction mixture was further stirred 2 hours at −78° C. The reaction mixture was poured into 50 ml of water. The aqueous phase was extracted with dichloromethane and the organic phase was washed with water and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent: dichloromethane) to give (3-chloro-2-pyridinyl)acetonitrile as an oil: 1,2 g (40%); mass spectrum: 153 (M+1). Step 2: Preparation of N-[2-(3-chloro-2-pyridinyl)ethyl]-2-(trifluoromethyl)benzamide (compound 6) To a solution of 0,152 g (1 mmol) of (3-chloro-2-pyridinyl)acetonitrile in 4 ml of methanol was successively added 0.238 g (1 mmol) of nickel(II) chloride hexahydrate, 0.724 g (2 mmol) of 2-trifluoromethylbenzoic anhydride and slowly added at 0° C., 0.265 g (7 mmol) of sodium borohydride. The reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate: 9/1) to give N-[2-(3-chloro-2-pyridinyl)ethyl]-2-(trifluoromethyl)benzamide as an oil: 90 mg (27%); mass spectrum: 31.9 (M+1). The following compounds of formula (I) are prepared according to a process identical to the one used for the preparation of compound 6, and illustrate as well the present invention : 7, 8 and 9. Example of Process G Preparation of N-[2-(5-methyl-2-pyridinyl)ethyl]-2-(iodo)benzamide (compound 14) Step 1: Preparation of 5-methyl-2-vinylpyridine To a solution of 3 g (17.4 mmol) of 2-bromo-5-methylpyridine in 30 ml of dimethylformamide was successively added 2 g (1.7 mmol) of tetrakis (triphenylphosphine)palladium and 5.52 g (17.4 mmol) of tributyl(vinyl)tin. The reaction mixture was stirred at 120° C. for 18 hours. After cooling, the reaction mixture was poured into 50 ml of water saturated with potassium fluoride and stirred for 1 hour. The mixture was filtered on supersel and the aqueous phase was extracted with ethyl ether. The organic phase was washed twice with water saturated with potassium fluoride, once with water and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give 3.5 g of a crude mixture as a yellow oil. The mixture was purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate: 4/1) to give 5-methyl-2-vinylpyridine as a yellow oil: 0.9 g (43%); mass spectrum: 120 (M+1). Step 2: Preparation of 2-[2-(5-methyl-2-pyridinyl)ethyl]-1H-isoindole-1,3(2H)-dione 0.5 g (4.2 mmol) of 5-methyl-2-vinylpyridine and 0.618 g (4.2 mmol) of phthalimide was added to 0.5 ml of benzyltrimethylammonium hydroxide (Triton B™) and the mixture was heated at 200° C. for 3 hours. The mixture was allowed to cool to room temperature and was directly purified by flash chromatography on silica gel (eluent: heptane/ethyl acetate: 5/1) to give 2-[2-(5-methyl-2-pyridinyl)ethyl]-1H-isoindole-1,3(2H)-dione as white crystals: 0.680 g (59%); mass spectrum: 267 (M+1). Step 3: Preparation of 2-(5-methyl-2-pyridinyl)ethanamine To a solution of 0.5 g (1.88 mmol) of 2-[2-(5-methyl-2-pyridinyl)ethyl]-1H-isoindole-1,3(2H)-dione in 5 ml of methanol, was added 0.45 g (7.5 mmol) of hydrazine hydrate. The reaction mixture was reflux for 1 hour until completion. The solvent was removed under vacuum and the residue was acidified with 1 N hydrochloric acid. The solid phthalhydrazide was removed by filtration. The filtrate was basified with sodium hydroxyde and extracted by chloroform. The organic phase was washed with water and dried over magnesium sulphate. The solvent was evaporated to give pure 2-(5-methyl-2-pyridinyl)ethanamine as a yellow oil: 0.240 g (94%); mass spectrum: 137 (M+1). Step 4: Preparation of N-[2-(5-methyl-2-pyridinyl)ethyl]-2-(iodo)benzamide (compound 14) To 0.06 mg (0.44 mmol) of 2-(5-methyl-2-pyridinyl)ethanamine in solution in 3 ml of acetonitrile, was successfully added 0.117 mg (0.44 mmol) of 2-iodobenzoyl chloride and 0.078 mg (0.44 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into aqueous potassiumcarbonate and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give pure N-[2-(5-methyl-2-pyridinyl)ethyl]-2-(iodo)benzamide as beige crystals: 0.08 g (53%); mass spectrum: 367 (M+1). The compounds 18, 19, 20 and 24 are prepared according to a process identical to the one used for the preparation of compound 14, and illustrate as well the present invention. EXAMPLES OF BIOLOGICAL ACTIVITY OF THE COMPOUND OF GENERAL FORMULA (I) Example A In Vivo Test on Alternaria brassicae (Leaf Spot of Crucifers) The active ingredient tested is prepared by potter homogenisation in a concentrated suspension type formulation at 100 g/l. This suspension is then diluted with water to obtain the desired active material concentration. Radish plants (Pernot variety) in starter cups, sown on a 50/50 peat soil-pozzolana substrate and grown at 18-20° C., are treated at the cotyledon stage by spraying with the aqueous suspension described above. Plants, used as controls, are treated with an aqueous solution not containing the active material. After 24 hours, the plants are contaminated by spraying them with an aqueous suspension of Alternaria brassicae spores (40,000 spores per cm3). The spores are collected from a 12 to 13 days-old culture. The contaminated radish plants are incubated for 6-7 days at about 18° C., under a humid atmosphere. Grading is carried out 6 to 7 days after the contamination, in comparison with the control plants. Under these conditions, good (at least 50%) or total protection is observed at a dose of 330 ppm with the following compounds: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 25, 26, 27, 28, 30, 31, 32, 34, 35, 36, 37, 38, 40, 41, 43, 45, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 67 and 68. Example B In Vivo Test on Erysiphe graminis f. sp. tritici (Powdery Mildew of Wheat) The active ingredient tested is prepared by potter homogenisation in a concentrated suspension type formulation at 100 g/l. This suspension is then diluted with water to obtain the desired active material concentration. Wheat plants (Audace variety) in starter cups, sown on 50/50 peat soil-pozzolana substrate and grown at 12° C., are treated at the 1-leaf stage (10 cm tall) by spraying with the aqueous suspension described above. Plants, used as controls, are treated with an aqueous solution not containing the active material. After 24 hours, the plants are contaminated by dusting them with Erysiphe graminis f. sp. tritici spores, the dusting being carried out using diseased plants. Grading is carried out 7 to 14 days after the contamination, in comparison with the control plants. Under these conditions, good (at least 50%) or total protection is observed at a dose of 330 ppm with the following compounds: 1, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 18, 38, 50, 43 and 45. Example C In Vivo Test on Botrytis cinerea (Cucumber Grey Mould) The active ingredient tested is prepared by potter homogenisation in a concentrated suspension type formulation at 100 g/l. This suspension is then diluted with water to obtain the desired active material concentration. Cucumber plants (Marketer variety) in starter cups, sown on a 50/50 peat soil-pozzolana substrate and grown at 18-20° C., are treated at the cotyledon Z11 stage by spraying with the aqueous suspension described above. Plants, used as controls, are treated with an aqueous solution not containing the active material. After 24 hours, the plants are contaminated by depositing drops of an aqueous suspension of Botrytis cinerea spores (150,000 spores per ml) on upper surface of the leaves. The spores are collected from a 15-day-old culture and are suspended in a nutrient solution composed of: 20 g/L of gelatin 50 g/L of cane sugar 2 g/L of NH4NO3 1 g/L of KH2PO4 The contaminated cucumber plants are settled for 5/7 days in a climatic room at 15-11° C. (day/night) and at 80% relative humidity. Grading is carried out 5/7 days after the contamination, in comparison with the control plants. Under these conditions, good (at least 50%) or total protection is observed at a dose of 330 ppm with the following compounds: 1, 2, 3, 4, 5, 6, 9, 10, 13, 18, 21, 22, 23, 25, 26, 27, 28, 29, 32, 34, 35, 38, 40, 43, 44, 45, 46, 47, 50, 51, 52, 53, 57 and 62. Example D In Vivo Test on Pyrenophora teres (Barley Net Blotch) The active ingredient tested is prepared by potter homogenisation in a concentrated suspension type formulation at 100 g/l. This suspension is then diluted with water to obtain the desired active material concentration. Barley plants (Express variety) in starter cups, sown on a 50/50 peat soil-pozzolana substrate and grown at 12° C., are treated at the 1-leaf stage (10 cm tall) by spraying with the aqueous suspension described above. Plants, used as controls, are treated with an aqueous solution not containing the active material. After 24 hours, the plants are contaminated by spraying them with an aqueous suspension of Pyrenophora teres spores (12,000 spores per ml). The spores are collected from a 12-day-old culture. The contaminated barley plants are incubated for 24 hours at about 20° C. and at 100% relative humidity, and then for 12 days at 80% relative humidity. Grading is carried out 12 days after the contamination, in comparison with the control plants. Under these conditions, good (at least 50%) or total protection is observed at a dose of 330 ppm with the following compounds: 1, 2, 3, 4, 5, 9, 10, 11, 12, 13, 16, 18, 19, 21, 28, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 65, 67, and 68. The N-{1-methylcarbamoyl-2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-ethyl}-4-phenylbenzamide disclosed by Patent Application WO 01/11965 (see compound 316 in Table D) showed poor effectiveness on Alternaria brassicae, and zero effectiveness on Botrytis cinerea at 330 ppm; the N-{1-ethylcarbamoyl-2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}-3-nitrobenzamide also disclosed by Patent Application WO 01/11965 (see compound 307 in Table D) showed poor effectiveness on Alternaria brassicae and zero effectiveness on Botrytis cinerea at 330 ppm; the N-{1-ethylcarbamoyl-2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-ethyl}-benzamide and the N-{1-methylcarbamoyl-2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}-benzamide also disclosed by Patent Application WO 01/11965 (see compounds 304 and 314 in Table D) showed zero effectiveness on Botrytis cinerea at 330 ppm; and the N-{1-ethylcarbamoyl-2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}-4-chlorobenzamide, the N-{1-ethylcarbamoyl-2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}-2-bromobenzamide and the N-{1-methylcarbamoyl-2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}-4-methoxybenzamide also disclosed by Patent Application WO 01/11965 (see compounds 306, 310 and 315 in Table D) showed zero effectiveness on Botrytis cinerea at 330 ppm.

20060418

20100525

20061102

97492.0

A01N2500

MORRIS, PATRICIA L

N-[2-(2-PYRIDINYL) ETHYL]BENZAMIDE COMPOUNDS AND THEIR USE AS FUNGICIDES

UNDISCOUNTED

ACCEPTED

A01N

ACCEPTED

Hybrid vehicle and method of controlling the vehicle

A controller (10) of a hybrid vehicle determines an engine torque at a point on an engine torque high efficiency line at the current engine rotation speed as a target engine torque, and determines the current engine torque from the current engine rotation speed and current accelerator depression amount. Then, when the gear position of a transmission (2) is neutral, the vehicle is stationary and a storage device (9) requires charging, the controller (10) sets the difference between the target engine torque and the current engine torque as a target power generation torque of a motor generator (4), sets a transitional time period corresponding to the target power generation torque, and performs control over the transitional time period to raise the power generation torque of the motor generator gradually to the target power generation torque.

1. A hybrid vehicle comprising an engine (1), a transmission (2) which changes a speed of a rotation of an input shaft and transmits the rotation to an output shaft, a motor generator (4), a power transmission mechanism (5) which connects a rotary shaft of the motor generator (4) and the input shaft of the transmission (2), a storage device (9) which is connected to the motor generator (4), and a controller (10), characterized in that the controller (10) sets an engine torque at a point on an engine torque high efficiency line at a current engine rotation speed as a target engine torque, calculates a current engine torque from the current engine rotation speed and a current accelerator depression amount, and when a gear position of the transmission (2) is neutral, the vehicle is stationary, and the storage device (9) requires charging, sets a difference between the target engine torque and the current engine torque as a target power generation torque of the motor generator (4), and controls the motor generator (4) such that a power generation torque of the motor generator (4) matches the target power generation torque. 2. The hybrid vehicle as defined in claim 1, characterized in that the controller (10) sets a transitional time period corresponding to the target power generation torque, and controls the motor generator (4) over the transitional time period to raise the power generation torque to the target power-generation torque. 3. The hybrid vehicle as defined in claim 1, characterized in that the controller (10) halts an operation of the engine (1) when the gear position of the transmission (4) is neutral, the vehicle is stationary, and the storage device (9) does not require charging. 4. A control method for a hybrid vehicle comprising an engine (1), a transmission (2) which changes a speed of a rotation of an input shaft and transmits the rotation to an output shaft, a motor generator (4), a power transmission mechanism (5) which connects a rotary shaft of the motor generator (4) and the input shaft of the transmission (2), and a storage device (9) which is connected to the motor generator (4), characterized in that the control method comprises: setting an engine torque at a point on an engine torque high efficiency line at a current engine rotation speed as a target engine torque, calculating a current engine torque from the current engine rotation speed and a current accelerator depression amount, and when a gear position of the transmission (2) is neutral, the vehicle is stationary, and the storage device (9) requires charging, setting a difference between the target engine torque and the current engine torque as a target power generation torque of the motor generator (4), and controlling the motor generator (4) such that a power generation torque of the motor generator (4) matches the target power generation torque. 5. The hybrid vehicle as defined in claim 2, characterized in that the controller (10) halts an operation of the engine (1) when the gear position of the transmission (4) is neutral, the vehicle is stationary, and the storage device (9) does not require charging.

TECHNICAL FIELD This invention relates to a parallel hybrid vehicle comprising an engine and a motor generator as a drive source of the vehicle. BACKGROUND ART JP2002-138876A, published by the Japan Patent Office in 2002, discloses a parallel hybrid vehicle comprising an engine and a motor generator as a drive source. In this conventional example, a map for setting an output apportionment ratio of the motor generator and engine in accordance with the SOC of a storage device is stored in a controller. The controller refers to the map to determine the output apportionment ratio in accordance with the SOC of the storage device, and controls the output of the motor generator and the output of the engine on the basis of the determined apportionment ratio and an accelerator depression amount. DISCLOSURE OF THE INVENTION In this type of hybrid system, when the vehicle is stationary and the gear position of the transmission is neutral, engine idling stop control may be performed. However, if an engine idling stop is performed without taking the state of charge (SOC) of the storage device into account, opportunities for charging the storage device may be lost, and if the state of charge of the storage device decreases, it may be difficult to start the vehicle using only the output of the motor generator. Further, the maximum output of the motor generator is large at low rotation speeds and decreases as the rotation speed increases, and it is therefore desirable that the output of the motor generator be used to the fullest extent when starting the vehicle. It is therefore an object of this invention to execute an idling stop appropriately, taking into consideration the state of charge of a storage device, and to enable maximal use of the output of a motor generator during restarting. This invention provides a hybrid vehicle comprising an engine, a transmission which changes the speed of the rotation of an input shaft and transmits this rotation to an output shaft, a motor generator, a power transmission mechanism which connects a rotary shaft of the motor generator and the input shaft of the transmission, a storage device which is connected to the motor generator, and a controller. The controller sets an engine torque at a point on an engine torque high efficiency line at the current engine rotation speed as a target engine torque, calculates the current engine torque from the current engine rotation speed and current accelerator depression amount, and when the gear position of the transmission is neutral, the vehicle is stationary, and the storage device requires charging, sets the difference between the target engine torque and the current engine torque as a target power generation torque of the motor generator, and controls the motor generator such that the power generation torque of the motor generator matches the target power generation torque. An embodiment of this invention and advantages of this invention will be described in detail below with reference to the attached drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a block diagram of a parallel hybrid vehicle according to this invention. FIG. 2 is a table defining the relationship between a state of charge of a storage device, and an output apportionment ratio between an engine and a motor generator. FIG. 3 is a flowchart showing the content of control executed by a main controller. FIG. 4 is a flowchart showing the content of control executed by the main controller in a power generation mode. FIG. 5 is a map showing the relationship of a specific fuel consumption to an engine rotation speed and an engine torque. FIG. 6A is a map defining the relationship of a rack position (fuel injection amount) to the engine rotation speed and an accelerator depression amount. FIG. 6B is a map defining the relationship of the engine torque to the rack position (fuel injection amount) and the engine rotation speed. FIG. 7 is a table defining the relationship between a target power generation torque and a transitional time period. FIG. 8 is a time chart showing the manner in which the target power generation torque changes. FIG. 9 is a view illustrating the content of the control executed in the power generation mode. BEST MODE FOR CARRYING OUT THE INVENTION Referring to FIG. 1 of the drawings, a hybrid vehicle comprises an engine 1 and a motor generator 2* serving as a drive source, and a step transmission 2 employing a planetary gear. A friction clutch 3 is interposed between the engine 1 and transmission 2. The engine 1 is a diesel engine or a CNG engine using high-pressure natural gas as a fuel. A rotary shaft 4a of the motor generator 4 is connected to an input shaft 2a of the transmission 2 via a power transmission mechanism 5. A speed change controller 6 which controls the gear position of the transmission 2 is provided in the transmission 2. The speed change controller 6 is connected to a select lever 7 and a main controller 10. When a driver manipulates the select lever 7, the speed change controller 6 controls the gear position of the transmission 2 to realize the gear position selected by the select lever 7. The clutch 3 is engaged and disengaged by a clutch actuator 8. The clutch actuator 8 engages or disengages the clutch 3 in accordance with a request from the main controller 10, thereby determining whether or not a driving force is transmitted from the engine 1 to the transmission 2 and power transmission mechanism 5. An engine controller 15 controls a fuel injection amount (fuel supply amount) of the engine 1. The rotation speed of the engine 1 is detected by an engine rotation speed sensor 16. The engine controller 15 controls the fuel injection amount of the engine 1 in accordance with a detection signal from the engine rotation speed sensor 16 and a request from the main controller 10. A brake actuator 21 which applies a braking force to the wheels is controlled by a brake controller 20 on the basis of information from the main controller 10 (a regenerative braking force of the motor generator 4) and the depression amount of a brake pedal 22 (a requested braking force) to compensate for the part of the requested braking force that cannot be provided fully by the regenerative braking force. The depression amount of the brake pedal 22 is detected by a brake sensor 23. The motor generator 4 employs a permanent magnet synchronous motor gPM synchronous motor) due to its high efficiency, small size, and light weight. The motor generator 4 is connected to a storage device 9 via an inverter 11. The storage device 9 employs an electric double layer capacitor having a high output density for regenerating braking energy with high efficiency, no waste, and in a short time period. The inverter 11 controls the motor generator 4 to an electric operation mode or a power generation mode in accordance with a request from the main controller 10. In the electric operation mode, the motor generator 4 is driven by converting the charged energy (direct current power) of the storage device 9 into alternating current power. In the power generation mode, on the other hand, the storage device 9 is charged by converting the generated energy of the motor generator 4 (alternating current power) into direct current power. The power transmission mechanism 5 is constituted by a drive gear 5a connected to the rotary shaft 4a of the motor generator 4, a driven gear 5b connected to the input shaft 2a of the transmission 2, and an idler gear 5c which meshes with the drive gear 5a and driven gear 5b. The rotation of the rotary shaft 4a of the motor generator 4 is reduced in speed by the power transmission mechanism 5 and transmitted to the input shaft 2a of the transmission 2. Conversely, the rotation of the input shaft 2a of the transmission 2 is increased in speed by the power transmission mechanism 5 and transmitted to the rotary shaft 4a of the motor generator 4. Detection signals from an accelerator depression amount sensor 13 which detects the depression amount (requested driving force) of an accelerator pedal 12, a clutch sensor 14 which detects the engagement and disengagement of the clutch 3, a gear position sensor 17 which detects the gear position of the transmission 2, a vehicle speed sensor 18 which detects the output side rotation speed of the transmission 2 (i.e. an output rotation speed sensor which detects the output rotation speed of the transmission 2), and a rotation speed sensor 19 which detects the rotation speed of the drive gear 5a, which is connected to the rotary shaft 4a of the motor generator 4, as the input side rotation speed of the transmission 2 (i.e. an input rotation speed sensor which detects the input rotation speed of the transmission 2), are input into the main controller 10. The main controller 10 controls the clutch actuator 8 and the inverter 11 of the motor generator 4 on the basis of these detection signals, as well as various information (information obtained from the engine controller 15, brake controller 20, speed change controller 6, and inverter 11) including the state of charge (SOC) of the storage device 9. The main controller 10 also outputs requests to the engine controller 15 and brake controller 20, and commands (speed change commands) to the speed change controller 6. FIG. 2 is an output apportionment map which is stored in the main controller 10 and defines the relationship between the SOC of the storage device 9 and the apportionment ratio between the output of the motor generator 4 and the output of the engine 1. The main controller 10 refers to the output apportionment map to determine the output apportionment ratio corresponding to the SOC of the storage device 9, and controls the output of the motor generator 4 and the output of the engine 1 on the basis of the apportionment ratio and the requested driving force (accelerator depression amount). In other words, the main controller 10 controls the inverter 11 such that the motor generator 4 generates its apportioned output, and outputs a request (a fuel supply amount corresponding to the apportioned output of the engine 1) to the engine controller 15 to have the engine 1 generate its apportioned output. When the output apportionment ratio of the motor generator 4 is one (and the output apportionment ratio of the engine 1 is zero), the inverter 11 is controlled with the clutch 3 in a state of disengagement such that an output corresponding to the accelerator depression amount is obtained only from the motor generator 4. When the output apportionment ratio of the motor generator 4 is less than one (and the output apportionment ratio of the engine 1 is greater than zero), the inverter 11 is controlled with the clutch 3 in a state of engagement such that the apportioned output of the motor generator 4 decreases steadily as the SOC of the storage device 9 decreases, and a request is output to the engine controller 15 to increase the apportioned output of the engine 1. When the output apportionment ratio of the engine 1 is one (and the output apportionment ratio of the motor generator is zero), a request is output to the engine controller 15 requesting that an output corresponding to the accelerator depression amount be obtained only from the engine 1. The main controller 10 cooperates with the brake controller 20 such that whenever the storage device 9 can be charged, the inverter 11 is controlled with the clutch 3 in a state of disengagement to obtain a regenerative braking force corresponding to the brake depression amount (brake pedal depression amount) from the motor generator 4, thereby charging the storage device 9. Further, when the requested braking force corresponding to the brake depression amount cannot be provided fully by the regenerative braking force of the motor generator 4, a request is output to the brake controller 20 to compensate for this part of the braking force with a braiding force generated by the brake actuator 21. Moreover, when it is determined, on the basis of the SOC of the storage device 9, that charging is required and there is leeway in the output of the engine 1 with the clutch 3 in a state of engagement, the inverter 11 is controlled to charge the storage device 9 using the power generation of the motor generator 4. FIG. 3 is a flowchart illustrating the content of the control executed by the main controller 10 when the vehicle is stationary, which is executed repeatedly in the main controller 10. In a step S1, the detection signal from the gear position sensor 17 is read to determine whether or not the gear position is neutral. In a step S2, the detection signal from the vehicle speed sensor 18 is read to determine whether or not the vehicle has stopped (whether or not the vehicle speed is zero or extremely low). When the determination of the step S1 is affirmative and the determination of the step S2 is affirmative, the process advances to a step S3. On the other hand, when at least one of the determinations in the step S1 and the step S2 is negative, the process is terminated. In the step S3, a determination is made on the basis of the SOC of the storage device 9 as to whether or not the storage device 9 needs to be charged (whether or not the SOC is smaller than a predetermined value SOCth). When the determination of the step S3 is affirmative, the process advances to the power generation mode of a step S4. On the other hand, when the determination of the step S3 is negative, the process advances to an idling stop mode (control to halt operations of the engine 1) of a step S5. FIG. 4 is a flowchart illustrating the content of the processing performed in the step S4, and accordingly the content of the control that is executed in the power generation mode. Maps shown in FIGS. 5-7 are stored in the main controller 10. In a step S41, the detection signal from the engine rotation speed sensor 16 and the detection signal from the accelerator depression amount sensor 13 are read. In a step S42, on the basis of the map shown in FIG. 5, an engine torque at a point on an engine torque high efficiency line at the current engine rotation speed is set as a target engine torque. In a step S43, a rack position (fuel injection amount) is determined from the engine rotation speed and accelerator depression amount by referring to the map shown in FIG. 6A. Further, the current engine torque (at the point in time when the engine rotation speed and accelerator depression amount are read in the step S41) is determined from the rack position and engine rotation speed by referring to the map shown in FIG. 6B, and a value obtained by subtracting the current engine torque from the target engine torque is set as a target power generation torque of the motor generator 4. In a step S44, a transitional time period corresponding to the target power generation torque is set by referring to the map shown in FIG. 7. In a step S45, the power generation torque of the motor generator 4 is raised gradually to the target power generation torque over the transitional time period set in the step S44. Once the transitional time period has elapsed and the power generation torque has reached the target power generation torque, a command is issued to the inverter 11 to maintain the target power generation torque for as long as the conditions of the power generation mode remain established, or in other words until at least one of the determinations in the steps S1-S3 becomes negative. It should be noted that once the target power generation torque has been set, the steps S41-S44 are not executed until at least one of the determinations in the steps S1-S3 becomes negative. By means of the constitution described above, when the vehicle is stationary (when the gear position of the transmission 2 is neutral and the vehicle speed is zero or extremely low) and the SOC of the storage device 9 is small, therefore requiring charging, an idling stop is not executed, and instead the power generation torque of the motor generator 4 is controlled to the target power generation torque. The storage device 9 is charged by the power generation of the motor generator 4, and hence the state of charge of the storage device 9 increases, enabling an increase in the number of opportunities for starting the vehicle using only the output of the motor generator 4 when the vehicle is restarted. The engine 1 is controlled such that the fuel injection amount is increased in accordance with the load (power generation torque) from the motor generator 4, and such that the engine torque is raised while maintaining the engine rotation speed at a constant level. The target engine torque is set such that the operating point of the engine 1 is on the engine torque high efficiency line, and therefore favorable fuel economy and exhaust performance can also be secured. FIG. 9 is a view illustrating the content of the control executed in the power generation mode. The power generation torque of the motor generator 4 is controlled to a target motor torque, which is a value obtained by subtracting an engine no-load torque (the torque required to rotate the engine itself) from the target engine torque. The power generation torque of the motor generator 4 is not raised momentarily in a single step to the target power generation torque, as shown by the dotted line in FIG. 8, but instead is raised gradually over the predetermined transitional time period, as shown by the solid line in FIG. 8. As a result, the load of the engine 1 (the power generation torque) varies gently so that disturbances in the engine rotation speed are avoided, and hence power generation can be performed with stability and without worsening the exhaust performance. On the other hand, when the vehicle is stationary and the state of charge of the storage device 9 is high such that charging of the storage device 9 is not needed, an idling stop is executed to halt operations of the engine 1, and therefore a reduction in fuel consumption produced by the engine idling stop can be obtained. Since the SOC of the storage device 9 is sufficient, the vehicle can be started using the output of the motor generator 4 alone when restarting the vehicle, and hence there is no reduction in the number of opportunities for starting the vehicle using the output of the motor generator 4 alone. It should be noted that in the embodiment described above, the control system is constituted by a plurality of controllers, but the number of controllers may be increased or decreased, and the control system may be constituted by a single controller. INDUSTRIAL APPLICABILITY This invention may be applied to a parallel hybrid vehicle comprising an engine and a motor generator as a drive source, and is useful for improving starting performance, fuel economy, and exhaust performance.

<SOH> BACKGROUND ART <EOH>JP2002-138876A, published by the Japan Patent Office in 2002, discloses a parallel hybrid vehicle comprising an engine and a motor generator as a drive source. In this conventional example, a map for setting an output apportionment ratio of the motor generator and engine in accordance with the SOC of a storage device is stored in a controller. The controller refers to the map to determine the output apportionment ratio in accordance with the SOC of the storage device, and controls the output of the motor generator and the output of the engine on the basis of the determined apportionment ratio and an accelerator depression amount.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a block diagram of a parallel hybrid vehicle according to this invention. FIG. 2 is a table defining the relationship between a state of charge of a storage device, and an output apportionment ratio between an engine and a motor generator. FIG. 3 is a flowchart showing the content of control executed by a main controller. FIG. 4 is a flowchart showing the content of control executed by the main controller in a power generation mode. FIG. 5 is a map showing the relationship of a specific fuel consumption to an engine rotation speed and an engine torque. FIG. 6A is a map defining the relationship of a rack position (fuel injection amount) to the engine rotation speed and an accelerator depression amount. FIG. 6B is a map defining the relationship of the engine torque to the rack position (fuel injection amount) and the engine rotation speed. FIG. 7 is a table defining the relationship between a target power generation torque and a transitional time period. FIG. 8 is a time chart showing the manner in which the target power generation torque changes. FIG. 9 is a view illustrating the content of the control executed in the power generation mode. detailed-description description="Detailed Description" end="lead"?

20060131

20080603

20060907

77657.0

B60K102

YOUNG, EDWIN

HYBRID VEHICLE AND METHOD OF CONTROLLING THE VEHICLE

UNDISCOUNTED

ACCEPTED

B60K

ACCEPTED

Record carrier comprising encryption indication information

The present invention relates to a record carrier (10) for storing user data in sectors (S) and management information (n) associated with said sectors. In order to provide a simple, low-cost, flexible and secure copy protection of the user data when being transmitted over a communication bus (6) of a PC it is proposed according to the present invention that the management information comprises an encryption indication information (M1) indicating that the user data stored in the associated sector (S) are to be encrypted by a read-out device (2) before being transmitted over a communication bus (6).

1. Record carrier (10) for storing user data in sectors (S) and management information (M) associated with said sectors (S), wherein said management information (M) comprises an encryption indication information (M1) indicating that the user data stored in the associated sector (S) are to be encrypted by a read-out device (2) before being transmitted over a communication bus (6). 2. Record carrier as claimed in claim 1, wherein said management information (M) is stored in a sector header (4) or in an additional sub-code channel. 3. Record carrier as claimed in claim 1, wherein said management information (M) further comprises an encryption amount information (M3) indicating which part or parts of the user data stored in the associated sector (S) are to be encrypted. 4. Record carrier as claimed in claim 1, wherein said management information (M) further comprises an encryption algorithm information (M4) indicating which encryption algorithm is to be used for encryption. 5. Record carrier as claimed in claim 1, wherein said management information (M) further comprises a key-hierarchy information (M5) indicating which key-hierarchy is to be used for determination of an encryption key to be used for encryption. 6. Record carrier as claimed in claim 1, wherein said management information (M) further comprises a decryption indication information (M2) indicating that the user data stored in the associated sector (S) are to be decrypted by the read-out device (2) before being encrypted again for transmission over said communication bus (6). 7. Record carrier as claimed in claim 6, wherein a decryption key for decryption of the user data is dependent on at least the encryption indication information (M1). 8. Read-out device for reading data from a record carrier (10) storing user data in sectors (S) and management information (M) associated with said sectors (S), wherein said management information (M) comprises an encryption indication information (M1) indicating that the user data stored in the associated sector (S) are to be encrypted by a read-out device (2) before being transmitted over a communication bus (6), comprising: a reading unit (21) for reading said user data and said management information (M) from said record carrier (10), a data interpreter (23) for interpreting said management information (M), an encryption unit (24) for encrypting user data of sectors (S) for which the associated encryption indication information (M1) indicates that said user data are to be encrypted and an output unit (25) for outputting said user data. 9. Read-out method for reading data from a record carrier (10) storing user data in sectors (S) and management information (M) associated with said sectors (S), wherein said management information (M) comprises an encryption indication information (M1) indicating that the user data stored in the associated sector are to be encrypted by a read-out (2) device before being transmitted over a communication bus (6), comprising the steps of: reading said user data and said management information (M) from said record carrier (10), interpreting said management information (M), encrypting user data of sectors (S) for which the associated encryption indication information (M1) indicates that said user data are to be encrypted and outputting said user data. 10. Recording device for recording data on a record carrier (10) comprising: an input unit (27) for receiving user data and a command (C) to record said user data in sectors (S) on a record carrier (10) from a communication bus (6), a command interpreter (26) for interpreting said command (C) so as to identify a decryption indication information (C2) included therein indicating which parts of the received user data are encrypted and are to be decrypted before recording on said record carrier (10), a decryption unit (24) for decrypting the parts of said user data for which the associated decryption indication information (M2) indicates that they are encrypted and are to be decrypted before recording on said record carrier (10), and a write unit (22) for recording said user data in sectors (S) on said record carrier (10) and a management information (M) associated with said sectors (S) comprising an encryption indication information (M1) indicating that user data stored in sectors (S) associated with said management information (M) are to be encrypted by a read-out (2) device before transmission over a communication bus (6). 11. Recording method for recording data on a record carrier (10) comprising the steps of: receiving user data and a command (C) to record said user data in sectors (S) on a record carrier (10) from a communication bus (6), interpreting said command (C) so as to identify a decryption indication information (C2) included therein indicating which parts of the received user data are encrypted and are to be decrypted before recording on said record carrier (10), decrypting the parts of said user data for which the associated decryption indication information (C2) indicates that they are encrypted and are to be decrypted before recording on said record carrier (10), and recording said user data in sectors (S) on said record carrier (10) and a management information (M) associated with said sectors (S) comprising an encryption indication information (M1) indicating that user data stored in sectors (S) associated with said management information (M) are to be encrypted by a read-out (2) device before transmission over a communication bus (6). 12. Recording method as claimed in claim 11, wherein said command (C) further comprises an encryption indication information (C1) and that a decryption key for decryption of the user data is dependent on said encryption indication information (C1). 13. Computer program comprising program code means for causing a computer to carry out the steps of the methods as claimed in claim 9 when said computer program is executed on a computer.

The present invention relates to a record carrier for storing user data in sectors and management information associated with said sectors. The present invention relates further to a read-out device for reading data from a record carrier and a corresponding read-out method. Still further, the present invention relates to a recording device and a corresponding recording method for recording data on a record carrier. Finally, the present invention relates to a computer program for implementing said methods. Optical disc drives connect with other components in a personal computer (PC) via a communication bus, in particular a so-called PCI-bus. It is easy for hackers to listen to the communication over this bus and to get access to transmitted user data. A so-called bus encryption, according to which user data are encrypted before transmission over the communication bus and decrypted by the receiving component after transmission, is generally used to protect data transmission against eavesdropping. However, bus encryption requires significant computational effort which degrades the performance of application or increases the costs of such systems. The computational efforts could be reduced by not encrypting all user data in all sectors, but only encrypting a few sectors or part of the user data in a sector, or by choosing an encryption algorithm that requires less computational effort. Such measures would, however, weaken the protection. Since different applications have different security requirements, and a single optical drive has to read and to protect data for many different applications, it is thus a problem to make an optical disc drive or, more generally, to provide a read-out device for reading data from a record carrier, that satisfies all needs with a single bus encryption method. In particular, this flexible security level shall be provided to protect user data during transmission over the communication bus when the user data is recorded on a record carrier, such as a recordable optical disc. Many copy protection methods have been created to prevent copying of user data. One of these methods is based on so-called re-encryption according to which some sectors of the disc are encrypted and which will be decrypted by the drive before transmitting it via a secure communication channel to another component in a PC. The advantage of re-encryption is that the key used by the drive to decrypt the sector does not leave the drive and is therefore not easily discovered by hackers. However, the decryption of the encrypted sector requires significant computational effort which degrades the performance of the drive or increases the costs thereof. Although the computational effort can be reduced by the same measures as mentioned above, the strength of the protection will be weakened. Since different applications have different security requirements it is therefore desired to provide a low-cost read-out device that is optimized for the security level of a single application and a general purpose read-out device that provides the right security level for all applications and can read record carriers for all applications. A method is therefore needed by which a general-purpose read-out device can determine if and, preferably, what type of encryption is to be used. Preferably, an additional information indicating if and which kind of decryption is required before encryption, should be provided. It is thus an object of the present invention to provide a record carrier, a recording device and method as well as a read-out device and method which provide a flexible security level to protect user data during transmission over the communication bus, also when the data is recorded on a record carrier such as a recordable optical disc. This object is achieved according to the present invention by a record carrier as claimed in claim 1 according to which the management information comprises an encryption indication information indicating that the user data stored in the associated sector are to be encrypted by a read-out device before being transmitted over a communication bus. A read-out device for reading data from such a record data is defined in claim 7 and comprises a data interpreter for interpreting said management information, an encryption unit for encrypting user data of sectors for which the associated encryption indication information indicates that said user data are to be encrypted and an output unit for outputting said user data. A recording device for recording data on such a record carrier is defined in claim 10 and comprises: an input unit for receiving user data and a command to record said user data in sectors on a record carrier from a communication bus, a command interpreter for interpreting said command so as to identify a decryption indication information included therein indicating which parts of the received user data are encrypted and are to be decrypted before recording on said record carrier, a decryption unit for decrypting the parts of said user data for which the associated decryption indication information indicates that they are encrypted and are to be decrypted before recording on said record carrier, and a write unit for recording said user data in sectors on said record carrier and a management information associated with said sectors comprising an encryption indication information indicating that user data stored in sectors associated with said management information are to be encrypted by a read-out device before transmission over a communication bus. Corresponding methods are defined in claims 9 and 11. A computer program for implementing said methods is defined in claim 13. The present invention is based on the idea to signal to the read-out device that particular user data shall be encrypted by the read-out device before they can be transmitted over the communication bus, in particular a PCI-bus of PC. An encryption indication information is thus provided in the management information and associated with all sectors in which user data are stored which shall be encrypted before transmission over the communication bus. This encryption indication information will be read and evaluated by the read-out device which then encrypts the associated user data before they are outputted to the communication bus. The recording device according to the present invention is adapted such that during recording of user data such encryption indication information is assigned to the user data and also recorded on the record carrier for later read-out by the read-out device. Such encryption indication information is written based on a corresponding decryption indication information included in a command received by the recording device along with the instruction to record particular user data on a record carrier. The invention thus provides a simple, flexible and low-cost solution providing copy protection during transmission of user data over a communication bus which are read from a record carrier. It should be noted that user data shall be understood as including any kind of data that are stored on a record carrier and can be transmitted over a communication bus, i.e. not only include data that are particularly meant for a user, such as audio, video or software data, but also include any other kind of data such as management data or control data. Preferred embodiments of the invention are defined in the dependent claims. According to a simple embodiment the management information is stored in the sector header of each sector and the encryption indication information is a single bit which is used to trigger encryption of user data stored in the associated sector. However, the management information can be also stored in a separate (additional) sub-code channel besides the normal data channel. According to further embodiments the management information comprises additional information indicating which part or parts of the user data are to be encrypted, which encryption algorithm is to be used for encryption, which key-hierarchy is to be used for determination of an encryption key to be used for encryption and/or indicating that the user data stored in the associated sectors are to be decrypted by the read-out device before being encrypted again for transmission. Again, these indicators could be single bits stored in the sector header. Preferably, the indication information that triggers bus-encryption is made independent from the indication information that triggers sector decryption because the security requirements for both methods may be different. If the triggers for bus encryption and sector decryption are independent, preferably the integrity of at least the bus encryption trigger is protected. This can be achieved by, e.g., making the sector decryption key dependent on at least the bus encryption trigger (for example XOR or hash the trigger into the key). The invention will now be explained in more detail with reference to the drawings in which FIG. 1 shows a block diagram of a PC, FIG. 2 shows a block diagram of a read-out and recording device according to the invention, FIG. 3 illustrates a first embodiment of the invention, FIG. 4 illustrates the first embodiment of the invention with a different parameter setting, FIG. 5 illustrates a second embodiment of the invention, FIG. 6 illustrates a third embodiment of the invention and FIG. 7 illustrates a fourth embodiment of the invention. FIG. 1 shows a block diagram of a PC 1 comprising a drive 2, for instance an optical disc drive, capable of reading data from a record carrier 10 and capable of writing data to said record carrier 10, a CPU (Central Processing Unit) 3, a memory 4 and a graphics card 5 all connected to a communication bus 6. For simplicity's sake no further details of the PC 1 are shown which may, of course, comprise further and other components as well. FIG. 2 shows a block diagram of a drive 2 according to the present invention. For reading data from the record carrier 10 a reading unit 21 is provided; for writing data to said record carrier 10 a writing unit 22 is provided. When reading user data U from the record carrier 10 which are stored in sectors S, as shown in FIG. 3 by way of example of an optical disc having sectors of 2048 bytes length each, associated management information M stored in the sector header H associated to each sector S and, in this example, having n bytes, is read as well and forwarded to a data interpreter 23. Therein, the management information M, in the example shown in FIG. 3 being one byte comprising 8 bits, are evaluated in order to determine if the read user data stored in the associated sector S shall be encrypted by an encryption/decryption unit 24 before output by an output unit 25 and subsequent transmission over the communication bus 6. In the embodiment shown in FIG. 3 the management information M only includes zero-bits meaning that no encryption of user data U is required before transmission over the communication bus. Thus, the user data will be directly outputted by the output unit 25 to the communication bus 6, i.e. the user data U will be communicated over the bus 6 in unencrypted form as shown in FIG. 3. In the embodiment shown in FIG. 4, the encryption indication information M1 included in the management information M indicates, by setting a one-bit, that the user data U stored in the sector S are to be encrypted before being outputted. Thus, the read user data U will be forwarded to the encryption/decryption unit 24 where they are encrypted, before being afterwards outputted to the communication bus. In this embodiment, only a fixed part Ue of the user data of the sector S is encrypted while other parts Uu are communicated in unencrypted form. In the embodiment shown in FIG. 5 already part Se of the user data U stored on the record carrier in sector S is encrypted while other parts Su of the sector S are not encrypted. In the associated management information M, besides the encryption indication information M1, an additional decryption indication information M2 is included indicating that (part of) the user data U stored in the sector S need to be decrypted first before again encrypted (indicated by M1) and transmitted over the communication bus. Preferably, the decryption key of the encrypted part Se is dependent on the first indicator M1 (and optionally also on indicator M2). Thus, the encryption/decryption unit 24 first decrypts the encrypted portion Se of the sector S before part of the completely unencrypted user data U of the sector S are encrypted and transmitted over the bus. Preferably, different encryption/decryption keys and/or encryption/decryption algorithms are used for these two steps of decryption/encryption provided according to this embodiment. The management information may further include additional information, such as an information indicating the amount of user data that needs to be decrypted before encryption, which algorithm to use for decryption and/or which key hierarchy to use for decryption. According to still another embodiment as shown in FIG. 6 an additional encryption amount information M3 is provided as additional management information in the sector header A indicating which parts of the sector S must be encrypted by the drive 2. For instance, as shown in FIG. 6, three parts of the sector S which shall be encrypted (Ue) are indicated by the encryption amount information M3 while other parts of the sector remain unencrypted (Uu) before being transmitted over the bus. Further information can be included in the management information, such as for instance an encryption algorithm information M4 indicating which encryption algorithm is to be used for encryption and/or a key hierarchy information M5 indicating which key-hierarchy is to be used for determination of an encryption key to be used for encryption. The embodiment of the drive 2 shown in FIG. 2 further comprises a data/command interpreter 26 and an input unit 27 for reception of data from the communication bus 6. These units will be used for recording of data to the record carrier 10. In this case a command instructing the drive 2 to record particular user data is received along with that user data by the input unit 27 and is evaluated by the data/command interpreter 26. This embodiment is illustrated in FIG. 7 where the command C comprises a decryption indication information C2 (similar to M2 shown in FIG. 5) indicating that encrypted user data Ue received from the bus 6 need to be decrypted and an encryption indication information C1 indicating that (part of) the whole user data need to be encrypted before storage on the record carrier. In this case the integrity of at least the trigger for sector encryption (C1) must be protected. This can be achieved by, e.g., making the bus decryption key dependent on at least the sector encryption trigger (for example XOR or hash the trigger into the key). These steps of encryption and decryption will be done by the encryption/decryption unit 24 before the partly encrypted user data are written to the record carrier 10 by the write unit 22. At the same time an appropriate management information M including indicators M1 and M2 is recorded in the sector header H. Of course, additional further information, similar to the additional further information illustrated above for the management information, can also be included in the command C. According to the invention a simple, low-cost, flexible and secure solution for protection of user data stored on a record carrier before transmission over a communication bus of a PC is provided.

20060130

20091020

20061026

85681.0

H04L900

LAFORGIA, CHRISTIAN A

RECORD CARRIER COMPRISING ENCRYPTION INDICATION INFORMATION

UNDISCOUNTED

ACCEPTED

H04L

ACCEPTED

Water feature

A water feature comprising a vessel (1) for containing water, an electrically powered submersible water pump (2) within the vessel (1) for pumping water to an outlet of the water feature and a solar panel (4) arranged to provide electrical power to the water pump (2). The solar panel (4) is arranged within said water vessel (1) above the water pump and so as to be beneath the water level (7) in the vessel (1) in use.

1. A water feature comprising (a) a vessel for containing water; (b) an electrically powered submersible water pump within the vessel for pumping water within the vessel to an outlet of the water feature; and (c) a solar panel arranged to provide electrical power to said water pump; wherein the solar panel is disposed within said water vessel above the water pump and so as to be beneath the water level in the vessel in use. 2. A water feature as claimed in claim 1, wherein the solar panel is arranged to divide the vessel into a first and second chamber. 3. A water feature as claimed in claim 1, wherein the outlet of the water feature is arranged to issue water through the solar panel. 4. A water feature as claimed in claim 1, wherein the outlet of the water feature is arranged to issue water in the form of a fountain. 5. A water feature comprising: (a) a vessel for containing water; (b) a water outlet for recirculating water into the vessel; (c) means for connecting the water outlet to the output of an electrically powered water pump; (d) a solar panel arranged to provide electrical power to said water pump; and (e) means for transmitting electrical power from the solar panel to the electrically powered water pump; wherein the solar panel is disposed within said water vessel so as to be beneath the water level in the vessel in use, and the means for transmitting electrical power from the solar panel to the electrically powered water pump is below the solar panel. 6. A water feature comprising: (a) a vessel for containing water; (b) a water outlet for recirculating water into the vessel; (c) means for connecting the water outlet to the output of an electrically powered water pump; (d) a solar panel arranged to provide electrical power to said water pump; and (e) means for transmitting electrical power from the solar panel to the electrically powered water pump; wherein the solar panel, the electrically powered water pump and the means for transmitting electrical power from the solar panel to the electrically powered water pump are disposed within said water vessel so as to be beneath the water level in the vessel in use, and both the pump and the solar panel are supported by the water vessel. 7. A controller for a solar powered electric device, comprising: (a) an input for receiving power from a photovoltaic cell; (b) an output for providing power to a solar powered electric device, said device having a predefined minimum operating voltage; and (c) switching means for supplying electrical power from said input to said output; wherein said switching means is automatic and adapted to supply power to said output only when the voltage received from said in put is equal to or higher than said predetermined minimum operating voltage of said electric device. 8. A method of controlling the supply of electrical energy from a photovoltaic cell to a solar powered electrical device, wherein the solar powered electric device has a predefined minimum operating voltage which is above zero; and wherein the method comprises the step of automatically preventing supply of electrical energy from the photovoltaic cell to the solar powered electrical device when the voltage is above zero but less than the predefined minimum operating voltage of the solar powered electrical device. 9. A water feature as claimed in claim 2, wherein the outlet of the water feature is arranged to issue water through the solar panel. 10. A water feature as claimed in claim 2, wherein the outlet of the water feature is arranged to issue water in the form of a fountain. 11. A water feature as claimed in claim 3, wherein the outlet of the water feature is arranged to issue water in the form of a fountain.

The present invention relates to water features and in particular garden water features which are powered by solar cells. The invention also relates to the control of solar powered devices for such water features and for other purposes. The use of solar cells as a source of power for garden products and ornaments is known in the art. For example, it is know to connect a solar panel to an electric pump to supply, or circulate, water to or around a garden water feature. The solar panel is selected so as to generate a sufficient amount of electrical energy to operate a given water pump. In areas of low light levels, or where overcast weather is prevalent, the use of solar panels to power electric motors can be problematic, particularly in terms of the lifetime of a motor. It is known the art to operate electric motors and pumps using energy from solar (photovoltaic) cells. According to the prior art there are two common methods of powering pumps. The first method of driving a pump is to use an electromagnetic drive. In these, a magnetic field is generated by means of a magnetic coil. As energy is supplied the magnet with the rotor is set in motion. This type of drive ensures a long service life (more than 30,000 hours) and the only part subject to wear is the rotor, which can be replaced at any time. With regard to operation using solar energy this drive has the disadvantage that considerable energy is required to create the magnetic field, which in turn requires a great deal of sun. These products have not caught on in the market as customers find the market prices unreasonable or, in view of the serious price difference (more than 300%) between the solar-powered pump and a mains-operated pump, opt for the mains-powered pump. The second method is to use a pump with an electric motor drive. In these, a conventional electric motor with brushes is used, which drives a rotor directly or via a magnetic clutch. This drive requires up to 200% less energy than an electromagnetic drive and therefore considerably less solar power. This drive has caught on in the market. The disadvantage of this drive is that the brushes of the electric motors are generally prone to wear, which leads to increased current consumption the longer they are used and hence to an increasing deterioration in the running performance, particularly in inadequate light conditions (grey morning light, cloud, shade). The maximum service life of a brush motor of this kind can be estimated at about 7,000 to 10,000 hours when operated by mains power. The service life when operated by solar energy is reduced by a further 50% because of two solar-specific properties. Firstly, because of the constantly altering sunshine conditions the motor is subjected to a constant stop-start rhythm, which leads to overloading of the brushes and also the motor. Secondly solar panels have the characteristic that their nominal voltage is applied even under poor lighting conditions. In the operation of electric motors this means that, in poor light, sparking may occur on the brushes as a result of this nominal voltage applied to the motor, as the current supplied from the solar module is not yet sufficient to run the motor. The brushes then become worn without the motor actually doing its job. There is therefore a need for a motor controller capable of extending the operational life of a motor when powered by a solar panel or cell, which prevents motor brush wear. Accordingly, one invention disclosed herein provides a controller for a solar powered electric device, comprising: (a) an input for receiving power from a photovoltaic cell; (b) an output for providing power to a solar powered electric device, said device having a predefined minimum operating voltage; and (c) switching means for supplying electrical power from said input to said output; wherein said switching means is automatic and adapted to supply power to said output only when the voltage received from said input is equal to or higher than said predetermined minimum operating voltage of said electric device. Viewed from another aspect, such an invention also provides a method of controlling the supply of electrical energy from a photovoltaic cell to a solar powered electrical device, wherein the solar powered electric device has a predefined minimum operating voltage which is above zero; and wherein the method comprises the step of automatically preventing supply of electrical energy from the photovoltaic cell to the solar powered electrical device when the voltage is above zero but less than the predefined minimum operating voltage of the solar powered electrical device. The solar powered electrical device could be, for example, a motor for any suitable equipment, where constant supply of electrical energy below a specified minimum voltage may cause unnecessary wear or damage. Preferably, the device is the electric motor of a pump for a water feature. In a preferred embodiment, the controller prevents power being supplied to the motor unless the power being received from the photovoltaic cells is above the start voltage of the motor. This prevents damage to the motor brushes and thereby increases the operational life of the motor. The start voltage chosen could, for example, be at least 3 V. The switching means may be any suitable switch for electrically connecting the photovoltaic cell to the motor or other device. The switching mans may for example be a transistor or thyristor. Preferably the switching means is a silicon controlled rectifier (SCR). Circuitry for controlling the switching means in accordance with the detected voltage level from the photovoltaic cell may incorporate a Zener diode or equivalent component. In a preferred arrangement, a Zener diode is chosen which has a suitable Zener breakdown voltage such that it will only switch on when the voltage from the photovoltaic cell is above the predetermined minimum operating voltage. That is used to trigger the gate of an SCR so as to connect the device to the voltage output by the photovoltaic cell. That voltage will increase with increasing sunlight. The SCR disconnects the photovoltaic cells from the motor when the voltage being generated by the photovoltaic cells becomes zero i.e. when there is no sunlight. As an alternative, the switching means may be provided with further circuitry to disconnect the photovoltaic cells from the motor when the voltage being supplied by the photovoltaic cells falls below a predefined voltage level. In water features according to the prior art, pumps are located beneath the surface of the water and are connected to a solar cell which, for reasons of aesthetics, are arranged some distance from the feature itself. The solar cell and pump are electrically connected by a length of electrical cable. Solar powered water features according to the prior art furthermore require the separate installation of water feature and solar panel and also require a length of electrical cable which must be laid or buried between the two. There is therefore a need for a solar powered water feature which overcomes the problems of the prior art and which can be powered using a solar cell or panel. One invention disclosed herein provides a water feature comprising (a) a vessel for containing water; (b) an electrically powered submersible water pump within the vessel for pumping water within the vessel to an outlet of the water feature; and (c) a solar panel arranged to provide electrical power to said water pump; wherein the solar panel is disposed within said water vessel above the water pump and so as to be beneath the water level in the vessel in use. One advantage of this arrangement of water feature is that there is no longer the need to site an exterior solar panel and to have a cable running from the water feature to the solar panel. Furthermore a user does not have to install the solar panel separately from the water feature since they can be supplied to an end user assembled together as a single, compact unit. In addition, the solar panel can conceal the pump, wiring, pipes and so forth from view. The solar panel itself is unobtrusive since, in use, it is covered by water in the vessel. In preferred embodiments, apart from the water feature outlet and any appropriate visible connection to the water pump, all operating components of the feature—such as the pump, the solar panel, interconnecting wiring and pipes—will be below the surface of water in the vessel in use. In an alternative arrangement the pump may be arranged separately from the vessel, for example if it is of non-submersible type and/or needs to draw water from another source. Thus, another invention disclosed herein provides a water feature comprising: (a) a vessel for containing water; (b) a water outlet for recirculating water into the vessel; (c) means for connecting the water outlet to the output of an electrically powered water pump; (d) a solar panel arranged to provide electrical power to said water pump; and (e) means for transmitting electrical power from the solar panel to the electrically powered water pump; wherein the solar panel is disposed within said water vessel so as to be beneath the water level in the vessel in use, and the means for transmitting electrical power from the solar panel to the electrically powered water pump is below the solar panel. In general the solar panel will be disposed in a horizontal plane. In another arrangement, the solar panel and pump are both within the vessel but are laterally separated. Thus, in general, an invention disclosed herein provides a water feature comprising: (a) a vessel for containing water; (b) a water outlet for recirculating water into the vessel; (c) means for connecting the water outlet to the output of an electrically powered water pump; (d) a solar panel arranged to provide electrical power to said water pump; and (e) means for transmitting electrical power from the solar panel to the electrically powered water pump; wherein the solar panel, the electrically powered water pump and the means for transmitting electrical power from the solar panel to the electrically powered water pump are disposed within said water vessel so as to be beneath the water level in the vessel in use, and both the pump and the solar panel are supported by the water vessel. The term “water feature” includes functional or ornamental garden products such as bird baths, cascades or fountains in which water is re-circulated. The pump may be arranged to generate a fountain above the solar panel or, alternatively, the pump may be arranged to circulate water around the product. For example, the feature may comprise a number of water vessels arranged above one another such that water can flow from an upper vessel to a lower vessel in a cascade. The solar powered pump may then re-circulate water to an upper vessel. The solar panel may be arranged on the bottom of the vessel if there is a separate pump outside the vessel or if there is a laterally displaced pump within the vessel, but is preferably arranged within the vessel so as to define a volume of water above the panel and a volume of water below the panel in which the pump is arranged. The panel is preferably at a depth so that it is at least partially concealed from view by the volume of water above the panel. However the depth of the panel in the water should not be excessive, so that insufficient light can reach the panel to power the pump. In a preferred arrangement the panel is arranged at such a depth that small birds can stand on the panel. In a preferred arrangement, the solar panel separates the vessel into two discrete volumes of water, contacting the vessel around the periphery. However, apertures through the panel or, for example spaces between the panel and the wall of the vessel, will normally be provided so as to give a return path for water to a pump disposed below the panel. Alternatively, the panel could be a free-standing unit submerged in the vessel without defining discrete volumes of water. The solar panel and pump may be arranged on a removable insert which can be placed into a corresponding recess in the vessel or water feature body, with the panel for example being supported on a peripheral ridge or other means part way up the vessel, or can alternatively be a unit which rests on the bottom of the vessel. The pump may issue water into a conduit for circulation around the feature, for example in a cascade from one or more additional containers before returning to the vessel, or may issue water in the form of a fountain. The solar panel and pump may be arranged such that water issues through the solar panel. Pumps suitable for use with water features are known in the art and are powered by means of energy from solar panels or cells, e.g. in the form of so-called “solar islands”. Generally pumps known in the art are submersible pumps. It would be possible for a pump to be placed under the surface of the water and connected to a solar panel positioned on or near the surface of the water by means of an unbreakable connection. The pump and solar panel would thus be a single unit. A considerable disadvantage of a product of this kind would be that in general the service life of a solar cells far exceeds that of a pump. Consequently, the product would become unusable if the pump is defective and would thus have to be thrown away even though the current source, which is generally the major cost factor of such products, is still operating perfectly well. Thus, in a preferred arrangement the water pump and solar panel are electrically connected by means of a water tight separable connection such as a plug and socket, so that the pump can be replaced separately from the solar panel. This is inventive in its own right and thus another invention disclosed herein provides a water feature having a water pump and solar panel as a unit to be disposed in water with at least the pump submerged, wherein the solar panel and the pump are electrically connected by means of a submerged, water tight separable connection. This invention may be used with the inventions discussed earlier, or separately. The particular advantage of this arrangement is that in the event of a defect, the pump and/or the solar panel can be replaced as necessary. A water feature in accordance with this invention could, for example, be a floating unit, with the solar panel arranged either above or below the water level. The various inventions disclosed above, including the control circuit for supplying electricity to e.g. a water feature pump, and the details of the water features, may be used alone or together in any desired combination. Preferred embodiments of the inventions will now be described, by way of example only, with reference to the accompanying drawings in which: FIG. 1 shows a cross-section of a water feature according to a present invention. FIG. 2 shows a plan view of a water feature according to a present invention. FIG. 3 shows a cross-section of a further embodiment of a water feature. FIG. 4 shows a cross section of a floating water feature with submersible pump. FIG. 5 is a schematic of an electric motor in cross section. FIG. 6 shows a circuit diagram illustrating the components used in the preferred embodiment of motor controller. FIGS. 7A & B show graphs of voltage and current for the motor controller under rising sun conditions. FIG. 1 shows a solar powered water feature in the form of a bird bath, viewed in section. FIG. 2 shows the same feature from above. The water feature body 1 in the form of a flat dish with a collecting basin arranged below it can be filled with water. A flat housing 5 which is circular in shape when viewed from above can be placed in the water feature body 1 in the manner of an insert which covers the collecting basin and thus forms part of the base of the flat dish. On the top of the housing 5 is provided a solar cell or panel 4. As a result of the shape of the water feature body 1 and the housing 5 inserted therein with the solar cell 4, the depth of the water is limited to a level which allows birds to stand in the water. The solar module 4 located under the surface of the water 7 provides the energy needed to operate a pump 2 through solar radiation. The pump 2 is mounted underneath the housing 5 and preferably secured thereto and is thus disposed in the collecting basin of the water feature body 1. The solar cell 4 and pump 2 are electrically connected by a connecting plug 3 which can be pulled apart. The water delivered by the pump 2 passes through a riser pipe 6 above the surface of the water 7 in the form of a fountain. The riser pipe 6 is preferably passed through a hole in the housing 5 and solar cell 4. The water can flow through holes 8 in the housing 5 from the upper part into the lower collecting basin of the water feature body 1, thus ensuring a constant supply of water to the pump 2. FIG. 3 shows an alternative embodiment of a water feature. A solar cell 24 and pump 22 are again mounted under the surface 27 of the water but in this case they are placed not one above the other but side by side. In this embodiment the solar cell is integrated directly in the water feature body 21 or placed therein. The electrical connection is made by a separable connecting plug 23 which is also located under the surface of the water. The solar cell 24 is a prefabricated unit and has waterproof glass on the top and at the sides. On the underside is provided a film which is sealed off at the edges by laser treatment. A corresponding laser seal may be provided for the passage of the riser pipe 26. FIG. 4 shows a water feature with solar cell and pump viewed in cross-section. The solar cell 31 receives solar radiation and supplies the energy required to operate a pump 32. The solar cell is attached to a float 33 of any suitable shape and material. The pump 32 is arranged underneath the solar cell 31 and preferably releasably attached thereto or to the float 33. The solar cell 31 and pump 32 are electrically connected by a separable connecting plug 34. The water conveyed by the pump 32 emerges through a riser pipe 35 above the surface of the water in the form of a fountain. The riser pipe 35 is preferably passed through a hole in the float 33 and solar cell 31. FIGS. 5 to 7 illustrate the motor/pump controller. A conventional six volt DC electric motor 40 is shown in FIG. 5 having brushes 41 connected to a commutator 42 mounted on an axle 43. The motor further comprises a permanent magnet 44 in which a moving coil 45 rotates. Energy is supplied from the controller to the commutator 42 via brushes 41. Energy is thereby supplied to the coil 45 via the commutator which generates a magnetic field within the permanent magnet 44 which starts spinning the motor. FIG. 6 is a schematic illustrating the control circuit according to an embodiment of the invention. The figure identifies specific components that are suitable for use in this embodiment. A battery 46 of photovoltaic cells of a solar panel is arranged in series with a switching device SCR and the electric motor 40. The switching device SCR is in the form of a silicon controlled rectifier. The SCR is open, preventing the supply of electrical current to the motor 40, until a suitable voltage is applied at the gate G. Connected across the output of the photovoltaic cells 46 is a voltage responsive circuit comprising a Zener diode ZD1 (3.6 V, 0.5 W) and two series resistors R1 (1.2 k, 0.25 W) and R2 (2.2 k, 0.25 W). A tap 47 is connected to a point between the two resistors R1 and R2, and to the gate G of the SCR. The tap is also connected to the negative line via a capacitor C1 (47 mFd, 25 V). The Zener diode only allows current to pass when the voltage across the diode is higher than the value of the breakdown voltage of the diode, which in this particular embodiment is 3.6 V. The value of the Zener diode is selected so that it will break down when the voltage produced by the photovoltaic cells 46 reaches the predetermined starting voltage of the electric motor which in this case has been predetermined at a nominal 3.6 V, the breakdown voltage of the Zener diode. At that point, a voltage will appear on the tap 47, and is applied to the gate G of the SCR so that the SCR closes and allows current to flow from the photovoltaic cells 46 to the electric motor 40. If the voltage produced by the photovoltaic cell drops so that the voltage across the Zener diode falls below the breakdown voltage (in this case, 3.6 V), then there will cease to be a voltage applied to the SCR gate G. However, the SCR remains closed until the voltage from the photovoltaic cell 46 is zero i.e. when there is not longer any sunlight shining on the photovoltaic cell. In the starting position in the morning the output from the photovoltaic cells 46 will be small due to low light levels. When the voltage is below the breakdown voltage of the Zener diode no current flows through the circuit and the SCR remains open. As the light intensity increases, so too does the voltage output from the cells 46 and the potential difference across the resistors and Zener diode. Once the voltage across the Zener diode reaches the breakdown voltage of the Zener diode, the diode breaks down and current flows through the resistors R1. A voltage is then supplied to the gate G of the SCR which then closes. Once the SCR closes the electric motor is connected to the photovoltaic cells and the motor and therefore the pump begins to rotate. Once the motor 40 begins to rotate a frequency will be generated which may interfere with the SCR gate. In order to prevent this, the capacitor C1 is provided which absorbs this frequency. The SCR remains closed until the voltage supplied to the SCR from the photovoltaic cells 46 is zero i.e. when there is no sunlight. The SCR then opens and is re-set to its ‘start’ position for the next day when the SCR is triggered or ‘gated’ by a signal at gate G. FIGS. 7A and 7B are graphs which shows the effect of the invention. As long the sun is not strong enough no voltage can reach the motor and no current flows through the motor. On dull or overcast days the SCR remains open thereby preventing any power being delivered to the motor brushes. Once the SCR is closed, when the output of the cells reaches the predetermined level, the voltage is applied to the motor. With increasing sunlight, this increases to a maximum, which in this case is 6 V. Current increases accordingly. It will be noted that after the Zener diode has broken down, there is a slight voltage drop before it rises again. This can be taken into account when determining the starting voltage of the motor and the value of the Zener diode.

20060912

20090203

20070510

60911.0

B05B1708

NGUYEN, DINH Q

WATER FEATURE

SMALL

ACCEPTED

B05B

ACCEPTED

CONTROL DEVICE FOR INTERNAL COMBUSTION ENGINE AND METHOD FOR DETERMINING MISFIRE IN INTERNAL COMBUSTION ENGINE

An internal combustion engine (1) generates power by burning an air-fuel mixture in a combustion chamber (3). The internal combustion engine (1) is provided with an in-cylinder pressure sensor (15) and an ECU (20). The ECU 20 calculates at two predetermined points control parameters each of which is a product of an in-cylinder pressure detected by the in-cylinder pressure sensor (15) and a value obtained by exponentiating an in-cylinder volume at the time of detecting the in-cylinder pressure by a predetermined index number, as well as determines a misfire condition in the combustion chamber (3) based on the difference component in the control parameters between the two predetermined points.

1. A control device for an internal combustion engine that generates power by burning an air-fuel mixture in a cylinder, comprising: in-cylinder pressure detecting means; calculating means that calculates a control parameter based on an in-cylinder pressure detected by the in-cylinder pressure detecting means and an in-cylinder volume at the time of detecting the in-cylinder pressure; and misfire determining means that determines a misfire condition in the cylinder based upon the control parameter calculated by the calculating means, wherein: the control parameter is a product of the in-cylinder pressure detected by the in-cylinder pressure detecting means and a value obtained by exponentiating the in-cylinder volume at the time of detecting the in-cylinder pressure by a predetermined index number; the calculating means calculates the control parameters in two predetermined points; and the misfire determining means determines that an inside of the cylinder is in a misfire condition by comparing a difference component in the control parameters between the two predetermined points with a predetermined threshold value. 2. The control device for the internal combustion engine according to claim 1, wherein: the misfire determining means determines that the inside of the cylinder is in a half-misfire condition when the difference component in the control parameters between the two predetermined points is below a first threshold value. 3. The control device for the internal combustion engine according to claim 2, wherein: when the misfire determining means determines that the inside of the cylinder is in the half-misfire condition, at least one of a throttle opening, a fuel injection quantity, an opened/closed timing of an intake valve or an exhaust valve, and an exhaust gas recirculating rate is corrected in such a way as to restrain a subsequent misfire. 4. The control device for the internal combustion engine according to claim 3, wherein: the misfire determining means that the inside of the cylinder is in a complete-misfire condition in a case where after the correction is made for a predetermined time, the difference component in the control parameters between the two predetermined points is below the first threshold value and also below a second threshold value, which is smaller than the first threshold value. 5. The control device for the internal combustion engine according to claim 1, wherein: one of the two predetermined points is set at a point after an intake valve opens and also before combustion starts, and the other is set at a point after the combustion starts and also before an exhaust valve opens. 6. A method for determining a misfire in an internal combustion engine that generates power by burning an air-fuel mixture in a cylinder comprising: (a) a step of detecting an in-cylinder pressure; (b) a step of calculating a control parameter based on the in-cylinder pressure detected in the step (a) and an in-cylinder volume at the time of detecting the in-cylinder pressure; and (c) a step of determining a misfire condition in the cylinder based on the control parameter calculated in the step (b), wherein: the control parameter to be calculated in the step (b) is a product of the in-cylinder pressure detected in the step (a) and a value obtained by exponentiating the in-cylinder volume at the time of detecting the in-cylinder pressure by a predetermined index number, in the step (b), the control parameters are calculated in two predetermined points; and in the step (c), it is determined that an inside of the cylinder is in a misfire condition by comparing a difference component in the control parameters between the two predetermined points with a predetermined threshold value. 7. The method for determining the misfire in the internal combustion engine according to claim 6, wherein: in the step (c), it is determined that the inside of the cylinder is in a half-misfire condition when the difference component in the control parameters between the two predetermined points is below a first threshold value. 8. The method for determining the misfire for the internal combustion engine according to claim 7, further comprising: (d) a step of correcting at least one of a throttle opening, a fuel injection quantity, an opened/closed timing of an intake valve or an exhaust valve, and an exhaust gas recirculating rate in such a way as to restrain a subsequent misfire when it is determined in the step (c) that the inside of the cylinder is in the half-misfire condition. 9. The method for determining the misfire for the internal combustion engine according to claim 8, further comprising: (e) a step of determining that the inside of the cylinder is in a complete-misfire condition in a case where after the correction in the step (d) is made for a predetermined time, the difference component in the control parameters between the two predetermined points is below the first threshold value and also below a second threshold value, which is smaller than the first threshold value. 10. The method for determining the misfire for the internal combustion engine according to claim 6, wherein: one of the two predetermined points is set at a point after an intake valve opens and also before combustion starts, and the other is set at a point after the combustion starts and also before an exhaust valve opens. 11. (canceled) 12. (canceled) 13. (canceled) 14. (canceled)

TECHNICAL FIELD The present invention relates to a control device for an internal combustion engine that generates power by burning an air-fuel mixture in a cylinder, and a method for determining a misfire in the internal combustion engine. BACKGROUND ART Conventionally, Patent Literature 1 has disclosed a firing condition-detecting device for an internal-combustion engine that overlaps in-cylinder pressure signals in respective combustion chambers detected by in-cylinder pressure detecting means to determine a misfire condition with a misfire determining index number calculated based on the overlapped in-cylinder pressure signals. As stated above, when each of the in-cylinder pressures in a plurality of the combustion chambers is overlapped, a significant change is recognized in symmetry property of a signal waveform before and after a top dead center, in accordance with presence or absence of a misfire. Therefore, the misfire determination can be made in the whole region of combustion in the internal combustion engine. In the conventional, firing condition-detecting device, however, the misfire determining index number is basically calculated by integrating an in-cylinder pressure detected by the in-cylinder pressure detecting means, per unit of a minute crank angle. Consequently, a load on calculation in the conventional firing condition-detecting device is substantial, so that it is not actually easy to apply the conventional device to an internal combustion engine for a vehicle and the like, for example. [Patent Literature 1] Japanese Patent Application Laid-open No. 11-82150 DISCLOSURE OF THE INVENTION The present invention provides a practical control device for an internal combustion engine and a method for determining a misfire in the internal combustion engine, which are capable of accurately determining a misfire condition in a cylinder at a low load. According to a control device for an internal combustion engine in the present invention, the control device for the internal-combustion engine that generates power by burning an air-fuel mixture in a cylinder comprises in-cylinder pressure detecting means, calculating means that calculates a control parameter based on an in-cylinder pressure detected by the in-cylinder pressure detecting means and an in-cylinder volume at the time of detecting the in-cylinder pressure, and misfire determining means that determines a misfire condition in the cylinder based upon the control parameter calculated by the calculating means. It is preferable that the control parameter is a product of the in-cylinder pressure detected by the in-cylinder pressure detecting means and a value obtained by exponentiating the in-cylinder volume at the time of detecting the in-cylinder pressure by a predetermined index number. It is preferable that the calculating means calculates the control parameters in two predetermined points, and the misfire determining means determines that an inside of the cylinder is in a half-misfire condition when a difference component in the control parameters between the two predetermined points is below a first threshold value. It is preferable that the misfire determining means determines that an inside of the cylinder is in a complete-misfire condition when the difference component in the control parameters between the two predetermined points is below the first threshold value and also below a second threshold value, which is smaller than the first threshold value. It is preferable that one of the two predetermined points is set at a point after an intake valve opens and also before combustion starts, and the other is set at a point after the combustion starts and also before an exhaust valve opens. According to a method for determining a misfire in an internal combustion engine in the present invention, the method for determining the misfire in the internal combustion engine that generates power by burning an air-fuel mixture in a cylinder comprises: (a) a step of detecting an in-cylinder pressure; (b) a step of calculating a control parameter based on the in-cylinder pressure detected in the step (a) and an in-cylinder volume at the time of detecting the in-cylinder pressure; and (c) a step of determining a misfire condition in the cylinder based on the control parameter calculated in the step (b). It is preferable that the control parameter is a product of the in-cylinder pressure detected in the step (a) and a value obtained by exponentiating the in-cylinder volume at the time of detecting the in-cylinder pressure by a predetermined index number. It is preferable that in the step (b), the control parameters are calculated in two predetermined points, and in the step (c), it is determined that an inside of the cylinder is in a half-misfire condition when a difference component in the control parameters between the two predetermined points is below a first threshold value. It is preferable that in the step (c), it is determined that the inside of the cylinder is in a complete-misfire condition when the difference component in the control parameters between the two predetermined points is below the first threshold value and also below a second threshold value, which is smaller than the first threshold value. It is preferable that one of the two predetermined points is set at a point after an intake valve opens and also before combustion starts, and the other is set at a point after the combustion starts and also before an exhaust valve opens. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing correlation between a control parameter PVκ used in the present invention and heat production in a combustion chamber. FIG. 2 is a schematic construction view showing an internal combustion engine in the present invention. FIG. 3 is a flow chart for explaining an operation in the internal combustion engine in the FIG. 2. BEST MODE FOR CARRYING OUT THE INVENTION The present inventors are dedicated to studying in order to enable highly accurate control for an internal combustion engine with a load on calculation being reduced. As a result, the present inventors have come to focus attention on a control parameter calculated based on an in-cylinder pressure detected by in-cylinder pressure detecting means and an in-cylinder volume at the time of detecting the in-cylinder pressure. In more detail, the present inventors, in a case where an in-cylinder pressure detected by in-cylinder pressure detecting means when a crank angle is θ dgrees is defined as P(θ), an in-cylinder volume V(@) when a crank angle is θ degrees, and a specific heat ratio is defined as κ, have focused on a control parameter obtained as a product of the in-cylinder pressure P(θ) and a value Vκ(θ) obtained by exponentiating the in-cylinder volume V(θ) with the specific heat ratio (predetermined index number) κ (hereinafter referred to as “PVκ” as needed). Moreover, the present inventors have found out that there is correlation between a change pattern for heat production Q in the cylinder in the internal combustion engine relative to the crank angle and a change pattern for the control parameter PVκ relative to the crank angle, as shown in FIG. 1. However, −360°, 0° and 360° correspond to a top dead center, and −180° and 180° correspond to a bottom dead center in FIG. 1. In FIG. 1, in a certain model cylinder a solid line shows a plot of a control parameter PVκ that is a product of an in-cylinder pressure detected for each predetermined minute crank angle and a value obtained by exponentiating an in-cylinder volume at the time of detecting the in-cylinder pressure by a specific heat ratio κ. Besides, in FIG. 1, a dashed line shows a plot of heat production Q in the model cylinder calculated as “Q=∫d Q” based on the following formula (1). In addition, “κ=1.32” is defined in any case for easiness. [ Formula ⁢ ⁢ 1 ] ⅆ Q ⅆ θ = { ⅆ P ⅆ θ · V + κ · P · ⅆ V ⅆ θ } · 1 κ - 1 ( 1 ) As shown in a result in FIG. 1, the change pattern for the heat production Q relative to the crank angle and the change pattern for the control parameter PVκ relative to the crank angle are nearly similar (identical). Especially, the change pattern for the heat production Q and the change pattern for the control parameter PVκ are extremely similar before or after combustion of an air-fuel mixture in a cylinder starts (at the time of spark ignition in a gasoline engine, and at the time of compression ignition in a diesel engine) (for instance, the range between approximately −180° and approximately 135° in FIG. 1). On the other hand, when a misfire occurs in a certain cylinder, heat production ∫d Q (a value in which d Q is integrated from θ1 to θ2, for instance, [however, θ1<θ2], hereinafter referred to as the same) from a certain timing before the combustion starts (the spark ignition or the compression ignition) to a certain timing after the combustion starts, is made smaller in the certain cylinder, as compared to a cylinder in which a misfire does not occur. In addition, the heat production ∫dQ also changes in accordance with the level of the misfire in a cylinder. Therefore, when such relationship between the heat production Q and the misfire condition in the cylinder, and correlation between the heat production Q in the cylinder and the control parameter PVκ found out by the present inventors are utilized, it is possible to accurately determine the misfire condition in the cylinder at a low load, based on the control parameter PVκ calculated based on the in-cylinder pressure detected by the in-cylinder pressure detecting means and the in-cylinder volume at the time of detecting the in-cylinder pressure. In this way, in a control device for an internal combustion engine in the present invention, based upon the above-mentioned novel findings, a misfire condition in a cylinder is determined based on a control parameter calculated based upon an in-cylinder pressure detected by in-cylinder pressure detecting means for detecting the in-cylinder pressure and an in-cylinder volume at the time of detecting the in-cylinder pressure, i.e. a control parameter (PVκ) that is a product of an in-cylinder pressure detected by the in-cylinder pressure detecting means and a value obtained by exponentiating an in-cylinder volume at the time of detecting the in-cylinder pressure by a predetermined index number. Moreover, it is preferable to determine that an inside of the cylinder is in a half-misfire condition in the case where the control parameter is calculated in two predetermined points, and a difference component in the control parameters between the two predetermined points is below a first threshold value. Further, it is preferable to determine that the inside of the cylinder is in a complete-misfire condition in the case where a difference component in the control parameters between the two predetermined points is below a first threshold value and below a second threshold value, which is smaller than the first threshold value. As stated above, the control parameter PVκ that the present inventors have focused attention on reflects heat production Q in a cylinder in the internal combustion engine. Moreover, the difference component in the control parameters PVκ between two predetermined points (for instance, two points before or after combustion starts in the cylinder) indicates heat production ∫d Q in the cylinder between the two points, and also can be calculated at an extremely low load. Furthermore, the heat production ∫d Q in the cylinder between the two points changes in accordance with the level of a misfire in the cylinder. For instance, the heat production ∫d Q is to be within a predetermined range in the case where the inside of the cylinder is in a half-misfire condition. Therefore, when the difference component in the control parameters PVκ between two predetermined points, and the first threshold value and the second threshold value are compared, a misfire condition in the cylinder can be accurately determined with a load on calculation being substantially reduced. In this case, it is preferable that one of the two predetermined points is set at a point after an intake valve opens and also before combustion starts, and the other is set at a point after the combustion starts and also before an exhaust valve opens. Hereinafter, the best mode for carrying out the present invention will be specifically described with reference to the drawings. FIG. 2 is a schematic construction view showing an internal combustion engine in the present invention. An internal combustion engine 1 as shown in FIG. 2 generates power by burning an air-fuel mixture in a combustion chamber 3 formed in a cylinder block 2 and reciprocating a piston 4 in the combustion chamber 3. The internal combustion engine 1 is preferably formed as a multi-cylinder engine. The internal combustion engine 1 in the embodiment is formed as a four-cylinder engine, for instance. An intake port in each combustion chamber 3 is respectively connected to an intake pipe 5 (an intake manifold), and an exhaust port in each combustion chamber 3 is respectively connected to an exhaust pipe 6 (an exhaust manifold). In addition, an intake valve Vi and an exhaust valve Ve are arranged in a cylinder head in the internal combustion engine 1 for each combustion chamber 3. Each of the intake valves Vi opens and closes a corresponding intake port, and each of the exhaust valves Ve opens and closes a corresponding exhaust port. Each of the intake valves Vi and each of the exhaust valves Ve, for instance, are operated by a valve operated mechanism (not shown) including a variable valve timing function. Further, the internal combustion engine 1 includes spark plugs 7 in number corresponding to the number of cylinders, and the spark plugs 7 are arranged in the cylinder head in such a way as to be exposed to the corresponding combustion chambers 3. The intake pipe 5 is connected to a surge tank 8 as shown in the FIG. 2. A charge line L1 is connected to the surge tank 8, and the charge line L1 is connected to an air inlet (not shown) through an air cleaner 9. Besides, a throttle valve 10 (an electronically controlled throttle valve in the embodiment) is installed in a mid-course of the charge line L1 (between the surge tank 8 and the air cleaner 9). On the other hand, a pre-catalytic device 11a including a three-way catalyst and a post-catalytic device 11b including a NOx occluded reduction-catalyst are connected to the exhaust pipe 6 as shown in FIG. 2. Moreover, the internal combustion engine 1 includes a plurality of injectors 12, and each of the injectors 12 is arranged in the cylinder head in such a way as to be exposed to the inside of each corresponding combustion chamber 3 as shown in FIG. 2. In addition, each of the pistons 4 in the internal combustion engine 1 is formed in a so-called bowl-top-face type, and includes a concave portion 4a thereon. Further, fuel such as gasoline is directly injected from each of the injectors 12 toward the concave portion 4a of the piston 4 in each combustion chamber 3 in a state where air is still aspired in each combustion chamber 3 in the internal combustion engine 1. Herewith, since a layer of an air-fuel mixture is formed (stratified) adjacent to the spark plug 7 in a state of being separated from the surrounding air layer in the internal combustion engine 1, a stable stratified combustion can be performed under an extremely lean mixture In addition, it should be noted that although the internal combustion engine 1 in the embodiment is described as a so-called direct injection engine, it is obvious that the present invention is not limited to the direct injection engine but also may be applied to an internal combustion engine of an intake pipe (an intake port) injection type. Each of the spark plugs 7, the throttle valve 10, each of the injectors 12, the valve operated mechanism and the like as described above are electrically connected to an ECU 20 that functions as the control device for the internal combustion engine 1. The ECU 20 includes a CPU, a ROM, a RAM, an input/output port, a storage unit and the like (not shown). Various types of sensors such as a crank angle sensor 14 for the internal combustion engine 1 are electrically connected to the ECU 20 as shown in FIG. 2. The ECU 20 controls the spark plug 7, the throttle valve 10, the injector 12, the valve operated mechanism and the like based on use of various types of maps stored in the storage unit, as well as detected values of the various types of the sensors or the like for a desired power output. Further, the internal combustion engine 1 includes in-cylinder pressure sensors 15 (in-cylinder pressure detecting means), each having a semiconductor device, a piezoelectric element or an optical fiber-detecting component and the like, in number corresponding to the number of cylinders. Each of the in-cylinder pressure sensors 15 is arranged in the cylinder head such that a pressure receiving face thereof is exposed to the inside of the corresponding combustion chamber 3, and electrically connected to the ECU 20. Each in-cylinder pressure sensor 15 detects an in-cylinder pressure in the corresponding combustion chamber 3, and sends a signal indicating the detected value to the ECU 20. Next, a procedure in the processing for determining a misfire in the internal combustion engine 1 will be explained with reference to FIG. 3. After the internal combustion engine 1 starts up, when the engine 1 is shifted from an idling condition to an idling-off condition, the ECU 20, as shown in FIG. 3, defines a target torque for the internal combustion engine 1 based on a signal or the like from an accelerator positioning sensor (not shown), as well as sets an intake air quantity (opening of the throttle valve 10) corresponding to the target torque by using a map prepared in advance or the like and a fuel injection quantity (fuel injection time) from each of the injectors 12 (step S10) Moreover, in a step S12, the ECU 20 sets the opening of the throttle valve 10 so as to be the opening obtained in the step S10 and also forces each injector 12 to inject fuel, for example, in a fuel quantity defined during an intake stroke in the step S10. Further, the ECU 20 monitors a crank angle for the internal combustion engine 1 based on a signal from the crank angle sensor 14. In addition, the ECU 20 obtains an in-cylinder pressure P(θ1) for each combustion chamber 3 at a point when a crank angle becomes θ1 degrees, based on a signal from the in-cylinder pressure sensor 15, after each of the intake valves Vi opens and also when a first timing (a timing when the crank angle becomes θ1degrees) set before ignition by each of the spark plugs 7 comes (step S14). Furthermore, the ECU 20 calculates a control parameter P(θ1)·Vκ(θ1) for each combustion chamber 3, which is a product of the obtained in-cylinder pressure P (θ1) and a value obtained by exponentiating an in-cylinder volume V(θ1) at a point when the in-cylinder pressure P (θ1) is detected, in other words, when the crank angle becomes θ1 degrees by a specific heat ratio κ (κ=1.32 in the embodiment), and stores the parameter in a predetermined storage area in the RAM (step S16). It is preferable that the first timing is set as a point after a sufficient period of time prior to a point when combustion starts in each of the combustion chambers 3 (ignition time). The first timing is, for instance, defined as a timing (θ1=−60°, in other words, 60° before a top dead center) when the crank angle indicated in the signal from the crank angle sensor 14 becomes −60°, in the embodiment. In addition, a value of Vκ(θ1) (a value of Vκ(−60°) in the embodiment) is stored in the storage unit after calculated in advance. After the processing in the step S16 is completed, the ECU 20 obtains an in-cylinder pressure P(θ2) at the time when the crank angle becomes θ2 degrees based on the signal from the in-cylinder pressure sensor 15 for each combustion chamber 3, after each spark plug 7 is ignited and also when a second timing (a timing when the crank angle becomes θ2 degrees) set before each exhaust valve Ve opens comes (step S18). Besides, the ECU 20 calculates a control parameter P(θ2)·Vκ(θ2) for each combustion chamber 3, which is a product of the obtained in-cylinder pressure P (θ2) and a value obtained by exponentiating an in-cylinder volume V(θ2) at a point when the in-cylinder pressure P (θ2) is detected, in other words, when the crank angle becomes θ2 degrees by a specific heat ratio κ (κ=1.32 in the embodiment), and stores the control parameter in a predetermined storage area in the RAM (step S20). It is preferable that the second timing is set as a point when combustion of the mixture in the combustion chamber 3 is nearly completed. The second timing is, for instance, defined as a timing (θ2=90°, in other words, 90° before a top dead center) when the crank angle indicated in the signal from the crank angle sensor 14 becomes 90°, in the embodiment. In addition, a value of Vκ(θ2) (a value of Vκ(90°) in the embodiment) is stored in the storage unit after calculated in advance. When the control parameters P(θ1)·Vκ(θ1) and P(θ2)·Vκ(θ2) are obtained as stated above, the ECU 20 calculates a difference component of the control parameters PVκ between the first timing and the second timing for each combustion chamber 3 as the following: ΔPVκ=P(θ2)·Vκ(θ2)−P(θ1)·Vκ(θ1) and stores the difference component in the predetermined storage area in the RAM (step S22). The difference component ΔPVκ shows heat production ∫d Q generated in each combustion chamber 3 for a period of time between the second timing and the first timing (between the two predetermined points) as stated above, i.e. an amount of heat generated in the combustion chamber 3 during the period of time from the first timing to the second timing. As described above, the difference component ΔPVκ of the control parameters PVκ that appropriately reflects the heat production between the first timing and the second timing is simply and promptly calculated for each combustion chamber 3 through the processing from the step S14 to the step S22. Herewith, a load on calculation in the ECU 20 can be substantially reduced, as compared to a case where a misfire condition in each combustion chamber 3 is determined by integrating an in-cylinder pressure per unit of a minute crank angle. At this point, the difference component ΔPVκ showing heat production ∫d Q in any of the combustion chambers 3 between the second timing and the first timing (between the two predetermined points) changes in accordance with the level of a misfire in the combustion chamber 3. For instance, the difference component ΔPVκ becomes below a predetermined value in a case where the combustion chamber 3 is in a half-misfire condition. Moreover, the difference component ΔPVκ becomes below a predetermined value (zero, theoretically) in a case where the combustion chamber 3 is in a complete-misfire condition. Therefore, when the difference component ΔPVκ is obtained in the step S22, the ECU 20 determines whether or not the difference component ΔPVκ is below a first threshold value a defined in advance, for each combustion chamber 3 (step S24). When it is determined that in step S24, the difference component ΔPVκ in all of the combustion chambers 3 is not below the first threshold value a, the ECU 20 assumes that a misfire does not occur in any of the combustion chambers 3, and the process returns to the step S10 and a series of the processing is repeated subsequently. On the other hand, when it is determined in step S24 that the difference component ΔPVκ in at least any of the combustion chambers 3 is below the first threshold value a, the ECU 20 assumes that the inside of the combustion chamber is in a half-misfire condition and increments a counter (not shown) corresponding to the combustion chamber by one (step S26). Besides, the ECU 20 determines whether or not a counter value in the counter is beyond a threshold value defined in advance (step S28). When it is determined in step S28 that the counter value in the counter is not beyond a threshold value defined in advance, the ECU 20 corrects, by using a certain map or the like, at least one of an opening of the throttle valve 10, a quantity of fuel injection from the injector 12, an opened/closed timing for an intake valve Vi and/or an exhaust valve Ve, or also an exhaust gas recirculating rate for an internal combustion engine equipped with an exhaust gas recirculating system, in accordance with the difference component ΔPVκ obtained in the step S22 (step S30). In other words, even if the difference component ΔPVκ of the control parameters PVκ between the first timing and second timing is below the first threshold value a in the internal combustion engine 1, when the frequency of the event that the difference component ΔPVκ is below the first threshold value a is low, the misfire that has occurred in the combustion chamber 3 is assumed as temporal. In addition, in such a case, the opening of the throttle valve, the quantity of fuel injection, the opened/closed timing for the valve and the like are corrected as needed (step S30). Herewith, occurrence of a subsequent misfire in the combustion chamber 3 is to be restrained. Moreover, when it is determined in the step S28 that a count value in the counter is beyond a predetermined threshold value, i.e. the frequency of the event that the misfire in the combustion chamber 3 has occurred is beyond a predetermined threshold value, the ECU 20 resets the counter (step S32) and also determines whether or not the difference component ΔPVκ obtained in the step S22 is below a second threshold value B (B<a, in this regard) (step S34). Further, when it is determined in the step S34 that the difference component ΔPVκ is below the second threshold β, the ECU 20 assumes that the inside of the combustion chamber 3 is in a complete-misfire condition due to an ignition failure of the spark plug 7 or the like, and shows a predetermined warning display (step S36). When it is determined in step S34 that the difference component ΔPVκ is not below the second threshold value β, the ECU 20 corrects, by using a certain map or the like, at least one of an opening of the throttle valve 10, a quantity of fuel injection from the injector 12, an opened/closed timing for an intake valve Vi and/or an exhaust valve Ve, or also an exhaust gas recirculating rate for an internal combustion engine equipped with an exhaust gas recirculating system, in accordance with the difference component ΔPVκ obtained in the step S22 (step S30). That is, even if the frequency of occurrence of the misfire is beyond the above threshold value, when the difference component ΔPVκ is not below the second threshold value β, the opening of the throttle valve, the quantity of fuel injection, the opened/closed timing for the valve and the like are corrected as needed (step S30). Herewith, occurrence of a subsequent misfire in the combustion chamber 3 is to be restrained. In addition, after the processing of the step S30 or the step S36, the ECU 20 returns to the step S10 and repeats a series of subsequent processing. In this way, in an internal combustion engine 1, a misfire condition in the combustion chamber 3 is accurately determined at a low load based on a control parameter calculated based upon an in-cylinder pressure P(θ) detected by an in-cylinder pressure sensor 15 and an in-cylinder volume V(θ) at the time of detecting the in-cylinder pressure P(θ), i.e. a control parameter (PVκ) that is a product of an in-cylinder pressure P(θ) detected by the in-cylinder pressure sensor 15 and a value obtained by exponentiating an in-cylinder volume V(θ) at the time of detecting the in-cylinder pressure P(θ) by a predetermined index number κ. In addition, in the internal combustion engine 1, when it is determined that the inside of the combustion chamber 3 is in a misfire condition (half-misfire condition), at least any of an opening of the throttle valve, a quantity of fuel injection, a valve opened/closed timing, an exhaust gas recirculating rate and the like is corrected for elimination of the misfire. Herewith, according to the internal-combustion engine 1, a desired power output thereof can be constantly produced while properly maintaining a rotational speed. In addition, it should be noted that although the internal combustion engine 1 is described as a gasoline engine, it is apparent that the present invention is not limited to the gasoline engine but also may be applied to a diesel engine. Especially, the present invention is effective for determining a misfire in a rich mixture when a diesel engine operates in the rich mixture, or for determining a misfire when a so-called rich limit operation is performed in various types of internal combustion engines. INDUSTRIAL APPLICABILITY The present invention is useful for realizing a practical control device for an internal combustion engine and a method for determining a misfire in an internal combustion engine, which are capable of accurately determining a misfire condition in a cylinder at a low load.

<SOH> BACKGROUND ART <EOH>Conventionally, Patent Literature 1 has disclosed a firing condition-detecting device for an internal-combustion engine that overlaps in-cylinder pressure signals in respective combustion chambers detected by in-cylinder pressure detecting means to determine a misfire condition with a misfire determining index number calculated based on the overlapped in-cylinder pressure signals. As stated above, when each of the in-cylinder pressures in a plurality of the combustion chambers is overlapped, a significant change is recognized in symmetry property of a signal waveform before and after a top dead center, in accordance with presence or absence of a misfire. Therefore, the misfire determination can be made in the whole region of combustion in the internal combustion engine. In the conventional, firing condition-detecting device, however, the misfire determining index number is basically calculated by integrating an in-cylinder pressure detected by the in-cylinder pressure detecting means, per unit of a minute crank angle. Consequently, a load on calculation in the conventional firing condition-detecting device is substantial, so that it is not actually easy to apply the conventional device to an internal combustion engine for a vehicle and the like, for example. [Patent Literature 1] Japanese Patent Application Laid-open No. 11-82150

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a graph showing correlation between a control parameter PV κ used in the present invention and heat production in a combustion chamber. FIG. 2 is a schematic construction view showing an internal combustion engine in the present invention. FIG. 3 is a flow chart for explaining an operation in the internal combustion engine in the FIG. 2 . detailed-description description="Detailed Description" end="lead"?

20060324

20070501

20060928

63491.0

G01M1508

HUYNH, HAI H

CONTROL DEVICE FOR INTERNAL COMBUSTION ENGINE AND METHOD FOR DETERMINING MISFIRE IN INTERNAL COMBUSTION ENGINE

UNDISCOUNTED

ACCEPTED

G01M

ACCEPTED

Weapon grip assembly

A weapon grip assembly (16) for attachment to a forward portion of a weapon is provided. The invention includes a base assembly (20) supported for operative engagement by a handle (22). The base assembly includes clamps (24) adapted to be secured to a forward portion of the weapon and further includes a post (38) having a clamp end adapted to retain the clamps (24) for pivot motion with respect thereto. The post (38) of the base assembly (20) is received within a bore of the handle, a mandrel (32) being interposed between the handle (22) and the clamps (24) of the base assembly (20). As the base assembly (20) is drawn into the handle (22), by rotation of the handle (22) about the post (38) of the base assembly (20), the mandrel (32) receives the clamp end of the post (38), with an upper free surface thereof engaging the clamps for pivoted closure about a portion of the weapon in furtherance of securing the weapon grip assembly (16) thereto.

1-28. (canceled) 29. A weapon grip assembly comprising a clamp base and clamps supported upon said clamp base for pivot motion with respect thereto in furtherance of grasping the forward portion of the weapon, said clamp base comprising a post having a clamp end adapted to retain said clamps at said clamp end of said post for individual pivot motion with respect thereto, each of said clamps being adapted to engage a lateral edge of a rail of a forward portion of a weapon, said post of said clamp base being receivable in an axial bore of a handle and adapted to be reversibly drawn into said axial bore, said assembly further comprising a mandrel interposed between said handle and said clamps. 30. The weapon grip assembly of claim 29 wherein a portion of said mandrel is configured to receive said clamp end of said clamp base. 31. The weapon grip assembly of claim 29 wherein said mandrel is axially translatable upon said post of said clamp base. 32. The weapon grip assembly of claim 30 wherein said mandrel operatively engages said clamp end of said post so as to limit axial translation of said mandrel upon said post. 33. The weapon grip assembly of claim 31 wherein said mandrel has a portion of an upper surface thereof adapted to operatively engage said clamps. 34. The weapon grip assembly of claim 33 wherein rotation of said handle relative to said clamp base causes pivot closure of said clamps via engagement of said upper portion of an upper surface thereof with said clamps. 35-38. (canceled) 39. A weapon grip assembly for facilitating grasping and support of a forward portion of a weapon, said weapon grip assembly comprising a base assembly supported by a handle, and a collar operatively interposed between said base assembly and said handle, said base assembly comprising a post having a clamp end adapted to mechanically and independently retain opposingly paired clamps for selective attachment to a forward portion of the weapon. 40. The weapon grip assembly of claim 39 wherein each of said clamps is separately pivotable with respect to said clamp end of said post. 41. The weapon grip assembly of claim 39 wherein said clamps are retained at said clamp end of said post for individual pivot motion with respect thereto. 42. The weapon grip assembly of claim 41 wherein said post is receivable in a cavity of said handle. 43. The weapon grip assembly of claim 42 wherein said post is adapted to be reversibly drawn into said cavity of said handle. 44. The weapon grip assembly of claim 43 wherein said post includes a threaded segment adjacent said clamp end. 45. The weapon grip assembly of claim 44 wherein said threaded segment of said post is reversibly advanceable within said cavity of said handle upon rotation of said handle with respect to said base assembly. 46. The weapon grip assembly of claim 45 wherein said handle includes a capped end. 47. The weapon grip assembly of claim 39 wherein each of said clamps is independently biased with respect to said clamp end of said post. 48. The weapon grip assembly of claim 47 wherein said post is reversibly received within a recess of said handle. 49. The weapon grip assembly of claim 48 wherein said clamps pivotingly respond to axial positioning of said collar relative to the post of said base assembly. 50. The weapon grip assembly of claim 49 wherein said collar surrounds a segment of said post. 51. The weapon grip assembly of claim 49 wherein said clamp end of said post is surrounded by a sidewall of said collar. 52. The weapon grip assembly of claim 49 wherein said clamp end of said post is received with a sidewall of said collar 53. The weapon grip assembly of claim 39 further comprising a latching assembly for selectively affixing said collar to said handle. 54. The weapon grip assembly of claim 52 wherein said latching assembly selectively locks said clamps in a preselect state of closure. 55. The weapon grip assembly of claim 39 wherein said collar includes a latching assembly for cooperative locking engagement of said collar with a portion of said handle. 56. The weapon grip assembly of claim 39 wherein a seal is formed between a portion of said collar and said clamp end of said post. 57. The weapon grip assembly of claim 56 wherein a resilient element is interposed between a base of said collar and said clamp end of said post so as to form said seal. 58. The weapon grip assembly of claim 39 wherein said collar is adapted to permit debris egress. 59. The weapon grip assembly of claim 39 wherein said base assembly further comprise an alignment mechanism configured for operative engagement with said collar. 60. The weapon grip assembly of claim 39 wherein said collar is adapted to operatively supporting an auxiliary device. 61. The weapon grip assembly of claim 60 wherein said collar is adapted to operatively support a target illumination device. 62. The weapon grip assembly of claim 39 wherein said collar is equipped with a bracket for supporting an auxiliary device. 63. The weapon grip assembly of claim 39 wherein said collar includes an upper surface configured to engage portions of the forward portion of the weapon adjacent an interface between said clamps and the forward portion of the weapon. 64. The weapon grip assembly of claim 62 wherein said a portion of said handle is adapted for locking integration with a portion of said collar. 65. A weapon grip assembly for facilitating grasping and support of a forward portion of a weapon, said weapon grip assembly comprising a base assembly supported by a handle, said base assembly comprising clamps adapted to be secured to a forward portion of the weapon, each of said clamps being separately pivotable with respect to said base. 66. The weapon grip assembly of claim 65 wherein each of said clamps are cooperatively united at an end thereof to a portion of said base via a pin. 67. A weapon grip assembly for facilitating grasping and support of a forward portion of a weapon, said weapon grip assembly comprising a base assembly supported by a handle, said base assembly comprising jaws adapted to be secured to a forward portion of the weapon, each of said jaws being independently biased with respect to said base. 68. The weapon grip assembly of claim 67 wherein each of said jaws are cooperatively united at an end thereof to a portion of said base via a pin. 69. The weapon grip assembly of claim 68 wherein said jaws are independently biased with respect to said base via compressible elements. 70. The weapon grip assembly of claim 69 wherein said compressible elements comprise compression springs. 71. The weapon grip assembly of claim 67 wherein each of said jaws is curved throughout a length thereof. 72. The weapon grip assembly of claim 67 wherein each of said jaws includes a profiled surface. 73. The weapon grip assembly of claim 67 wherein each of said jaws includes a notched surface. 74. The weapon grip assembly of claim 67 wherein each of said jaws includes an upper portion defining a lip.

This is a regular application filed under 35 U.S.C. §111(a) claiming priority under 35 U.S.C. §363, of international application Serial No. PCT/US03/35601, having an international filing date of Nov. 6, 2003, and further claiming priority under 35 U.S.C. §119(e) (1), of provisional application Ser. No. 60/492,509, having a filing date of Aug. 5, 2003. TECHNICAL FIELD The present invention generally relates to a weapon grip assembly, more particularly, to a weapon grip assembly for forwardly supporting a weapon or weapon system. BACKGROUND OF THE INVENTION Weapons having barrels for discharging munitions are primarily adapted to be griped in the vicinity of the trigger, more particularly via a “pistol grip.” A wide variety of styles and configurations are know for pistol grips, key considerations being functionality, ergonomics, and aesthetics. For “long” barreled weapons, rifles for instance, forward support of same is accomplished via hand placement upon the forend, e.g., a barrel handguard or the like (i.e., a lower portion of the forward portion of the weapon). With the advent and advancement of weapon systems, for instance tactical weapons, the functionality of the “weapon” has become quite diverse, a challenge being to maintain an ease of use of the variety of features thereof, and avoidance of a cumbersome, inflexible and heavy weapon system. Many members of the armed services and law enforcement officers, are issued, and carry a tactical weapon system which includes a “host weapon” (e.g., a rifle) which is equipped with, or may be equipped with, a variety of “supplemental devices,” for instance a 40 mm grenade launcher. Such host weapons, sometimes referred to as modular weapon systems, are further configurable or adaptable to receive a variety of rails, interbars, or rail systems, upper/lower receiver and/or handguard components, buttstocks, or other accessories (e.g., sites, illumination devices, sling attachments or anchors, etc.). Traditionally, weapon system accessories have been manufacturer specific, each manufacturer of modular weapon systems providing items for integration with their rail, rail system etc. Although forward pistol grips are known and commercially available for integration with a forend assembly of a weapon, more particularly a rail or rail system, the variety of forend configurations available for a weapon have precluded a more versatile, “one size fits all” solution for forwardly supporting a weapon system in its variety of configurations. For instance, in a weapon system comprising a host weapon (e.g., rifle) and a supplemental device (e.g., grenade launcher), the launcher mounts to the rifle in a position which places the launcher in the front half of the rifle, and below the rifle barrel. This location has been the standard of armed forces worldwide since the introduction of the rifle mounted grenade launcher about 40 years ago. While the above described attachment method of the launcher to the host rifle may be the most practical solution for the integration of these separate devices, it does not provide the user with the best solution for carrying or operating the rifle or the launcher when the two devices are combined. Carrying or operating the rifle/launcher combined weapon system requires that one of the operator's hands be placed on the pistol grip of the rifle, near the rifle trigger, while the other hand is placed near the forward end of the weapon system, beneath the grenade launcher, to support the system in a position chosen by the operator for carrying and/or operation of either device. The right hand, typically used to support the rear end of the rifle at the pistol grip, and to operate the rifle trigger, is partially wrapped around the pistol grip which allows the operator to close their fingers around same, and use their index finger to fire the rifle. The left hand, typically used to support the forward end of the rifle (i.e., the end away from the user) is placed below the grenade launcher, in a palm-up cup or cradle position, with the fingers and thumb wrapped partially around the launcher handguard to both support the weight of the rifle/launcher combination and control its orientation in all axes. The palm-up position required of the operator's left hand is necessary because of the ribbed handguard of the 40 mm launcher barrel cannot be gripped by the operator's hand in any other way. Because the barrel is located below the launcher receiver, the handguard does not and cannot fully encircle the barrel, making it thereby impossible for the operator to wrap their hand around the barrel to establish a strong grasp on the barrel. This results in weak control of the weapon system and increased operator fatigue due to the necessitated hand position and orientation with respect to the weapon system, more particularly, the launcher thereof. The diameter along the launcher handguard is over 2.25 inches, which is more than 50% larger than the optimal grip diameter for an operator with average sized hands to grip an object by wrapping their fingers around it, and having at least one finger wrap back to their thumb. The launcher barrel handguard is not sized to provide the best gripping surface, it is sized to accommodate the 40 mm barrel within it. With the knowledge that this rifle/launcher combination is now front-heavy because of the shift in the rifle's center of gravity with the addition of the launcher, and that the handguard's diameter and orientation are controlled by the functional characteristics of the launcher, both a user and non-user understands why this weapon system combination, while highly desirable for its capabilities, is hard to control and is fatiguing to carry and operate, primarily because of the hand position and orientation required. The only solution to relieving the fatigue and adding additional control over the system for the operator is to change the way in which the operator holds the launcher. There are many obstacles to developing a better way to grip the launcher. To provide maximum comfort, leverage and efficiency to the operator, the area in which the launcher is handled should not be changed, only the operator's hand position. The only way to change the hand position as required to grip the launcher is to add a gripping device. Adding any component, assembly or device to a 40 mm grenade launcher barrel presents a variety of challenges, some of which are discussed herein below. First, the M203 40 mm barrel handguard is made of a thin plastic material which is designed primarily to serve as a location for the operator to place their hand. As there is very little heat produced when firing through an M203 barrel, the handguard is not specifically required to perform an insulating function. Second, the M203 40 mm handguard surface is interrupted by two cartridge retainer rivets and a handguard locator rivet. Such structures may interfere with attachment solutions, and therefore require consideration. Third, the M203 40 mm barrel is a thin wall design which precludes using fasteners which only partially penetrate the barrel wall. As a matter of fact, the barrel handguard is adhesively adhered to the barrel because the barrel walls prohibit the use of fasteners. Furthermore, weapon barrels are generally not pierced by fasteners because of their prime function to contain exploding gases. Any solution requiring a fastener which breaches the barrel wall is not possible. Further still, the thin wall of the barrel prevents any attachment solution which could distort the barrel by applying pressure unevenly, such a barrel being incapable of proper performance. Fourth, the barrel assembly of the M203 is designed for removal from the receiver without tools. This allows for easy cleaning by the operator as the barrel is the component most dirtied by firing. Being able to clean the barrel as a separate component keeps the rest of the receiver, and the rifle to which it is attached, uncontaminated by the cleaning process. Any grip attachment solution which prevents or inhibits this barrel removal process is undesirable. Furthermore, cleaning the barrel can be a messy affair using solvents to remove barrel reside and then repeatedly rinsing the barrel to remove the solvent residue. The barrel and handguard get contaminated on the outside during the process and must also be cleaned. A dry handguard is essential for the operator to maintain a grip. Any grip attachment solution that remains on the barrel during the cleaning process becomes another area to clean and is therefore undesirable. Fifth, the barrel is also removable from the receiver to allow an armorer to perform repairs. Without removal it would be impossible to re-stake or change the barrel extension, repair or replace the cartridge locator or the cartridge locator spring. To perform these repairs the barrel is placed in a vise or other holder which positions and supports the barrel assembly along the sides and on the bottom during repairs. Any grip attachment solution that remains in place in any of these areas would inhibit maintenance activities and is likewise undesirable. Finally, the handguard can be removed from the barrel for the repair of the cartridge retaining springs or for replacement of the handguard itself. Any grip attachment solution which is permanently affixed to the handguard would either inhibit or make this activity or exchange impossible. Thus, it is highly desirable and advantageous to provide a weapon grip assembly for supporting a forend of a weapon or weapon system, more particularly a versatile weapon grip assembly for select integration with a 40 mm grenade launcher which: is commercially available “off-the-shelf” and requires no developmental effort; can be fitted to any M203 launcher now in service, with no modifications of same required; is small, lightweight and rugged; is not permanently mounted onto the launcher barrel assembly; can be quickly attached and detached from the launcher handguard by the operator without tools; conforms tightly to barrel surfaces; does not pierce the barrel or handguard; can be adjustably positioned on the launcher to suit operator size preferences and comfort; can aid and/or improve the firing accuracy of the weapon system (e.g., rifle and launcher) by allowing the operator to have improved control on the weapons because of a better grip; does not hamper or prolong maintenance activities of the launcher or rifle; does not implicate nor involve additional launcher or rifle operational considerations or limitations; requires no additional operator training for use thereof; improves operator weapon control, and thus, its safety; reduces operator fatigue by improving the method by which the launcher and rifle are operated and carried; allows the operator to easily focus all energy into motions associated with opening/closing the launcher barrel by reducing the effort required to grip the barrel while in motion; enhances the loading and re-loading operations of the M203, making them faster and more controllable, thereby allowing faster aimpoint acquisition by the operator for firing the next round; provides improved firing speed and accuracy which makes the operator safer and more effective; allows the operator to easily maintain or re-establish a firm grip on the launcher and rifle in humid, wet or snowy conditions or in the presence of any other contaminants which now make these actions difficult with the current hand position required to grip the launcher handguard; and, allows the operator to easily maintain or re-establish a firm grip on the launcher and rifle while using the weapons while walking, running or after a fall or other unexpected activity. This improvement in control makes the operator more effective and safer to others around them. With weapon adaptability being an important consideration or factor for a weapon user, a “Rail Adaptor System” (RAS) has become a popular accessory for/on combat rifles and the like. There exists many versions of such systems, made by many manufacturers, see for example those produced by Knight's Armament Co. Typically, a RAS is installed in place of the weapon hand guard (i.e., substituted therefore), and is intended to provide a universal structure (i.e., a rail) for mating attachment (i.e., receipt) of accessories, e.g., a flashlight, a thermal scope, a laser, etc., to the rifle at 3, 6, 9, and 12-O'clock positions about the weapon barrel. Known systems incorporate different rail lengths and integration techniques for attachment to the weapon. Some RAS consist of a two-piece assembly, namely, a first portion providing rails at the 3, 9, and 12-O'clock positions, a second portion providing a rail at/for the 6-O'clock position. It is advantageous that the rail of the 6-O'clock position be separately removable so as to permit grenade launcher installation (i.e., in lieu thereof, as each structure competes for the same physical space, and generally uses the same attachment points on the weapon). The RAS system was originally proposed by the United States Army in 1998 so as to provide to all vendors a common style of attachment point to the M-16 rifle. While specifying the beveled lateral edge of the rail (i.e., its profile), the circumferential clock positions for the rails about the weapon barrel, and the call outs of the spacing between the crossbars of the rail and their marking (e.g., B22, B28, etc. for “bottom,” with “T” designated for “top”), implementation of the solution (i.e., weapon integration strategies) was left to those in the marketplace. In addition to the aforementioned accessories (i.e., flashlights, scopes, aiming aids, etc.), rail mount grips (e.g., vertical forend grips), are available for affixation to the rail, with heretofore know rail mount grips characterized by a female mounting flange which is slidingly received upon a rail of the RAS, and is thereafter selectively bound against a portion of the rail via, for example, a threaded fastener which is tightened to engage or press against the rail so as to secure the grip thereto. In a rail mount grip offered by Knight's Armament Co., a binding stud is threadingly received within an axial bore of a hand grip having a rail receiving flange. The binding stud includes a base or cap end which defines a lower-most extremity for the device, and a free end opposite thereof having a nub (e.g., a centrally located projection) on a top surface thereof. Upon sliding the grip, via the flange, longitudinally along and upon the rail, the binding stud is upwardly extended, relative to the grip, such that the nub on the top surface of the free end thereof locates one of the many slots or spaced apart channels in the rail (i.e., the knob is dimensioned to be received within any one of said slots or spaced apart channels). Thereafter, the binding stud is further tightened into pressing engagement with a portion of the rail. The subject design has proved problematic, with the nub being susceptible to breakage and or deformation, and requiring further operator attention to appropriately position the grip upon the rail such that the nub will in fact fall into one of the many locating slots. Since the slot and the raised portions between the slots of the rail are the same width, the operator has a 50-50 chance of getting it right the first time. Miss the location, and the grip will not tighten up. A further drawback of presently known rail mount grips is the requirement that they be slid on, more particularly, they be slid onto the rail of the RAS from the weapon front (i.e., the muzzle end) toward the weapon back (i.e. the butt stock end). Known grips cannot be slid onto the rear end of the rail because there is not enough clearance between the rail end and rifle receiver to allow access for alignment of the flange with the rail. This is a critical consideration should any other accessory be mounted on the rail forward of the grip. Should a user wish to remove the grip from the weapon, or move it to a different rail to improve handling, a lot of busy time is had configuring or reconfiguring the weapon. Thus, it remains advantageous to provide a weapon grip which is versatilely mountable to the rail of a RAS, further still, to provide a rail mount grip which has an easily operable secure fastening or affixation mechanism, namely one which abandons heretofore known sliding engagements and/or binding studs. Further desirable and advantageous is a forend grip for a weapon or weapon system which is versatile in its securement methodology. For instance, and as alluded to herein, a weapon grip having an adaptability or convertibility for receipt by a variety of known weapon or weapon system structures is particularly desirable, more particularly, a weapon grip characterized by grasping jaws. For instance, a weapon grip having replaceable or substitutable jaws for grasping a grenade launcher barrel on the one hand, or a rail of a RAS on the other hand is especially advantageous. More specific features and advantages obtained in view of those features will become apparent with reference to the drawing figures and DETAILED DESCRIPTION OF THE INVENTION. SUMMARY OF THE INVENTION A preferred weapon grip assembly of the subject invention attaches to a forward portion of a weapon, for instance, to a handguard, by at least partially encircling same (i.e., clasping a portion thereof) with two clamps (i.e., jaws) of a base assembly which is supported for operative engagement by a handle. The base assembly further includes a post (e.g., a threaded stud) having a clamp end adapted to retain each of the clamps for pivot motion with respect thereto. The post of the base assembly is received within a bore of the handle, a mandrel being interposed between the handle and the clamps of the base assembly. As the base assembly is drawn into the handle, by rotation of the handle about the post of the base assembly, the mandrel receives or seats the clamp end of the post, with an upper free surface thereof engaging the clamps for pivoted closure about a portion of the weapon in furtherance of securing the weapon grip assembly thereto. The handle of the weapon grip assembly advantageously includes a stowage space accessible at a free end thereof. A cap is further provided for sealing the stowage space. The preferred weapon grip assembly further includes a latching mechanism for reversibly securing the mandrel to the handle such that the mandrel and the handle ride upwardly upon the post of the base assembly to actuate the clamps and “lock” them in position about the weapon. Preferably, but not necessarily, the weapon grip assembly further includes an alignment and retention mechanism for positioning and holding (i.e., orientingly uniting) the mandrel upon the base assembly, more particularly, the clamp end thereof. The subject weapon grip advantageously may be supplied with alternate clamping elements so as to be alternately equipped, that is to say, the weapon grip may be quickly and easily converted for grasping a grenade launcher barrel, or a rail of a RAS. In the former case, each of the jaws are curved throughout their length to grasp a launcher barrel, each of the jaws further having a surface (i.e., a barrel engaging surface) for receiving a rib of a barrel handguard. In the latter case, each of the jaws include a profiled surface, more particularly a rail receiving surface for engaging a lateral edge of a rail of a RAS. The clamps are configured such that upon being pivotally draw towards one another, a rail receiving channel is formed within which a rail of the RAS is captured or capturable. BRIEF DESCRIPTION OF THE DRAWINGS Referring now to the drawings wherein like numerals are used to designate like parts of the invention throughout the figures: FIG. 1 illustrates the weapon grip assembly of the subject invention, in combination with a representative, non-limiting weapon, namely, an assault weapon; FIG. 2 is a perspective “forward” view of a preferred embodiment of the weapon grip assembly of the subject invention; FIG. 3 is a perspective “rear” view of the weapon grip assembly of FIG. 2; FIG. 4 is an exploded view of the weapon grip assembly of FIG. 2; FIG. 5 is a “front” elevational cross section of the weapon grip assembly of FIG. 2, illustrating the clamps thereof in a readied condition for receipt of a forward portion of a weapon, more particularly an M203 style grenade launcher; FIG. 6 is a view as FIG. 5, the clamps of the subject invention shown pivoted from their static FIG. 5 position, and in secure engagement with the handguard of the grenade launcher; FIG. 7 is a section taken along lines 7-7 of FIG. 6 illustrating a locking mechanism for the handle, in addition to an alignment and retention mechanism for the mandrel; FIG. 8 is a section taken along lines 8-8 in FIG. 7 further illustrating the locking mechanism for the handle; FIG. 9 is a section taken along lines 9-9 in FIG. 6 illustrating the interface of a clamp of the subject invention with the weapon handguard; FIG. 10 is a section taken along lines 10-10 of FIG. 5 illustrating items housed within a stowage compartment of the handle; FIG. 11 is a perspective rear view of the weapon grip assembly of the subject invention, in combination with a grenade launcher, and equipped with an accessory, namely a flashlight assembly; FIG. 12 illustrates the accessory of FIG. 11 in exploded view; FIG. 13 is an exploded view, as FIG. 3, of an alternate embodiment of the subject invention; and, FIG. 14 is an exploded view, as FIG. 3, of a further embodiment of the subject invention illustrating, among other things, an alternate handle latching mechanism; FIG. 15 illustrates a further embodiment of the subject invention, more particularly, a sectional view of an alternate clamp or jaw configuration in readiness for integration with a rail of a rail adaptor system; and, FIG. 16 is an exploded partial view, similar to that FIG. 4, illustrating the alternate jaws of the embodiment of FIG. 15 relative to the clamp end of the post. DETAILED DESCRIPTION OF THE INVENTION As a preliminary matter, the structures and features of the weapon grip or grip assembly of the subject invention, shown in FIG. 1 attached to a weapon system, are generally illustrated in the views of FIGS. 2-12. The functionality of the subject weapon grip assembly is best appreciated with reference to FIGS. 5-9, wherein there is specifically shown a variety of relationships between select structures and/or subassemblies of the subject invention and the weapon system, and among said select structures and/or subassemblies. Finally, further alternate, non-limiting embodiments of the subject weapon grip assembly are shown in FIGS. 13-16, more particularly, an embodiment emphasizing an alternate interface between the base assembly and the handle (FIG. 13); a further embodiment emphasizing an alternate handle latching mechanism (FIG. 14); and, still further, an embodiment emphasizing an alternate clamp or jaw configuration (FIGS. 15 & 16). With reference to FIG. 1, there is generally illustrated a preferred embodiment of the weapon grip assembly 16 of the subject invention in operative engagement with a representative weapon, namely an assault weapon 18 (i.e., a weapon system). Generally, the weapon grip assembly 16 of the subject invention includes a base assembly 20 extending from, or supported by, a handle 22. The base assembly 20 includes clamps or jaws 24 adapted to be secured to a forward portion of the weapon 18 (e.g., a handguard of the forward portion thereof), more particularly, each of the clamps 24 preferably includes a weapon receiving surface 26. Operatively, the grasping function of the clamps 24 of the base assembly 20 is implicated via manipulation of the handle 22 relative thereto, more particularly, the interplay between structures of the handle 22 and base assembly 20 permit the clamps 24 to be reversibly secured to the forward portion of the weapon 18, as will be later discussed in greater detail, particularly with respect to FIGS. 5-9. The weapon grip assembly 16 of FIG. 1 is representatively shown operatively depending from a grenade launcher 28, e.g., a M203 style 40 mm launcher. The weapon grip assembly 16 is selectively positionable for attachment to a ribbed barrel handguard 30 of the launcher 28 so as to depend therefrom. It should be understood and readily appreciated, especially in light of the subject disclosure, that the subject weapon grip assembly is not intended to be limited to attachment to a grenade launcher. It is emphatically noted that the clamps of the subject weapon grip assembly are generally intended to clasp a forward portion of the weapon or weapon system, the clasping function of the base assembly being particularly advantageous in the context of the subject weapon grip assembly. Advantageously, the subject weapon grip assembly is designed for affixation to a forward portion of a weapon, such as a handguard, for forwardly supporting same. It is especially desirable to provide a weapon grip assembly which, with little or no modification, can facilitate forward support a weapon such as a rifle, as well as such weapon equipped with a supplemental device (e.g., grenade launcher), as are widely used by law enforcement and military personnel. With general reference now to FIGS. 2 & 3, and particularly reference to FIG. 4, the preferred embodiment of the weapon grip assembly 16 of the subject invention generally includes a base assembly 20 extending from, or being generally supported by a handle 22, and a mandrel or collar 32 interposed between a portion of the base assembly 20 and the handle 22. Preferably, but not necessarily (note the devices of FIGS. 13 & 14), the weapon grip assembly 16 further includes an alignment and retention mechanism 34 (i.e., a retainer), for positioning and holding (i.e., orientingly uniting) the mandrel 32 upon the base assembly 20, and still further, preferably, but not necessarily, includes a latching mechanism 36 for reversibly securing the handle 22 to mandrel 32, thereby fixing subject spatial relationship(s) between the handle 22 and the base assembly 20 as will be later discussed. The base assembly 20 of the weapon grip assembly 16 includes clamps or jaws 24 adapted to be secured to the forward portion of the weapon, and a post 38 having a clamp end 40 adapted to retain the clamps 24 (FIG. 4). The clamps 24 are retained or anchored to the clamp end 40 of the post 38 for pivot motion with respect thereto, and are further preferably individually biased so as to readily accept the forward portion of the weapon system (i.e., the weapon grip assembly is intended to have a readied condition for affixation to the weapon, namely a pre-application/pre-affixation status or “static” condition). The base assembly components, namely the clamps 24 and post 38, are preferably fabricated from aluminum, and are hard-coat anodized in black. Each of the clamps 24 of the base assembly 20 generally has a weapon receiving surface 26 opposite an exterior or outer surface 42, and opposing ends, namely a free end 44 opposite a base end 46. As is best seen in FIG. 4, the base end 46 of each of the clamps 24 is preferably adapted for pivot motion (e.g., hinged engagement) upon the clamp end 40 of the post 38 (i.e., the distance between the free ends 44 of the clamps 24 is not fixed, that is to say, there exists a range of travel between the free ends 44 of the clamps 24). The base end 46 of each of the clamps 24 preferably has a lobe-like configuration, i.e., a surplusage of material on the exterior surface of the clamp: the base end 46 has a local exterior surface which extends or protrudes beyond a Gontour of an outer radius of the clamp 24, (more particularly, a contour or profile associated with the exterior surface 42 thereof), see FIGS. 4 and 5/6. Each lobe 48 (i.e., locally thick segment or terminus) of the base end 46 of the clamp 24 includes a thru hole 50 for receipt of a pin 52 which traverses opposing upstanding wall segments 54 of the clamp end 40 of the post 38 via a set of paired and aligned thru holes 53, thereby securing the clamp 24 to the post 38. The pins 52, and pin holes 50, 53, are of a specific design so as to allow the pins 52 to be inserted from one side of the clamp end 40 of the post 38 yet be held in secure, fixed position by an interference fit on the other side thereof. This assembly method permits field replacement of a clamp which may become damaged, while avoiding screw-type fasteners which can become loosened. The pins are a strong steel material coated for corrosion protection. The clamp pin 52 defines a pivot axis for each of the clamps 24, the range of pivot motion for the clamps 24 being regulated by the mandrel 32, that is to say, the interrelationships and interactions of and between the components of the weapon grip assembly of the subject invention, e.g., the handle 22/base assembly 20, in response to the geometry and configuration of the weapon system to be clasped. The lobe configuration for the base end 46 of the clamp 24, essentially the excess material in the vicinity of the pivot axis thereof, ensures structural integrity in the vicinity of the clamps thru hole 50, for of long term reliable pivoting thereof. As previously noted, in furtherance of readily receiving and grasping a portion of a weapon system, a static condition for the weapon grip assembly 16 advantageously positions (e.g., biases) the jaws 24 of the base assembly 20 in an “open” condition (FIG. 5). A compression spring 56, one for each of the clamps 24, is seated so as to be interposed between an exterior surface of the lobe 48 of the base end 46 thereof, and a surface 58 from which the opposing upstanding wall segments 54 of the clamp end 40 of the post 38 extend (i.e., a “floor” of the clamp receiving “space,” see FIGS. 4 and 5/6). In the static condition for the weapon grip assembly 16 (FIG. 5), the springs 56 bias each of the clamps 24 (i.e., impart a force upon the base end 46 of the clamp 24) such that the clamps 24 are “open,” in readiness for capturing a portion of the weapon. The biasing effect of the springs 56 upon the clamps 24 is negated, or more generally regulated, to the point where the springs 56 are compressed and the free ends 44 of the clamps 24 secured to the weapon 18 (FIG. 6), by the mandrel 32 as will be later discussed. A further advantageous feature of the subject invention is that the clamps 24 cannot open far enough to allow the opening springs 56 to come loose and fall out. This is because of the special relationship between the locations of the clamps end pin holes 53, the clamp pin holes 50, spring holes 60, the length of the springs 56, and the height of the side walls 54 of the clamp end 40 of post 38. A further functionality of the springs 56 is to eliminate any rattle that might otherwise be caused by an operator carrying the weapon grip assembly 16 without the clamps 24 being manually moved to their fully closed position. As should be readily appreciated, any excess noise at critical times can endanger the operator. The free ends 44 of each of the clamps 24 preferably, but not necessarily, have a profiled tip 62, that is to say, the tip 62 of the free end 44 is not square or squared. Rather than having a single planar surface joining or uniting the exterior 42 and weapon receiving 26 surfaces, a combination of planar surfaces, extending from the exterior 42 and weapon receiving 26 surfaces of the free end 44, unite, at about a 90° angle, to define the free end terminus or tip 62. The subject clamp tip configuration is advantageous in that it permits mating of each of the clamps 24 with the upper portion of the handguard 30, e.g., a vertical lip 64 thereof, such that motion circumferentially about the launcher handguard 30 is prohibited, yet the relationship between the clamp tip 62 and the handguard 30 permits a calculated amount of play to accommodate inherent manufacturing tolerances of the handguard, as well as those between the variants of known manufacturers tolerances of the grip, as well as debris infiltrations (FIG. 6). Each of the clamps 24 of the base assembly 20, in furtherance of clamping, is preferably curved throughout a length thereof, that is to say between the base 46 and the free end 44 of same. The weapon receiving surface 26 of each of the clamps 24 is adapted to cooperatively engage (e.g., receive or seat) an exterior surface of the handguard 30 of the forward portion of the weapon (see FIG. 9). For instance, in the context of receipt upon the grenade launcher 28 of FIG. 1, the weapon receiving surface 26 includes a concave segment 66, more particularly a radiused groove, for receipt or seating of a rib 68 of the barrel handguard 30. Although the “flats” 70 of the handguard 30 might intuitively be preferable for receipt of a grip or handle, the ribs 68 thereof provide integral indexing and 90° alignment with a longitudinal axis of the launcher barrel 72. The radiused groove 66 of the weapon receiving surface 26, among other things: facilitates operator selection a specific rib location on the handguard for handle placement vis-a-vis the weapon grip assembly; maintains the select position; and, helps the weapon grip assembly in its entirety, especially the handle thereof, to resist fore and aft motion (i.e., longitudinal movement) when the operator is pulling/pushing on it while operating or carrying the weapon system. Each of the clamps 24 further includes a radiused recess 74 across a short axis thereof, above a length mid-point for same (i.e., positioned closer to the free end 44 of the clamp 24 rather than the base end 46 thereof). The radiused recess 74 effectively traverses (i.e., laterally traverses) the weapon receiving surface 26 from one lateral side edge to another lateral side edge. Depending on the handguard producer, a rivet 76 of (FIG. 5) a locater disk, not shown, can protrude significantly from the launcher barrel 72. The radiused recess 74 of the weapon receiving surface 26 allows the clamps 24 of the base assembly 20 to be positioned on top of, or over, the rivet 76 without consideration for its protrusion (i.e., permits unencumbered attachment thereover, FIG. 6), so as not to limit positioning options relative to the launcher. As previously noted, the base assembly 20 also includes post or stud 38 which, among other things, supports the clamps of the base assembly 20. At least a portion of the post 38 is threaded for integration with the handle 22, as evidenced by reference to FIG. 4, more particularly, the threaded portion of the post 38, and thus entire base assembly 20, is intended to be drawn towards or into the handle 22. An extremely close fit of the clamps 24 and the clamp end 40 of the post 38 to the handguard 30 is especially advantageous for proper functioning of the subject device. The more perfect the fit, the less pressure will be needed to hold the grip assembly in proper position. In furtherance thereof, the upstanding wall segments 54 of the clamp end 40 of the post 38 (i.e., the walls between which the clamps 24 are interposed for pivoted support, FIG. 4) include a profiled (e.g., beveled) upper edge 78 (i.e., barrel rib contact surface, see FIG. 7). The upper edge 78, more particularly, the outer upper edge, of each upstanding wall segment 54 is adapted to abut a portion of a rib 80 adjacent the rib 81 seized by the clamp or jaw 24. The aforementioned structural feature prevents forward and backward release of the weapon grip assembly 16, yet safely allows a small amount of rocking at high push/pull pressures. The mandrel or collar 32 of the weapon grip assembly 16 of the subject invention is positioned to operatively unite the handle 22 with the base assembly 20, namely, engage or receive the clamp end 40 of the post 38 and the clamps 24 themselves. In furtherance thereof, the mandrel 32 preferably has upper 84 and lower 86 portions, the lower portion 86 being received or seated upon the top of the handle 22, the upper portion 84 receiving or seating the clamp end 40 of the post 38, and engaging the clamps 24. The mandrel 32 is generally received upon the post 38 of the base assembly 20, see e.g., FIGS. 4 & 5, so as to “ride” the handle 22 “up” the post 38 of the base assembly 20 as will be later detailed with reference to FIGS. 5 & 6. The mandrel 32 is preferably fabricated from aluminum, and is hard-coat anodized in black. Structurally, the upper portion 84 of the mandrel 32 includes at least one set of opposingly paired walls 88, primary walls for the sake of the discussion, between which extends a “floor” 90 (i.e., the walls 88 upwardly extend from the floor 90). Preferably, but not necessarily (see FIGS. 13 & 14), the upper portion 84 of the mandrel 32 includes a further set of opposingly paired walls, namely, secondary walls 92. The floor 90, which includes a thru hole or aperture for receipt of the post 38 of the base assembly 20, in combination with the upstanding walls 88, 92, effectively “house” the clamp end 40 of the of the post 38, and thereby protect the pivot linkage of the clamps 24 with the post 38 (compare FIGS. 2 or 3 with FIG. 4). A sealed interface between the mandrel 32 and the post 38 of the base assembly 20 is advantageous, and achieved via the imposition of a o-ring 94, which is received about the post 38 adjacent the clamp end 40, between the clamp end 40 of the post 38 and the floor 90 of the upper portion 84 of the mandrel 32. This seal helps assure that fluids or other contaminants do not enter or migrate into the handle 22. The seal also smooths the final 30° of tightening motion (i.e., rotation) of the handle by the operator, and makes releasing the grip from the handguard easier. Finally, in furtherance of maintaining a debris free environment, the upper portion 84 of the mandrel 32 preferably includes apertures 96 to facilitate egress of debris which might otherwise collect within the upper portion 84 thereof. Each of the primary walls 88 of the upper portion 84 of the mandrel 32 preferably include a profiled (e.g., beveled) top edge 98 which defines a point of contact (i.e., a contact line or surface) for and/or between the mandrel 32, namely the upper portion 84 thereof, and each of the clamps 24. As may be readily appreciated based upon the disclosure to this point, the clamps 24 of the base assembly 20 pivotingly respond to axial positioning of the mandrel 32 relative to the post 38 of the base assembly 20. With particular and further reference now to FIG. 7, the alignment and retention mechanism 34 of the subject invention ensures proper positioning of the mandrel 32 on the post 38 while limiting vertical or axial travel with respect thereto, such that the primary walls 88 of the upper portion 84 of the mandrel 32 are at all times positioned to underlay and ultimately engage the clamps 24 of the base assembly 20. The alignment and retention mechanism 34 generally includes a detent assembly 100, namely a detent pin 102 and compression spring 104, carried by the post 38, more particularly the clamp end 40 of the post 38. The detent pin 102, which preferably has a radiused free end 106, is maintained in an extended position by the force of the compression spring 104. The detent pin 102 is held captive by a wide round base 108, upon which the spring 104 acts, which cannot fit through a hole 100 from which the radiused free end 106 of the detent pin 102 extends or protrudes. The compression spring 104 is retained within the clamp end 40 of the post 38 by a threaded set screw 112, preferable further secured using thread locking compound as is well know. The radiused free end 106 of the detent pin 102 of the alignment and retention mechanism 34 biasingly extends from the bore 110, beyond a lateral surface 114 of one of the opposing upstanding wall segments 54 of the clamp end 40 of the post 38. The upper portion 84 of the mandrel is adapted to lockingly receive the detent pin 102. In furtherance thereof, one of the secondary walls 92 of the upper portion 84 of the mandrel 32 includes an aperture or slot 116 therethrough for receipt of the detent pin 102, the travel of the mandrel 32 relative to the base assembly 20 being thereby limited to the geometry or configuration of the slot 116. An upper edge of the subject secondary wall 92 is delimited by a ramped surface 119 which, upon fitting the mandrel 32 upon the post 38, momentarily compresses the detent pin 102 for subsequent biased extension, and therefore positioning into a capture within the slot 16. An integral tool 120 is preferably, but not necessarily, provided as part of the base assembly 20 to actuate the detent pin 102 (i.e., compress the pin 102, i.e. the radiused free end 106 thereof, into the bore) in furtherance of removing the mandrel 32 from the base assembly 20. The detent pin tool 120 is adapted to be reversibly received within an axial bore 122 of the post 38 as shown. The lower portion 86 of the mandrel 32, which includes a wall 124 downwardly extending from the upper portion 84 of the mandrel 32, essentially receives a top portion 126 of the handle 22. The wall 124 of the lower portion 86 of the mandrel 32, which is circumferentially configured to cooperatively engage (i.e., encircle) the top or upper portion 126 of the handle 22, depends from the upper portion 84 of the mandrel 32 such that the “underside” of the floor 90 of the upper portion 84 of the mandrel 32, in combination with the wall 124 of the lower portion 86 thereof, defines a space into which the top of the handle 126 is received. Integral with the mandrel 32 is the latching assembly 36 for reversibly securing the subject weapon grip assembly to a weapon system. The latching assembly or system 36 preferably, but not necessarily (see also FIGS. 13 & 14), includes a detent pin 128 having a chisel tip 130, a compression spring 132 for biasing the pin 128, and an actuator (e.g., stud 134) extending from the detent pin 128 (FIGS. 7 & 8). A vertical bore 136 of the mandrel 32 receives the spring 132 and detent pin 128 for biasing the pin 128, more particularly the chisel tip 130, toward the top of the handle 126 which is adapted to selectively (i.e., indexingly) receive same. The wall 124 of the lower portion 86 of the mandrel 32 includes an aperture or slot 138 through which extends a portion of the actuator (i.e., a shaft 140 of the stud 134 passes through the aperture 138 for threaded engagement within a threaded side bore of the detent pin 128). The aperture 138 (e.g., a vertically oriented oval or the like) permits vertical travel of the actuator 134, and therefore detent pin 128. As will be later detailed, the actuator 134 is positioned for easy thumb manipulation in furtherance of disengagement of the chisel tip 130 of detent pin 128 from the top portion 126 of the handle 22. The handle or hand grip 22 of the subject weapon grip assembly is generally configured so as to comfortably “fit” a typical user's hand, even when using gloves. It is essential that the handle be readily grasped in a variety of environmental conditions. The handle is preferably fabricated from a copolymer acetal resin, more particularly, a copolymer acetal resin marketed by E.I. Du Pont De Nemours under the Delrin® mark, due to its superior physical and manufacturing characteristics. As is readily appreciated with reference to FIGS. 4 and 5 or 6, the handle 22 generally has a round cross section, preferably, but not necessarily, a non-uniform circular cross section throughout a length thereof. An exterior surface 144 extends between opposing ends of the handle, namely, the free (i.e., top 146 and bottom 148) ends thereof, circumferentially extending longitudinally about a longitudinal axis of the handle. The handle 22 further preferably includes discrete upper 150 and lower 152 compartments, approximately corresponding to upper 126 and lower 154 handle portions. The upper compartment 156 (e.g., a bore) is accessible at the top end 146 of the handle 22 (FIG. 4), whereas the lower compartment 152 is accessible at the lower 154 end portion of the handle 22 which is preferably adapted to receive a cap, more particularly and advantageously, a reversibly locking cap 156. The lower 154 portion of the handle 22 is preferably uniform in dimension throughout its length, and includes grooves in the exterior surface 144 thereof, more particularly, spaced apart circumferential grooves 158 as shown, e.g., FIG. 5. It should be noted that alternate surface adaptations in the lower handle portion 154, to facilitate sure comfortable hand gripping, are readily appreciated, well know, and contemplated in the context of the subject invention. The upper portion 126 of the handle 22 is advantageously of non-uniform dimension throughout its length, more particularly, and with respect to the longitudinal axis of the handle 22 and the lower handle portion 154, a radius of the handle 22 initially upwardly decreases, then upwardly increases, terminating in a rounded top edge 160 for the handle 22 (FIG. 5). In addition to ergonomic considerations, the subject configuration, more particularly, that portion of the handle 22 received within the lower portion 86 of the mandrel 32 (see FIGS. 5-7), provides mechanical advantages in furtherance of attachment of the assembly to a weapon. As previously noted, the top of the handle 126 is adapted to preferably receive a subassembly of the weapon grip assembly, namely, the mandrel 32 in combination with the base assembly 20. The upper compartment 150, (e.g., an axial or longitudinal bore) receives the post 38 of the base assembly 20 therein, more particularly, the threads of the post 38 are received for integration a threaded portion 162 of the bore 150, more particularly, a Helicoil® threaded metal insert 164, provided to assure a long term reliable interface between the base assembly 20 and the handle 22. The bore 150 is of a sufficient length to accommodate the operative travel length of the post 38 within the handle 22 (i.e., the post 38 may be drawn into the handle 22, for securing the clamps 24 about a portion of the weapon, without bottoming out). The top edge 160 of the handle 22 includes spaced apart notches 166 for receipt of the chisel tip 130 of the detent pin 128 of the latching mechanism 36. Rotation of the handle 22 about the post 38, (i.e. within the bore 150 of the upper handle portion 126), implicates the latching mechanism 36: as the top perimeter edge 160 of the handle 22 contacts the detent pin 128 with “forward” rotation of the handle (i.e., tightening), a ramp surface 168 of the chisel tip 130 permits the detent pin 128 to easily move from one notch to another of the spaced apart notches 166 (i.e., ride over the surfaces delimiting the notches); manipulation of the actuator 134 of the latching mechanism 34 is required to overcome the bias force supplied to the detent pin 128, and thereby permit “reverse” rotation of the handle 22 (i.e., loosening) relative to the subassembly, and thus the weapon grip assembly (FIGS. 7 & 8). The lower portion 154 of the handle 22 is adapted to receive a cover or cap 156 which is reversibly receivable at the free end 148 of the handle 22 (FIG. 4), more particularly a mouth 170 of the lower compartment 152 of the handle 22. The cap 156 generally includes a head 172 and stem 174 extending from a surface thereof, the stem 174 bearing threads or other means of integration with the handle 22 (FIGS. 4, 5/6). An o-ring 176 is advantageously received upon the threaded stem 174 of the cap 156 so as to sealing seat the head 172 of the cap 156 relative to the mouth 170 of the lower compartment 152 of the handle 22. The head 172 of the cap 156 is preferably configured so as to generally conform with the configuration of the free end 148 of the handle 22 (FIG. 5 or 6), thereby providing a seamless or pseudo-seamless exterior finish for a base of the handle 22 (i.e., the interface of the free end 148 of the handle 22 with the cap 156 does not form an abrupt exterior contour, nor does the head 172 of the cap 156 include any protrusions). In furtherance thereof, the head 172 of the cap 156 is generally cylindrical, having a diameter substantially equivalent to that of the free end 148 of the handle 22. Although not shown, the cap head 172 advantageously includes slots, grooves, dimples or other surface features (i.e., indentations). For instance, an exterior surface of the cap head 172 might include crossing slots which can be used by the operator to open (i.e., release) the cap via a 40 mm cartridge case, knife or coin if necessary, or may further or alternately include fluted edge portions (i.e., the union of the exterior surface with the sidewall of the cap head may form an irregular edge which is easily grasped) to aid the operator in gripping the cap for affixation/removal. The head 172 of the cap 156 preferably, but not necessarily, includes a latching mechanism 178, functionally equivalent to the latching mechanism 36, previously discussed, which prevents unwanted loosening of the cap 156 from the handle 22 (FIGS. 4 & 5). Keeping the cap in place prevents it from being lost by unplanned removal caused by operator handling of the handle of the weapon grip assembly. The cap latch mechanism 178, as best seen in FIG. 4, preferably includes a pawl 180 which rotates or pivots about a pin 182 which is received and retained within a transverse bore 184 of the head 172 of the cap 156. The pawl 180 is biased by a compression spring 186 located under a distal portion thereof, namely a free end 190, which is opposite a latch end 192 of the pawl. As will later be explained, the spring 186 holds the latch end 192 of the pawl 180 in a “latched” position with respect to the free end 148 of the handle 22. The cap head 172 is adapted, e.g., grooved, channeled, slotted, etc., to receive the pawl 180 of the latch mechanism 178 such that in a static (i.e. locked condition), no part thereof extends beyond an exterior surface of the cap head 172 (FIG. 1 or FIGS. 5/6). As best seen with respect to FIG. 4, the cap head 172 includes a notch or break 193 in its perimeter (i.e., sidewall) for seating or otherwise receiving the latch end 192 of the pawl 180. The latch end 192 is dimensioned so as to exceed the “thickness” of the cap head 172 (i.e., the height of the sidewall) such that a portion thereof mates or cooperatively engages the free end 148 of the handle 22. In furtherance of securing the end cap 156 in place, the handle 22 includes mating slots or notches 194 (i.e., castellations) into which the latch end 192 of the pawl 180 may be received so as to provide for positive engagement of the pawl 180 with the handle 22, thereby preventing the movement (i.e., rotation) of the end cap 156 in one direction, yet providing unrestricted movement in the other direction. More particularly, the mouth 170 of the lower compartment 152 of the handle 22 preferably includes spaced apart notches 194 (i.e., material has been removed so as to form a squared crown edge) for indexed receipt of the latch end 192 of the pawl 180 therein. As the operator turns the end cap 156, the latch end 192 of the pawl 180 ratchets past/over the notches 194 of the free end 148 of the handle 22, until the operator stops turning the end cap 156, and the latch end 192 engages an aligned or registered handle notch or slot of the spaced apart notches or slots 194 (FIG. 5 or 6). Such engagement by the latch pawl 180 prevents the cap from being turned in a loosening direction inadvertently. The operator can be confident that the cap assembly will not disengage without specific intended action. As previously noted, the lower compartment 152 of the handle 22 defines a stowage space 196 for the weapon grip assembly of the subject invention. The lower portion 154 of the inside of the handle 22 is hollow, and is preferably, but not necessarily, specifically contoured to provide additional functionality. The depth of the storage space 196 as well as the contour of the interior wall surface, within the lower compartment thereof, have been specifically sized to accommodate either two (2) AA batteries 198 (FIG. 5, solid line, and FIG. 10), or two (2) DL123 batteries 200 (FIG. 5, broken line). Other items, including but not limited to gum, cigarettes, matches, etc. also fit into the storage space 196 in lieu of batteries. A spring, more generally a biasing or resilient element 202, is further provided within the stowage space 196 to bias the compartment contents against the walls defining same. As should be readily appreciated, any content shifting is to be avoided, primarily to avoid rattling or other noise which would give away the user's position, motion or otherwise be a distraction. Referring now specifically to FIGS. 5 & 6, there is illustrated the preferred embodiment of the subject weapon grip assembly 16 ready for affixation to a portion of a weapon (e.g. a grenade launcher, more particularly, a M203 40 mm launcher 28) and affixed to the weapon, respectively. As shown, the launcher 28 includes a barrel 72 attached to a receiver 73. A barrel handguard 30 substantially surrounds the launcher barrel 72 and cooperatively engages a portion of the receiver 73. The launcher handguard 30 has a characteristically “ribbed” exterior surface, i.e., the surface comprises a plurality of ribs or ridges 68 spaced apart by a plurality of flats 70. The grenade launcher barrel 72 further, characteristically, includes a handguard locator rivet 76, and a pair of cartridge retainer rivets 77 (FIG. 1). As previously discussed, a static or standby condition for the weapon grip assembly has the clamps or jaws 24 in a biasingly open position for receipt of the launcher barrel 72 (FIG. 5). In such condition, the handle 22 is minimally integrated with the base assembly 20, more particularly, the subassembly of the mandrel 32 and base assembly 20. As is readily appreciated by comparison of FIG. 5 with FIG. 6, the mandrel 32 of FIG. 5 has not yet been positioned to overcome the bias acting upon the clamps 24 to effectively pivot same for closure about the barrel 72 (FIG. 6). As the post 38 of the base assembly 20 is drawn into the handle 22, i.e., as the handle 22 is rotated clockwise thereabout, the mandrel 32 “rides” upwardly along with the handle 22 relative to the post 38, more generally, the base assembly 20, to operatively engage the clamps 24 for closure. As best seen in FIG. 11, the weapon receiving surface 26 of the clamp 24 receives a select rib 82 of the launcher handguard 30. The free end 44 of the clamp 24 meets up with (i.e., is positioned adjacent) the handguard 30 at its union with the receiver 73 such that rotation of the weapon grip assembly 16 about the barrel 72 is prohibited. Longitudinal motion (e.g., pivoting with respect to the launcher barrel length) is prohibited by the combination of an upper portion of the base assembly 20 and the inside contour 93 of the clamps (FIG. 7). A key feature of the design of the preferred embodiment of the subject invention is to observe that once tightened, even lightly, it is impossible to pull the weapon grip assembly off the handguard of a weapon at angles near 90° because the open ends of the clamps wrap closely around the handguard, above its maximum diameter. This means that inward pressure need not be excessively exerted on the handguard to make the grip work (i.e., no vise-like clasping is necessary), only an “interference” fit of the clamps around the diameter of the handguard is necessary to prevent the weapon grip assembly from disengagement from the handguard. The tightness achieved by turning the handle is only used to force the grip clamps to remain close to the handguard contours in spite of being pulled by the operator in normal use. It's not about clamping down to grab, it's about just staying very close. The clamps will not let go unless they fail by spreading, the design and material of the clamps makes spreading virtually impossible within the range of pressures that can be exerted by a person handling and using the weapon system configured as FIG. 1. Movement of the weapon grip assembly backward and forward (i.e., along the length of the handguard) is controlled by the combined, cooperative or associative fit of the mandrel 32 and the clamp end 40 of the post 38 with or to the handguard ribs 80 adjacent the rib 82 selected for capture by the jaws 24 (i.e., three consecutive handguard ribs are implicated in the attachment of the subject grip assembly, see FIG. 7). Movement of the weapon grip assembly circularly around or about the handguard is controlled by the fit of the free end 44 of the clamps 24 to the vertical lip 64 of the handguard 30 (i.e., the handguard 30/receiver 73 interface). There is a calculated amount of play to allow for manufacturing tolerances of the handguard, tolerances of the grip, and for debris. Referring now to FIGS. 11 & 12, the subject weapon grip assembly 16 is shown equipped with an accessory, namely a flashlight assembly 204. It should be understood that a variety of known accessory items including, but not limited to, a flashlight are advantageously supported or otherwise carried by the subject weapon grip assembly. In furtherance thereof, a channeled bracket 206 is contemplated for affixation, using threaded fasteners 207, to an exterior surface 85 of the upper portion 84 of the mandrel 32, more particularly, one of the opposingly paired primary walls 88 thereof. By this design, accessories may be mounted on either or both sides of the weapon grip assembly, at an operators preference. In the instant case, the flashlight assembly 204 includes a flashlight 208 having a remotely operable power switch (i.e. a pad switch 210 tethered to an end cap 212 opposite a forward end 214 of the flashlight 208), a bracket 216 for integrating the flashlight 208 to the accessory bracket 206 affixed to the mandrel 32, and a spring clip 218 for retaining the pad switch 210 at the handle 22 of the weapon grip assembly 16. The spring clip 218 generally includes resilient members 220, extending from a base 222, which are conformingly received within the grooves 158 of the lower portion 154 of the handle 22. An exterior surface 224 of the base 222 of the spring clip 218 includes a portion of a hook and loop fastener system, or other reversible fixation means, so as to reversibly hold the pad switch 210 extending from the flashlight 208. As is readily appreciated with respect to FIG. 11, the weapon grip assembly provides advantageous location of the flashlight, and further provides advantageous positioning of the switch for supremely efficient and easy actuation of same and allows rotation of the handle of the grip assembly so as to remove same from the weapon without disassembly of flashlight assembly components (i.e., the switch). Referring now only generally to FIGS. 13-16, there are shown alternate contemplated embodiments of the subject weapon grip. More particularly, FIGS. 13 & 14, as FIG. 4, illustrate a weapon grip assembly for reversibly securing a hand hold to a forward portion of a weapon, namely a handguard, whereas the device of FIGS. 15 & 16 includes an alternate clamp or jaw configuration, namely, a jaw which is readily received about a rail of a known rail adaptor system (RAS). It should be readily appreciated that the subject weapon grip may include (e.g., be provided with) alternate, interchangeable clamps or jaws in furtherance of offering device versatility which has become an important consideration of users of such weapons and or weapon systems. Again, the subject further embodiments are not intended to be in any way limiting or exhaustive of the further device styles, and/or features contemplated. It is again noted that like numerals are used to designate like parts. With regard to the device of FIG. 13, the alignment and retention mechanism 34 for the mandrel 32, relative to the base assembly 20 of the device of FIG. 4, has been omitted. Consistent with the omission, the mandrel 32 of the subject embodiment need not include an upper portion 84 having the secondary walls 92 of the previous embodiment (FIG. 4), instead, the upper portion 84 of the mandrel 32 need only include a single set of opposingly paired walls 88 (i.e., primary walls as previously discussed, again, note FIG. 4). The mandrel 32 is preferably shaped and sized to fit the profiles of the top end 146 of the handle 22, the clamp end 40 of the post 38, and the outside surface 42 of the clamps 24. The fit of the mandrel 32 to the handle 22 is sized to cover the entire top end 146 of the handle 22, and match its outer diameter with a smooth transition since an operator's hand is likely to be in contact with this area of the assembly. The underside of the lower portion 86 of the mandrel 32 is smooth, as it is intended to closely and tightly contact the top end 146 of the handle 22 when the weapon grip assembly is fitted to the barrel handguard. As with the prior embodiment, the upper contoured edge or surface 78 of the clamp end 40 of the post 38, in combination with the clamps 24 themselves, effectively provide for an interference fit for the weapon grip assembly, namely, by partially encircling a select handguard rib 82, “filling” the flats 70 immediately adjacent the selected rib 82, and abutting the ribs 80 adjacent the select rib 82 (FIG. 9). The remaining structures of the device of FIG. 13, including their interrelationships, are readily appreciated by comparison with the FIG. 4, and reference to the discussion with respect thereto. With regard to the device of FIG. 14, it too generally omits the alignment and retention mechanism 34 for the mandrel 32 (FIG. 4), and generally includes an upper mandrel portion as described with respect to the device of FIG. 13. In contradistinction to the embodiments previously detailed, the subject device includes an alternate latching assembly 230 for reversibly securing the subject weapon grip assembly to a weapon, and an alternate interface between or for the handle 22 and base assembly 20. The mandrel 32 of the weapon grip assembly of FIG. 14, more particularly, a lower portion 86 thereof, incorporates a latching assembly 230 comprising a pawl 232, a pivot pin 234 and biasing spring 236. The hand grip or handle 22, at and about an upper end portion 126, incorporates mating slots 238 for a latch end 240 of the pawl 232. Receipt of the latch end 240 of the pawl 232 by a slot of the mating slots 238 the handle 22 provides positive engagement of the latching assembly 230, and the mandrel 32/base assembly 20 thereby, with the handle 22. Movement in one direction (i.e., a handle loosening direction) is prevented or thereby prohibited, whereas movement of the handle in the other direction (i.e., a handle tightening direction) is permitted or unrestricted. The pawl 232 of the latching assembly 230 rotates around the pin 234 which is carried and retained by the mandrel 32, for instance, by fitting the pin 234 into a hole 242 in the lower portion 86 of the mandrel 32. The pawl 232 is biased by the torsion spring 236 wrapped around portions of the pin 234 (i.e., on both or opposite sides of the pawl 232). By the arrangement shown, the latch end 240 of the pawl 232 is held (i.e., biased) in the “latched” position (i.e., the latch end 240 of the pawl 232 pivots until received within a slot of the mating slots 238 of the handle 22). As an operator turns the handle 22 of the weapon grip assembly, closing the clamps 24 around the launcher handguard 30, or other component of the weapon for clasping, the pawl 232 ratchets past the handle slots 238 until handle rotation ceases, the latch end 240 of the pawl 232 engaging the handle slot which most closely lines up or registers therewith. This engagement by the latch pawl 232 prevents the handle 22 from being turned in a loosening direction loosening. The operator can be confident that the system will not disengage without specific intended action. To remove the handgrip, the operator depresses the upper exterior surface of the pawl 232, e.g., the knurled area 244 shown, against the spring pressure, while rotating the handle in the handle loosening direction. While depressed, the pawl 232 will allow unrestricted movement of the handle, upon release thereof, the pawl 232 will resume a position ready to re-lock the rotation of the handle against rotation in the handle loosening direction. With regard to the interface of the subassembly comprising the combination of the mandrel 32 and base assembly 20 to or with the handle 22, the handle 22 preferably includes an aperture 150 (i.e., a bore) in a top surface 146 thereof. A steel threaded insert 246, which is sized to mate with the threaded post or stud 38 of the base assembly 20, is securingly received within the bore 150. Fastening means, e.g., a threaded fastener 248 in combination with a washer 250 as show, operatively unite the handle 22 to the subassembly, more particularly, the threaded fastener 248 is received within an axial bore of the post 38 which is threadingly received within the insert 246. The insert 246 assures that operators will not damage the grip handle 22 with the base assembly threaded stud 38 should the handle be over-tightened during attachment of the weapon grip assembly to the weapon. The depth of the handle bore 150 allows the stud 38 to be inserted into the handle 22 as needed for proper operation of the clamps 24. As previously noted, the post 38 of the base assembly 20 is threaded to allow it to be drawn into the handle 22 by rotation thereof. This allows complete control of device attachment and detachment actions with only one, hand. The thread pitch on the stud 38 has been specifically chosen such that it permits the operator to completely close the clamps around the barrel handguard, from a clamp opening width wide enough to fit over the handguard rib, in about one turn of the handle. This is advantageous so as to allow easy and quick operation. The imparted pitch also allows the handle to be tightened by the strongest operator without fear of stripping the threads, while retaining the tightness set by the operator without the need for a locking mechanism. The base threaded stud 38 preferably has a keyway, not shown, running the length thereof. The keyway allows accessory fittings, attached or attachable to the device upon a bracket received upon the post 38, to maintain a proper alignment independent of the handle position or motion (e.g., it allows a flashlight or aiming laser bracket to remain pointed “forward” at all times while the handle 22 is rotated). Such bracket can be used so as to position an accessory on either lateral (i.e., left or right) surface of the handle, and more than one bracket can be stacked so that ancillary or accessory equipment can be used on both the right and left sides simultaneously. Referring now to FIGS. 15 & 16, there is illustrated portions of a further embodiment of the subject weapon grip, namely, clamps 324 for grasping a rail 325 of a RAS. As a preliminary matter, the clamps or jaws supporting structures of FIG. 15 are generally as indicated and previously discussed with respect to FIG. 5, and the jaw supporting structures of FIG. 16 are generally as indicated and previously discussed with respect to FIG. 4. It should be understood that while the weapon grip of FIG. 15/16 is preferably a stand alone, dedicated device, the rail receiving jaws 324 may be optionally provided (i.e., packaged or bundled) as part of, or with, one of the previously presented embodiments so as to easily and reversibly convert, in the field as may be advantageous and or necessary, from a grenade launcher grip configuration into a RAS grip configuration. The subject embodiment of the weapon grip is characterized by opposingly paired jaws 324 (i.e., clamping jaws), each of which has a profiled surface 327, namely, a profiled lateral surface (FIGS. 15 and 16). The jaws 324 are arranged upon a clamp base 329 (i.e., the clamp end 40 of the post 38 of the clamp base 329) such that the profiled surfaces 327 thereof are in opposition: as the clamps 324 are drawn together, a rail receiving surface or volume is formed within which a rail of the forward portion of the weapon is captured (FIG. 15). With the actuatable jaws 324 adapted to receive a lateral edge 331 of the rail of a RAS, and thereby in unison grasp the rail, supremely fast secure placement of the grip anywhere along the rail length is achievable, with no removal from the rail of already present accessories so as to slidingly position heretofore known grips. The RAS jaws 324, as the launcher receiving jaws (FIG. 4), are joined to the clamp base 329 via pin 52 which traverses opposing upstanding wall segments 54 of the clamp end 40 of the post 38 of the clamp base 329 via a set of paired and aligned thru holes 53, thereby securing the clamp 324 to the post 38. The clamp pin defines a pivot axis for each of the clamps. A compression spring 56, one for each of the clamps 324, is seated so as to be interposed between an exterior surface of a base thereof, and a surface 58 from which the opposing upstanding wall segments 54 of the clamp end 40 of the post 38 extend (i.e., a “floor” of the clamp receiving “space,” note also FIGS. 4 and 5/6). In the static condition for the weapon grip assembly (FIG. 15), the springs 56 bias each of the clamps 324 (i.e., impart a force upon the base end 46 of the clamp 324) such that the clamps 324 are “open,” in readiness for capturing a portion of the weapon. The biasing effect of the springs 56 upon the clamps 324 is negated, or more generally regulated, to the point where the springs 56 are compressed and the free ends 44 of the clamps 24 secured about the rail, by the mandrel 32, more particularly its implication in the jaw actuation process. More particularly, the range of pivot motion of the jaws is regulated or limited, at least indirectly, by the mandrel: being interposed between the top of the handle and the jaws and received about the post of the clamp base, as previously discussed, the mandrel “rides” the post of the clamp base as it is drawn into the axial bore of the handle during rotation of the handle relative to the clamp base. As previously discussed with reference to FIG. 7, alignment and retention mechanism 34 (FIG. 16) of the subject invention ensures proper positioning and thus functioning of the mandrel 32 on the post 38 (FIG. 15) while limiting the range of vertical or axial travel with respect thereto, such that the primary walls 88 of the upper portion 84 of the mandrel 32 are at all times positioned to underlay and ultimately engage the clamps 24 of the base assembly 20. There are other variations of the subject invention, some of which will become obvious to those skilled in the art. It will be understood that this disclosure, in many respects, is only illustrative. Changes may be made in details, particularly in matters of shape, size, material, and arrangement of parts, as the case may be, without exceeding the scope of the invention. Accordingly, the scope of the subject invention is as defined in the language of the appended claims.

<SOH> BACKGROUND OF THE INVENTION <EOH>Weapons having barrels for discharging munitions are primarily adapted to be griped in the vicinity of the trigger, more particularly via a “pistol grip.” A wide variety of styles and configurations are know for pistol grips, key considerations being functionality, ergonomics, and aesthetics. For “long” barreled weapons, rifles for instance, forward support of same is accomplished via hand placement upon the forend, e.g., a barrel handguard or the like (i.e., a lower portion of the forward portion of the weapon). With the advent and advancement of weapon systems, for instance tactical weapons, the functionality of the “weapon” has become quite diverse, a challenge being to maintain an ease of use of the variety of features thereof, and avoidance of a cumbersome, inflexible and heavy weapon system. Many members of the armed services and law enforcement officers, are issued, and carry a tactical weapon system which includes a “host weapon” (e.g., a rifle) which is equipped with, or may be equipped with, a variety of “supplemental devices,” for instance a 40 mm grenade launcher. Such host weapons, sometimes referred to as modular weapon systems, are further configurable or adaptable to receive a variety of rails, interbars, or rail systems, upper/lower receiver and/or handguard components, buttstocks, or other accessories (e.g., sites, illumination devices, sling attachments or anchors, etc.). Traditionally, weapon system accessories have been manufacturer specific, each manufacturer of modular weapon systems providing items for integration with their rail, rail system etc. Although forward pistol grips are known and commercially available for integration with a forend assembly of a weapon, more particularly a rail or rail system, the variety of forend configurations available for a weapon have precluded a more versatile, “one size fits all” solution for forwardly supporting a weapon system in its variety of configurations. For instance, in a weapon system comprising a host weapon (e.g., rifle) and a supplemental device (e.g., grenade launcher), the launcher mounts to the rifle in a position which places the launcher in the front half of the rifle, and below the rifle barrel. This location has been the standard of armed forces worldwide since the introduction of the rifle mounted grenade launcher about 40 years ago. While the above described attachment method of the launcher to the host rifle may be the most practical solution for the integration of these separate devices, it does not provide the user with the best solution for carrying or operating the rifle or the launcher when the two devices are combined. Carrying or operating the rifle/launcher combined weapon system requires that one of the operator's hands be placed on the pistol grip of the rifle, near the rifle trigger, while the other hand is placed near the forward end of the weapon system, beneath the grenade launcher, to support the system in a position chosen by the operator for carrying and/or operation of either device. The right hand, typically used to support the rear end of the rifle at the pistol grip, and to operate the rifle trigger, is partially wrapped around the pistol grip which allows the operator to close their fingers around same, and use their index finger to fire the rifle. The left hand, typically used to support the forward end of the rifle (i.e., the end away from the user) is placed below the grenade launcher, in a palm-up cup or cradle position, with the fingers and thumb wrapped partially around the launcher handguard to both support the weight of the rifle/launcher combination and control its orientation in all axes. The palm-up position required of the operator's left hand is necessary because of the ribbed handguard of the 40 mm launcher barrel cannot be gripped by the operator's hand in any other way. Because the barrel is located below the launcher receiver, the handguard does not and cannot fully encircle the barrel, making it thereby impossible for the operator to wrap their hand around the barrel to establish a strong grasp on the barrel. This results in weak control of the weapon system and increased operator fatigue due to the necessitated hand position and orientation with respect to the weapon system, more particularly, the launcher thereof. The diameter along the launcher handguard is over 2.25 inches, which is more than 50% larger than the optimal grip diameter for an operator with average sized hands to grip an object by wrapping their fingers around it, and having at least one finger wrap back to their thumb. The launcher barrel handguard is not sized to provide the best gripping surface, it is sized to accommodate the 40 mm barrel within it. With the knowledge that this rifle/launcher combination is now front-heavy because of the shift in the rifle's center of gravity with the addition of the launcher, and that the handguard's diameter and orientation are controlled by the functional characteristics of the launcher, both a user and non-user understands why this weapon system combination, while highly desirable for its capabilities, is hard to control and is fatiguing to carry and operate, primarily because of the hand position and orientation required. The only solution to relieving the fatigue and adding additional control over the system for the operator is to change the way in which the operator holds the launcher. There are many obstacles to developing a better way to grip the launcher. To provide maximum comfort, leverage and efficiency to the operator, the area in which the launcher is handled should not be changed, only the operator's hand position. The only way to change the hand position as required to grip the launcher is to add a gripping device. Adding any component, assembly or device to a 40 mm grenade launcher barrel presents a variety of challenges, some of which are discussed herein below. First, the M203 40 mm barrel handguard is made of a thin plastic material which is designed primarily to serve as a location for the operator to place their hand. As there is very little heat produced when firing through an M203 barrel, the handguard is not specifically required to perform an insulating function. Second, the M203 40 mm handguard surface is interrupted by two cartridge retainer rivets and a handguard locator rivet. Such structures may interfere with attachment solutions, and therefore require consideration. Third, the M203 40 mm barrel is a thin wall design which precludes using fasteners which only partially penetrate the barrel wall. As a matter of fact, the barrel handguard is adhesively adhered to the barrel because the barrel walls prohibit the use of fasteners. Furthermore, weapon barrels are generally not pierced by fasteners because of their prime function to contain exploding gases. Any solution requiring a fastener which breaches the barrel wall is not possible. Further still, the thin wall of the barrel prevents any attachment solution which could distort the barrel by applying pressure unevenly, such a barrel being incapable of proper performance. Fourth, the barrel assembly of the M203 is designed for removal from the receiver without tools. This allows for easy cleaning by the operator as the barrel is the component most dirtied by firing. Being able to clean the barrel as a separate component keeps the rest of the receiver, and the rifle to which it is attached, uncontaminated by the cleaning process. Any grip attachment solution which prevents or inhibits this barrel removal process is undesirable. Furthermore, cleaning the barrel can be a messy affair using solvents to remove barrel reside and then repeatedly rinsing the barrel to remove the solvent residue. The barrel and handguard get contaminated on the outside during the process and must also be cleaned. A dry handguard is essential for the operator to maintain a grip. Any grip attachment solution that remains on the barrel during the cleaning process becomes another area to clean and is therefore undesirable. Fifth, the barrel is also removable from the receiver to allow an armorer to perform repairs. Without removal it would be impossible to re-stake or change the barrel extension, repair or replace the cartridge locator or the cartridge locator spring. To perform these repairs the barrel is placed in a vise or other holder which positions and supports the barrel assembly along the sides and on the bottom during repairs. Any grip attachment solution that remains in place in any of these areas would inhibit maintenance activities and is likewise undesirable. Finally, the handguard can be removed from the barrel for the repair of the cartridge retaining springs or for replacement of the handguard itself. Any grip attachment solution which is permanently affixed to the handguard would either inhibit or make this activity or exchange impossible. Thus, it is highly desirable and advantageous to provide a weapon grip assembly for supporting a forend of a weapon or weapon system, more particularly a versatile weapon grip assembly for select integration with a 40 mm grenade launcher which: is commercially available “off-the-shelf” and requires no developmental effort; can be fitted to any M203 launcher now in service, with no modifications of same required; is small, lightweight and rugged; is not permanently mounted onto the launcher barrel assembly; can be quickly attached and detached from the launcher handguard by the operator without tools; conforms tightly to barrel surfaces; does not pierce the barrel or handguard; can be adjustably positioned on the launcher to suit operator size preferences and comfort; can aid and/or improve the firing accuracy of the weapon system (e.g., rifle and launcher) by allowing the operator to have improved control on the weapons because of a better grip; does not hamper or prolong maintenance activities of the launcher or rifle; does not implicate nor involve additional launcher or rifle operational considerations or limitations; requires no additional operator training for use thereof; improves operator weapon control, and thus, its safety; reduces operator fatigue by improving the method by which the launcher and rifle are operated and carried; allows the operator to easily focus all energy into motions associated with opening/closing the launcher barrel by reducing the effort required to grip the barrel while in motion; enhances the loading and re-loading operations of the M203, making them faster and more controllable, thereby allowing faster aimpoint acquisition by the operator for firing the next round; provides improved firing speed and accuracy which makes the operator safer and more effective; allows the operator to easily maintain or re-establish a firm grip on the launcher and rifle in humid, wet or snowy conditions or in the presence of any other contaminants which now make these actions difficult with the current hand position required to grip the launcher handguard; and, allows the operator to easily maintain or re-establish a firm grip on the launcher and rifle while using the weapons while walking, running or after a fall or other unexpected activity. This improvement in control makes the operator more effective and safer to others around them. With weapon adaptability being an important consideration or factor for a weapon user, a “Rail Adaptor System” (RAS) has become a popular accessory for/on combat rifles and the like. There exists many versions of such systems, made by many manufacturers, see for example those produced by Knight's Armament Co. Typically, a RAS is installed in place of the weapon hand guard (i.e., substituted therefore), and is intended to provide a universal structure (i.e., a rail) for mating attachment (i.e., receipt) of accessories, e.g., a flashlight, a thermal scope, a laser, etc., to the rifle at 3, 6, 9, and 12-O'clock positions about the weapon barrel. Known systems incorporate different rail lengths and integration techniques for attachment to the weapon. Some RAS consist of a two-piece assembly, namely, a first portion providing rails at the 3, 9, and 12-O'clock positions, a second portion providing a rail at/for the 6-O'clock position. It is advantageous that the rail of the 6-O'clock position be separately removable so as to permit grenade launcher installation (i.e., in lieu thereof, as each structure competes for the same physical space, and generally uses the same attachment points on the weapon). The RAS system was originally proposed by the United States Army in 1998 so as to provide to all vendors a common style of attachment point to the M-16 rifle. While specifying the beveled lateral edge of the rail (i.e., its profile), the circumferential clock positions for the rails about the weapon barrel, and the call outs of the spacing between the crossbars of the rail and their marking (e.g., B22, B28, etc. for “bottom,” with “T” designated for “top”), implementation of the solution (i.e., weapon integration strategies) was left to those in the marketplace. In addition to the aforementioned accessories (i.e., flashlights, scopes, aiming aids, etc.), rail mount grips (e.g., vertical forend grips), are available for affixation to the rail, with heretofore know rail mount grips characterized by a female mounting flange which is slidingly received upon a rail of the RAS, and is thereafter selectively bound against a portion of the rail via, for example, a threaded fastener which is tightened to engage or press against the rail so as to secure the grip thereto. In a rail mount grip offered by Knight's Armament Co., a binding stud is threadingly received within an axial bore of a hand grip having a rail receiving flange. The binding stud includes a base or cap end which defines a lower-most extremity for the device, and a free end opposite thereof having a nub (e.g., a centrally located projection) on a top surface thereof. Upon sliding the grip, via the flange, longitudinally along and upon the rail, the binding stud is upwardly extended, relative to the grip, such that the nub on the top surface of the free end thereof locates one of the many slots or spaced apart channels in the rail (i.e., the knob is dimensioned to be received within any one of said slots or spaced apart channels). Thereafter, the binding stud is further tightened into pressing engagement with a portion of the rail. The subject design has proved problematic, with the nub being susceptible to breakage and or deformation, and requiring further operator attention to appropriately position the grip upon the rail such that the nub will in fact fall into one of the many locating slots. Since the slot and the raised portions between the slots of the rail are the same width, the operator has a 50-50 chance of getting it right the first time. Miss the location, and the grip will not tighten up. A further drawback of presently known rail mount grips is the requirement that they be slid on, more particularly, they be slid onto the rail of the RAS from the weapon front (i.e., the muzzle end) toward the weapon back (i.e. the butt stock end). Known grips cannot be slid onto the rear end of the rail because there is not enough clearance between the rail end and rifle receiver to allow access for alignment of the flange with the rail. This is a critical consideration should any other accessory be mounted on the rail forward of the grip. Should a user wish to remove the grip from the weapon, or move it to a different rail to improve handling, a lot of busy time is had configuring or reconfiguring the weapon. Thus, it remains advantageous to provide a weapon grip which is versatilely mountable to the rail of a RAS, further still, to provide a rail mount grip which has an easily operable secure fastening or affixation mechanism, namely one which abandons heretofore known sliding engagements and/or binding studs. Further desirable and advantageous is a forend grip for a weapon or weapon system which is versatile in its securement methodology. For instance, and as alluded to herein, a weapon grip having an adaptability or convertibility for receipt by a variety of known weapon or weapon system structures is particularly desirable, more particularly, a weapon grip characterized by grasping jaws. For instance, a weapon grip having replaceable or substitutable jaws for grasping a grenade launcher barrel on the one hand, or a rail of a RAS on the other hand is especially advantageous. More specific features and advantages obtained in view of those features will become apparent with reference to the drawing figures and DETAILED DESCRIPTION OF THE INVENTION.

<SOH> SUMMARY OF THE INVENTION <EOH>A preferred weapon grip assembly of the subject invention attaches to a forward portion of a weapon, for instance, to a handguard, by at least partially encircling same (i.e., clasping a portion thereof) with two clamps (i.e., jaws) of a base assembly which is supported for operative engagement by a handle. The base assembly further includes a post (e.g., a threaded stud) having a clamp end adapted to retain each of the clamps for pivot motion with respect thereto. The post of the base assembly is received within a bore of the handle, a mandrel being interposed between the handle and the clamps of the base assembly. As the base assembly is drawn into the handle, by rotation of the handle about the post of the base assembly, the mandrel receives or seats the clamp end of the post, with an upper free surface thereof engaging the clamps for pivoted closure about a portion of the weapon in furtherance of securing the weapon grip assembly thereto. The handle of the weapon grip assembly advantageously includes a stowage space accessible at a free end thereof. A cap is further provided for sealing the stowage space. The preferred weapon grip assembly further includes a latching mechanism for reversibly securing the mandrel to the handle such that the mandrel and the handle ride upwardly upon the post of the base assembly to actuate the clamps and “lock” them in position about the weapon. Preferably, but not necessarily, the weapon grip assembly further includes an alignment and retention mechanism for positioning and holding (i.e., orientingly uniting) the mandrel upon the base assembly, more particularly, the clamp end thereof. The subject weapon grip advantageously may be supplied with alternate clamping elements so as to be alternately equipped, that is to say, the weapon grip may be quickly and easily converted for grasping a grenade launcher barrel, or a rail of a RAS. In the former case, each of the jaws are curved throughout their length to grasp a launcher barrel, each of the jaws further having a surface (i.e., a barrel engaging surface) for receiving a rib of a barrel handguard. In the latter case, each of the jaws include a profiled surface, more particularly a rail receiving surface for engaging a lateral edge of a rail of a RAS. The clamps are configured such that upon being pivotally draw towards one another, a rail receiving channel is formed within which a rail of the RAS is captured or capturable.

20060131

20081125

20060831

60868.0

F41C2300

CLEMENT, MICHELLE RENEE

WEAPON GRIP ASSEMBLY

SMALL

ACCEPTED

F41C

ACCEPTED

Consumable electrode arc welding method

The invention includes means for, when welding a crater in a welding termination portion, moving a torch in a direction allowing the whole of the torch to part apart from a molten pool and, therefore, the invention can prevent all welding wires from coming into contact with the molten pool. Also, the invention can check not only the crater-welded welding wire but also all of the remaining welding wires for deposition and, if there is detected a deposited wire, can energize the deposition detected wire again to thereby be able to remove the deposition of the wire.

1. A consumable electrode arc welding method in which two or more wires are fed and energized in a torch and the torch is moved in the welding preceding direction to thereby form weld beads for welding, comprising: a first step of stopping the feeding and energization of all wires except for a specified wire of the two or more wires at a welding termination position; and a second step of moving the torch a given amount from the welding termination position to a position existing not only in the opposite direction to the welding preceding direction but also in a direction allowing the torch to part apart from the weld beads. 2. A consumable electrode arc welding method as set forth in claim 1, further including a third step of moving the torch substantially parallel with the weld beads in the welding proceeding direction from the position of the torch moved in the second step. 3. A consumable electrode arc welding method as set forth in claim 1, wherein a wire to be specified in a torch is a wire positioned so as to move most precedingly in the torch when moving the torch in the welding proceeding direction. 4. A consumable electrode arc welding method as set forth in claim 1, wherein, in the second and third steps, using the wire specified in the torch, welding is executed under a welding termination time welding condition different from a welding condition used until then. 5. A consumable electrode arc welding method as set forth in claim 4, wherein, in the second and third steps, a crater processing welding for filling in a crater formed in a welding termination portion is executed under the welding termination time welding condition. 6. A consumable electrode arc welding method as set forth in claim 2, further including: a fourth step of stopping the feeding and energization of the wires at the position of the torch moved in the third step; a fifth step of checking all wires for deposition on the weld beads; and, a sixth step of, when a deposited wire is detected in the fifth step, resuming energization on at least the deposition detected wire. 7. (canceled) 8. A consumable electrode arc welding method as set forth in claim 3, further including: a fourth step of stopping the feeding and energization of the wires at the position of the torch moved in the third step; a fifth step of checking all wires for deposition on the weld beads; and, a sixth step of, when a deposited wire is detected in the fifth step, resuming energization on at least the deposition detected wire. 9. A consumable electrode arc welding method as set forth in claim 4, further including: a fourth step of stopping the feeding and energization of the wires at the position of the torch moved in the third step; a fifth step of checking all wires for deposition on the weld beads; and, a sixth step of, when a deposited wire is detected in the fifth step, resuming energization on at least the deposition detected wire.

TECHNICAL FIELD The present invention relates to a consumable multiple electrode arc welding method for welding by feeding two or more wires in a torch and, in particular, to a welding control method for controlling the welding of a welding termination part. BACKGROUND ART As a consumable electrode arc welding method for welding by feeding a wire in a torch, conventionally, there has been used a consumable single electrode arc welding method for welding by feeding a single wire in a torch. Also, recently, there has been also used a consumable multiple electrode arc welding method for welding by feeding two or more wires in a torch. Especially, in recent years, the consumable multiple electrode arc welding method has been applied to an automatic can manufacturing process, that is, because of its high deposition metal welding, it has been used as one of production efficiency enhancing means. Here, the term “high deposition metal welding” means the welding that forms molten deposition metal with high efficiency. Also, in these consumable electrode arc welding methods, it is generally known that a weld bead recess called a crater is formed in the welding termination part, which makes it necessary to weld the welding termination part further for filling the crater in. To fill the crater in, in the consumable single electrode arc welding method for welding by feeding a single wire in a torch, the welding termination portion is welded by stopping the torch for a given time at the welding termination position while discharging an arc of a given condition to thereby fill the crater in. On the other hand, in the consumable multiple electrode arc welding method for welding by feeding two or more wires, due to the high molten metal welding thereof, a crater tends to be larger than in the consumable single electrode arc welding method. Because of this, simply by stopping the torch for a given time at the welding termination position for welding the crater, the crater cannot be filled in sufficiently. Thus, conventionally, for example, in a tandem welding method which is one of consumable multiple electrode arc welding methods, there has been proposed a welding operation to be executed in the welding termination portion for filling such crater in. For instance, according to the JP-A-2002-361413 publication, there is disclosed a method in which, when a welding operation reaches a welding termination position, after the arc generation of a consumable electrode preceding in the welding proceeding direction is terminated, while keeping the arc generation of a consumable electrode following in the welding proceeding direction, the welding operation in the welding proceeding direction is continued for welding the welding termination portion. Also, in the JP-A-2002-361414 publication, when a welding operation reaches a welding termination position, after the arc generation of a consumable electrode following in a welding proceeding direction is terminated, while keeping the arc generation of a consumable electrode preceding in the welding proceeding direction, the torch is moved back in the opposite direction to the welding preceding direction for welding. DISCLOSURE OF THE INVENTION Problems to be Solved by the Inventiion However, in the above-mentioned conventional consumable multiple electrode arc welding methods, there is a possibility that, while a welding operation to fill the crater in is in execution using only one of the multiple consumable electrodes, the wires of the remaining consumable electrodes not used for welding may come into contact with a welding pool and may be deposited in the welding termination time. When such wire deposited state occurs, for example, in an automatic welding machine such as a welding robot, the succeeding operations cannot be carried out continuously. In view of the above, it is an object of the invention to provide a welding method which can prevent the occurrence of the wire deposited states of all welding wires in the welding termination time in the consumable multiple electrode arc welding method. Means for Solving the Problems To solve the above-mentioned problems found in the conventional consumable multiple electrode arc welding method, according to the invention, there is provided a consumable electrode arc welding method in which two or more wires are fed and energized in a torch and, while moving the torch in the welding proceeding direction, weld beads are formed for welding, comprising: a first step of stopping the feeding and energization of all of the above wires except for a specified wire at a welding termination position; and, a second step of moving the torch by a given amount from the welding termination position to a position in a direction which is opposite to the welding proceeding direction and parts away form the weld beads. And, the consumable electrode arc welding method of the invention further includes a third step of moving the torch substantially parallel with the weld beads in the welding proceeding direction from the position of the torch to which the torch has been moved in the second step. Also, according to the invention, a wire to be specified in one torch is a wire which, when moving the torch in the welding proceeding direction, is to be moved most precedingly in the torch. And, according to the invention, a welding operation using a specified wire in one torch is performed under a welding termination time welding condition different from the welding condition that has been used so far. Also, according to the invention, in the second and third steps, a crater processing operation for filling in a crater occurring in the welding termination portion is executed under the welding termination time welding condition. Further, the invention further includes a fourth step of stopping the feeding and energization of the wires at the position of the torch to which the torch is moved in the third step, a fifth step of checking all wires for deposition on the weld beads, and a sixth step of, when the deposited wires are detected in the fifth step, resuming energization of at least the deposition detected wires. Effects of the Invention As described above, according to a welding control method for controlling the welding of the consumable multiple electrode arc welding termination portion, all wires can be prevented from coming into contact with a molten pool, thereby being able to prevent all wires from being deposited on the molten pool. Also, even when any one of the wires is deposited on the molten pool, the deposition can be removed, which can prevent the whole of the welding machine from stopping its operation due to occurrence of the deposition. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a view of an embodiment 1 of a consumable electrode arc welding method, showing a stage before reaching a welding termination position. FIG. 2 is a view of the embodiment 1 of a consumable electrode arc welding method, showing a stage where its welding operation reaches a welding termination position. FIG. 3 is a view of the embodiment 1 of a consumable electrode arc welding method, showing a first stage of a method for controlling the welding of a welding termination portion. FIG. 4 is a view of the embodiment 1 of a consumable electrode arc welding method, showing a second stage of a method for controlling the welding of a welding termination portion. FIG. 5 is a control processing flow chart of the welding termination control of the welding termination portion used in the embodiment 1 of the invention. FIG. 6 is a control processing flow chart for the welding termination control of the welding termination portion used in the embodiment 1 of the invention. DESCRIPTION OF REFERENCE CHARACTERS 1: Torch w: Welding proceeding direction 2, 3: Wire 6: Weld bead L, Tz: Given moving amount 201: Step of stopping feeding and energization of all wires except for a specified wire 204: Step of moving a torch by a given amount to a position existing in a direction which is obliquely opposite to the welding proceeding direction and parts apart from the weld bead. 207: Step of moving a torch substantially parallel with the weld bead in the welding proceeding direction 202, 205: Step of setting a welding termination time welding condition different from a normal welding condition used until then. 301: Step of stopping the feeding and energization of all wires except for a specified wire. 304: Step of moving a torch by a given amount to a position existing in a direction which is obliquely opposite to the welding proceeding direction and parts apart from the weld bead to a position. 307: Step of moving a torch substantially parallel with the weld bead in the welding proceeding direction. 302, 305: Step of setting a welding termination time welding condition different from a normal welding condition used until then. 310: Step of stopping the feeding and energization of wires. 312: Step of checking all wires for deposition on the weld bead. 313: Step of resuming energization of the wire. BEST MODE FOR CARRYING OUT THE INVENTION Now, description will be given below of the best mode for carrying out the invention with reference to FIGS. 1 to 6. Specifically, as the most practically used example of consumable multiple electrode arc welding terminating methods which execute a welding operation by feeding two or more wires in a torch, there is taken a method for terminating tandem welding which uses two wires by arranging them on a welding line. Embodiment 1 In FIGS. 1 to 4, reference character w designates the welding proceeding direction of the present welding, 1 a torch, 2 a consumable electrode wire preceding in the welding proceeding direction w of the present welding (which is hereinafter referred to as a preceding wire), 3 a consumable electrode wire following in the welding preceding direction w of the present welding (which is hereinafter referred to as a following wire), 4 an arc generated from the preceding wire, 5 an arc generated from the following wire, 6 a weld bead formed, 7 a molten pool, and 8 a welding base metal, respectively. Also, during the welding, the respective wires 2 and 3 are successively fed by a feed device (not shown). Further, welding machines (not shown) are separately connected to the respective wires, while the respective welding machines are allowed to execute welding operations not only by controlling not only the energization of the wires 2 and 3 but also by controlling a feed device for feeding the wires 2 and 3. Firstly, FIG. 1 is a view showing a stage before the welding reaches a welding termination position, that is, showing a state in which the present welding is being executed by generating the arcs 4 and 5 from the two wires 2 and 3 respectively. And, just below the arcs 4 and 5, there exists a molten pool 7 which is composed of molten metal and, as the welding proceeds in the w direction, the molten pool 7 is hardened to thereby form the weld bead 6. Next, FIG. 2 is a view of a stage in which the present welding reaches the welding termination portion, showing a state just before execution of the welding control to be executed in the welding termination portion, which is the characteristic of the present embodiment. By the way, as will be described later, this welding control, which is to be executed starting from the welding termination portion, is the characteristic of the present embodiment. And, in this stage, the molten metal quantity of the molten pool 7 is not sufficient when compared with the weld bead 6 formed so far; and, therefore, if the welding is terminated as it is, in the end portion of the resultant weld bead, as shown in the drawings, there is produced a crater 7a. This makes it necessary to execute a welding operation for filling the crater 7a in. For this purpose, there can be expected extra welding for filling in the crater 7a using two wires but, by so doing, there is a possibility that excessive deposition is caused. In view of this, as shown in FIG. 2, the feeding of the following wire 3 is stopped, only the preceding wire 2 is left and the generation of the arc 5 is stopped. In other words, the arc 4 of the preceding wire 2 is left, whereas the generation of the arc 5 of the following wire 3 is stopped. Further, FIG. 3 is a view of a first stage of a welding controlling method for controlling the welding of a welding termination portion according to the present embodiment. In FIG. 3, reference character 1a designates a torch position (shown by a representative point) in the welding termination position, and 1b stands for a torch position (shown by a representative point) to which the torch 1 moved to the welding termination position is to be next moved, while the torch positions 1a, 1b are distant from each other by a distance L in the horizontal direction and by a distance Tz in the vertical direction. And, if the torch 1 advances up to the torch position 1a, the welding is executed while moving the torch 1 not only in the opposite direction to the welding proceeding direction w but also in the upward direction, that is, in an obliquely upward direction shown by an arrow mark a up to the torch position 1b which is distant by the preset distance L in the horizontal direction and by the preset distance Tz in a direction where the welding wire 2 parts vertically from the molten pool 7. In this manner, because of the moving operation of the torch in the direction where the welding wires 2 and 3 part from the molten pool 7 and in the oblique direction to the welding proceeding direction w shown by the arrow mark a, the two wires 2 and 3 can be prevented from coming into contact with the molten pool 7. By the way, the speed of the torch moving operation in the arrow mark a and the welding condition are controlled under a previously set condition which is different from the condition that has been used so far. Further, FIG. 4 is a view of a second stage of a welding controlling method for controlling the welding of a welding termination portion according to the present embodiment. As shown in FIG. 4, while moving the torch 1 from the torch position 1b to the torch position 1c (shown by a representative point) in the horizontal direction shown by an arrow mark b substantially parallel to the welding proceeding direction w, the welding is further carried out to fill the crater 7a in. In this manner, in the torch moving operation in the arrow b direction as well, continuously with the torch moving operation in the arrow mark a direction in FIG. 3, the torch is moved while keeping the vertical distance Tz allowing the welding wires 2 and 3 to part from the molten pool 7, thereby being able to prevent the two welding wires 2 and 3 from coming into contact with the molten pool 7. By the way, the numerical values of these distances L and Tz are determined according to the welding conditions and, as such numerical values, there should be selected the numerical values that can provide a nice look to the shape of the welding termination position as well as can prevent the wires 2 and 3 from depositing on the molten pool 7. Also, the operation speed and welding condition at the then time are controlled under a previously set condition. And, after the torch 1 arrives at the final welding termination position, that is, the torch position 1c, the energization of the wire 3 is ended. In this case, like the termination time in the conventional welding method using a single wire, after the torch 1 is caused to stop for a given time and the welding is carried out, the energization may be ended. By the way, in the present embodiment, there has been shown an example in which the welding proceeding direction w of the torch 1 is moved in the horizontal direction. However, of course, this is not limitative but the welding proceeding direction w of the torch 1 may be any direction depending on the shape of the member to be welded and installation condition thereof. Also, in connection with this, the direction of the torch 1 parting from the molten pool 7 is not limited to the vertically upward direction but there can also be employed any direction, provided that such direction allows the torch 1 to part from the molten pool 7. Next, description will be given below of a control processing flow for welding termination control with reference to FIG. 5. FIG. 5 is a flow chart for a control processing flow for controlling welding termination control. Firstly, in FIG. 5, in Step 201, energization of all wires except for a specified wire to be used for welding a crater is stopped. This corresponds to a portion where, while keeping generation of an arc from a preceding wire 2 shown in FIG. 2, the energization of the following wire 3 is ended to terminate the ark generation of the wire 3. Next, in Step 202, the welding condition applied to the energizing wire (that is, the preceding wire 2) is switched over to the welding condition of the welding to be executed through the torch moving operation in the arrow mark a direction shown in FIG. 3. By the way, when it is not necessary to switch the welding condition, this step 202 may be skipped without executing any operation. Next, in Step 203, the movement of the torch is stopped for a given time so as to wait for stabilization of the switched welding condition. By the way, in this step 203 as well, if such waiting is not necessary depending on a welding machine to be used, this step 203 may be skipped. Next, in Step 204, the torch moving operation in the arrow mark a direction shown in FIG. 3 is executed. Further, in Step 205, the welding condition applied to the energizing wire is switched over to the welding condition of the welding to be executed by moving the torch in the arrow mark b direction shown in FIG. 4. By the way, in this case as well, if the switching of the welding condition is not necessary, this step 205 may be skipped without carrying out any operation. Next, in Step 206, the movement of the torch is stopped for a given time so as to wait for stabilization of the switched welding condition. By the way, in this step 206 as well, if such waiting is not necessary depending on a welding machine to be used, this step 206 may be skipped. Next, in Step 207, the torch moving operation in the arrow mark b direction shown in FIG. 4 is executed. Further, in Step 208, the welding condition applied to the energizing wire is switched over to the welding condition of the final welding to be executed by stopping the movement of the torch. By the way, in this case as well, if the switching of the welding condition is not necessary, this step 208 may be skipped without carrying out any operation. Next, in Step 209, the movement of the torch is stopped for a given time. In this step 209 as well, if such switching of the welding condition is not necessary depending on a welding machine to be used, this step 209 may be skipped. Finally, in Step 210, the energization of all wires and feeding of the wires are stopped to thereby stop the arc generation. The foregoing description is the description of the example corresponding to the welding control method for controlling the welding of the consumable multiple electrode arc welding termination portion according to the present embodiment. As has been described above, according to the present embodiment, while the crater filling-in welding is in execution, the wires 2 and 3 are moved in a direction parting away from the molten pool 7, thereby being able to prevent the wires against deposition. By the way, in the present embodiment, description has been given of a tandem welding example of consumable multiple electrode arc welding methods in which the welding is executed by feeding two wires in a torch. However, the number of wires is not limited to two but, even when the number of wires is three or more, there can be obtained a similar effect by energizing the wires except for a wire and stopping the feeding of the wires. Embodiment 2 Next, description will be given below of a welding controlling method for controlling the welding of the consumable multiple electrode arc welding termination portion according to an embodiment 2 with reference to FIG. 6. By the way, the present embodiment, in connection with a series of operations to be executed for welding the consumable multiple electrode arc welding termination portion shown in FIGS. 1 to 4 in the embodiment 1, shows an example of a different welding control method from the welding control method which has been described previously with reference to FIG. 5 FIG. 6 is a flow chart for a control processing flow for the welding termination control according to the present embodiment. Here, in FIG. 6, Steps 301 to 309 correspond to Steps 201 to 209 in FIG. 5 respectively and the operations of the control processings are all the same. Therefore, in the present embodiment, from Step 301 to Step 309, to avoid the duplicate description, the description thereof is simplified here and description will be given below mainly of Step 310. As a processing just before Step 310, in Step 307, the torch is moved in the arrow mark b direction shown in FIG. 4 and, further, in Step 308, after the welding condition applied to the energizing wire is switched over to a welding condition for the final welding to be executed while stopping the movement of the torch, as the need arises, in Step 309, the welding is stopped for a given time. Next, in and after Step 310, the processing for removing the wire deposition is executed. Firstly, in Step 310, the energization of all wires and feeding of the wires are stopped to thereby stop the arc generation. Next, in Step 311, there is provided a stop state for a given time so as to wait not only for the complete stop of the arc generation and wire feeding but also for the stabilization of the states of the wires and weld beads. By the way, if provision of such stop state is not necessary, this step 311 may be skipped. Next, in Step 312, all wires are checked for deposition. As a method for checking the wires for deposition, there is used a method which, using the fact that, if any wire is deposited, a current flows between the deposited wire and base metal, applies a voltage to the wire and checks whether a current flows between the wire and base metal or not. Or, if there is available a method capable of detecting the deposition of a wire, such method can also be used. For example, when a welding machine to be used has a function for detecting the wire deposition, using this function, the state signal of the welding machine is input to thereby detect the deposited state of the wire. Here, the reason why the deposition check is executed on all wires is to check not only the preceding wire but also the following wire for deposition. In other words, in the present embodiment, as an example thereof, there is taken a consumable multiple electrode arc welding control method for controlling the welding by feeding two wires in a torch; however, even when the number of wires to be fed is three or more, all of the wires should be checked for deposition. And, if no deposition is found in Step 312, the welding termination control is completed. If any one of the wires is found deposited, the processing advances to Step 313. Further, in Step 313, in order to remove the deposited state of the wire, at least the welding wire, which has been found deposited, is energized again. In this case, the welding condition and energizing time are previously set by a given method. Further, after then, the processing advances to Step 314, the number of times of execution of a series of processings executed from Step 310 to Step 313 is counted and the counted number is checked whether it reaches a given number which has been set previously. And, when the deposited state of the wire cannot be removed even if the counted number reaches the given number, an error is generated to thereby stop all operations. Also, when the counted number does not reach the given number, the processing goes back to Step 310, and the wire deposition removing processings in Step 310 and in its following steps are executed again. As has been described above, according to the present embodiment, in Step 313, by energizing again the deposited wire, the deposited state of the wire can be removed, thereby being able to prevent occurrence of a state in which the operation of the whole of the welding machine must be stopped. Although the invention has been described heretofore in detail with reference to the specific embodiments, it is obvious to those who are skilled in the art that further changes and modifications are possible without departing from the spirit and scope of the invention. The present application is based on the JP application (JP application 20004-123953) filed on 20th of Apr. 2004 and the contents thereof is incorporated into the present application for reference. INDUSTRIAL PRACTICABILITY A consumable multiple electrode arc welding method according to the invention, in a consumable multiple electrode arc welding method of a type feeding two or more wires in a torch, not only can prevent the wires from being deposited in the welding termination time but also can provide a method for removing the deposited state of the wire if the wire is found deposited. Thus, the invention is industrially useful as a control method for controlling an automatic welding machine such as a welding robot.

<SOH> BACKGROUND ART <EOH>As a consumable electrode arc welding method for welding by feeding a wire in a torch, conventionally, there has been used a consumable single electrode arc welding method for welding by feeding a single wire in a torch. Also, recently, there has been also used a consumable multiple electrode arc welding method for welding by feeding two or more wires in a torch. Especially, in recent years, the consumable multiple electrode arc welding method has been applied to an automatic can manufacturing process, that is, because of its high deposition metal welding, it has been used as one of production efficiency enhancing means. Here, the term “high deposition metal welding” means the welding that forms molten deposition metal with high efficiency. Also, in these consumable electrode arc welding methods, it is generally known that a weld bead recess called a crater is formed in the welding termination part, which makes it necessary to weld the welding termination part further for filling the crater in. To fill the crater in, in the consumable single electrode arc welding method for welding by feeding a single wire in a torch, the welding termination portion is welded by stopping the torch for a given time at the welding termination position while discharging an arc of a given condition to thereby fill the crater in. On the other hand, in the consumable multiple electrode arc welding method for welding by feeding two or more wires, due to the high molten metal welding thereof, a crater tends to be larger than in the consumable single electrode arc welding method. Because of this, simply by stopping the torch for a given time at the welding termination position for welding the crater, the crater cannot be filled in sufficiently. Thus, conventionally, for example, in a tandem welding method which is one of consumable multiple electrode arc welding methods, there has been proposed a welding operation to be executed in the welding termination portion for filling such crater in. For instance, according to the JP-A-2002-361413 publication, there is disclosed a method in which, when a welding operation reaches a welding termination position, after the arc generation of a consumable electrode preceding in the welding proceeding direction is terminated, while keeping the arc generation of a consumable electrode following in the welding proceeding direction, the welding operation in the welding proceeding direction is continued for welding the welding termination portion. Also, in the JP-A-2002-361414 publication, when a welding operation reaches a welding termination position, after the arc generation of a consumable electrode following in a welding proceeding direction is terminated, while keeping the arc generation of a consumable electrode preceding in the welding proceeding direction, the torch is moved back in the opposite direction to the welding preceding direction for welding.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a view of an embodiment 1 of a consumable electrode arc welding method, showing a stage before reaching a welding termination position. FIG. 2 is a view of the embodiment 1 of a consumable electrode arc welding method, showing a stage where its welding operation reaches a welding termination position. FIG. 3 is a view of the embodiment 1 of a consumable electrode arc welding method, showing a first stage of a method for controlling the welding of a welding termination portion. FIG. 4 is a view of the embodiment 1 of a consumable electrode arc welding method, showing a second stage of a method for controlling the welding of a welding termination portion. FIG. 5 is a control processing flow chart of the welding termination control of the welding termination portion used in the embodiment 1 of the invention. FIG. 6 is a control processing flow chart for the welding termination control of the welding termination portion used in the embodiment 1 of the invention. detailed-description description="Detailed Description" end="lead"?

20060201

20070710

20060914

68571.0

B23K910

SHAW, CLIFFORD C

CONSUMABLE ELECTRODE ARC WELDING METHOD

UNDISCOUNTED

ACCEPTED

B23K

ACCEPTED

Pyridazine derivatives and their use as therapeutic agents

Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I): where x, y, W, V, R2, R3, R4, R5, R6, R6a, R7, R7a, R8, R8a, R9 and R9a are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.

1. A method of inhibiting human stearoyl-CoA desaturase (hSCD) activity comprising contacting a source of hSCD with a compound of formula (I): wherein: x and y are each independently 1, 2 or 3; W is —O—, —C(O)O—, —N(R1)—, —S(O)t— (where t is 0, 1 or 2), —N(R1)S(O)2—, —OC(O)— or —C(O)—; V is —C(O)—, —C(S)—, —C(O)N(R1)—, —C(O)O—, —S(O)2—, —S(O)2N(R1)— or —C(R11)H—; each R1 is independently selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12hydroxyalkyl, C4-C12cycloalkylalkyl and C2-C19aralkyl; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; or R3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R13)2; R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each independently selected from hydrogen or C1-C3alkyl; or R7 and R7a together, or R8 and R8a together, or R9 and R9a together, or R6 and R6a together are an oxo group, provided that when V is —C(O)—, R7 and R7a together or R8 and R8a together do not form an oxo group, while the remaining R7, R7a, R8, R8a, R9, R9a, R6 and R6a are each independently selected from hydrogen or C1-C3alkyl; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remaining R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or C1-C3alkyl; R11 is hydrogen or C1-C3alkyl; and each R13 is independently selected from hydrogen or C1-C6alkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof. 2. A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I): wherein: x and y are each independently 1, 2 or 3; W is —O—, —C(O)O—, —N(R1)—, —S(O)t— (where t is 0, 1 or 2), —N(R1)S(O)2—, —OC(O)— or —C(O)—; V is —C(O)—, —C(S)—, —C(O)N(R1)—, —C(O)O—, —S(O)2—, —S(O)2N(R1)— or —C(R11)H—; each R1 is independently selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12hydroxyalkyl, C4-C12cycloalkylalkyl and C7-C19aralkyl; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; or R3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R13)2; R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each independently selected from hydrogen or C1-C3alkyl; or R7 and R7a together, or R8 and R8a together, or R9 and R9a together, or R6 and R6a together are an oxo group, provided that when V is —C(O), R7 and R7a together or R8 and R8a together do not form an oxo group, while the remaining R7, R7a, R8, R8a, R9, R9aa, R6 and R6a are each independently selected from hydrogen or C1-C3alkyl; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remaining R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or C1-C3alkyl; R11 is hydrogen or C1-C3alkyl; and each R13 is independently selected from hydrogen or C1-C6alkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof. 3. The method of claim 2 wherein the mammal is a human. 4. The method of claim 3 wherein the disease or condition is selected from the group consisting of Type II diabetes, impaired glucose tolerance, insulin resistance, obesity, fatty liver, non-alcoholic steatohepatitis, dyslipidemia and metabolic syndrome and any combination of these. 5. The method of claim 4 wherein the disease or condition is Type II diabetes. 6. The method of claim 4 wherein the disease or condition is obesity. 7. The method of claim 4 wherein the disease or condition is metabolic syndrome. 8. The method of claim 4 wherein the disease or condition is fatty liver. 9. The method of claim 4 wherein the disease or condition is non-alcoholic steatohepatitis. 10. A compound of formula (Ia): wherein: x and y are each independently 1, 2 or 3; W is —O—, —C(O)O—, —N(R1)—, —S(O)t— (where t is 0, 1 or 2), —N(R1)S(O)2—, —OC(O)— or —C(O)—; V is —C(O)—, —C(S)—, —C(O)N(R1)—, —C(O)O—, —S(O)2—, —S(O)2N(R1)— or —C(R11)H—; each R1 is independently selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12hydroxyalkyl, C4-C12cycloalkylalkyl and C7-C19aralkyl; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl, provided that, when W is —C(O)—, R2 can not be C1-C6alkyl substituted by —S(O)tR14 where R14 is hydrogen, C1-C6alkyl, C7-C12aralkyl, pyrazinyl, pyridinonyl, pyrrolidionyl or imidazolyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; or R3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R13)2; R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each independently selected from hydrogen or C1-C3alkyl; or R7 and R7a together, or R8 and R8a together, or R9 and R9a together, or R6 and R6a together are an oxo group, provided that when V is —C(O)—, R7 and R7a together or R8 and R8a together do not form an oxo group, while the remaining R7, R7a, R8, R8a, R9, R9a, R6 and R6a are each independently selected from hydrogen or C1-C3alkyl; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remaining R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or C1-C3alkyl; R11 is hydrogen or C1-C3alkyl; and each R13 is independently selected from hydrogen or C1-C6alkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof. 11. The compound of claim 10 wherein: x and y are each 1; W is —O—; V is —C(O)— or —C(S)—; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C7-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each hydrogen. 12. The compound of claim 11 wherein: V is —C(O)—; R2 is C7-C12aralkyl optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl and C1-C6trihaloalkoxy; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. 13. The compound of claim 12 wherein: R2 is C7-C12aralkyl optionally substituted by one or more substituents selected from halo, C1-C6alkyl, C1-C6trihaloalkyl and C1-C6trihaloalkoxy; and R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6trihaloalkyl and C1-C6trihaloalkoxy. 14. The compound of claim 13, namely, [4-(6-Phenethyloxy-pyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethyl-phenyl)-methanone. 15. The compound of claim 11 wherein: V is —C(O)—; R2 is C1-C12alkyl or C2-C12alkenyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. 16. The compound of claim 11 wherein: V is —C(O)—; R2 is C3-C12cycloalkyl or C4-C12cycloalkylalkyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. 17. The compound of claim 16 wherein: R2 is C4-C12cycloalkylalkyl; and R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6trihaloalkyl and C1-C6trihaloalkoxy. 18. The compound of claim 17, namely, {4-[6-(2-Cyclopropyl-ethoxy)-pyridazin-3-yl]-piperazin-1-yl}-(2-trifluoromethyl-phenyl)-methanone. 19. The compound of claim 10 wherein: x and y are each 1; W is —S(O)t— (where t is 0, 1 or 2); V is —C(O)— or —C(S)—; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each hydrogen. 20. The compound of claim 19 wherein: V is —C(O); R2 is C7-C12aralkyl optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl and C1-C6trihaloalkoxy; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR2, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. 21. The compound of claim 20 wherein: R2 is C7-C12aralkyl optionally substituted by one or more substituents selected from halo, C1-C6alkyl, C1-C6trihaloalkyl and C1-C6trihaloalkoxy; and R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6trihaloalkyl and C1-C6trihaloalkoxy. 22. The compound of claim 21 selected from the group consisting of the following: [4-(6-Phenethylsulfanyl-pyridazin-3-yl)-piperazin-1-yl]-(2-trifluoromethyl-phenyl)-methanone; {4-[6-(2-Phenyl-ethanesulfinyl)-pyridazin-3-yl]-piperazin-1-yl}-(2-trifluoromethyl-phenyl)-methanone; and {4-[6-(2-Phenyl-ethanesulfonyl)-pyridazin-3-yl]-piperazin-1-yl}-(2-trifluoromethyl-phenyl)-methanone. 23. The compound of claim 19 wherein: V is —C(O)—; R2 is C1-C12alkyl or C7-C12alkenyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R2)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. 24. The compound of claim 23 wherein R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6trihaloalkyl and C1-C6trihaloalkoxy. 25. The compound of claim 24, namely, {4-[6-(3-Methyl-butylsulfanyl)-pyridazin-3-yl]-piperazin-1-yl}-(2-trifluoromethyl-phenyl)-methanone. 26. The compound of claim 10 wherein: x and y are each 1; W is —N(R1)—; V is —C(O)— or —C(S)—; R1 is hydrogen or C1-C6alkyl; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each hydrogen. 27. The compound of claim 26 wherein: V is —C(O)—; R1 is hydrogen or C1-C6alkyl; R2 is C7-C12aralkyl optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl and C1-C6trihaloalkoxy; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. 28. The compound of claim 27 wherein R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6trihaloalkyl and C1-C6trihaloalkoxy. 29. The compound of claim 28 selected from the group consisting of the following: [4-(6-Phenethylamino-pyridazin-3-yl)-piperazin-1-yl]-(2-trifluoromethyl-phenyl)-methanone; and {-[6-(Methyl-phenethyl-amino)pyridazin-3-yl]-piperazin-1-yl}-(2-trifluoromethyl-phenyl)-methanone. 30. The compound of claim 26 wherein: V is —C(O)—; R1 is hydrogen or C1-C6alkyl; R2 is C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl or C4-C12cycloalkylalkyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. 31. The compound of claim 10 wherein: x and y are each 1; W is —N(R1)S(O)2—; V is —C(O)— or —C(S)—; R1 is hydrogen or C1-C6alkyl; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each hydrogen. 32. The compound of claim 31 wherein: V is —C(O)—; R1 is hydrogen or C1-C6alkyl; R2 is C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl or C4-C12cycloalkylalkyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. 33. The compound of claim 32 wherein: R2 is C1-C12alkyl; and R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6trihaloalkyl and C1-C6trihaloalkoxy. 34. The compound of claim 33, namely, Propane-1-sulfonic acid {6-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-pyridazin-3-yl}-amide. 35. The compound of claim 31 wherein: V is —C(O)—; R1 is hydrogen or C1-C6alkyl; R2 is C7-C12aralkyl optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl and C1-C6trihaloalkoxy; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. 36. A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 10. 37. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 10.

FIELD OF THE INVENTION The present invention relates generally to the field of inhibitors of stearoyl-CoA desaturase, such as pyridazine derivatives, and uses for such compounds in treating and/or preventing various human diseases, including those mediated by stearoyl-CoA desaturase (SCD) enzymes, preferably SCD1, especially diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like. BACKGROUND OF THE INVENTION Acyl desaturase enzymes catalyze the formation of double bonds in fatty acids derived from either dietary sources or de novo synthesis in the liver. Mammals synthesize at least three fatty acid desaturases of differing chain length specificity that catalyze the addition of double bonds at the delta-9, delta-6, and delta-5 positions. Stearoyl-CoA desaturases (SCDs) introduce a double bond in the C9-C10 position of saturated fatty acids. The preferred substrates are palmitoyl-CoA (16:0) and stearoyl-CoA (18:0), which are converted to palmitoleoyl-CoA (16:1) and oleoyl-CoA (18:1), respectively. The resulting mono-unsaturated fatty acids are substrates for incorporation into phospholipids, triglycerides, and cholesteryl esters. A number of mammalian SCD genes have been cloned. For example, two genes have been cloned from rat (SCD1, SCD2) and four SCD genes have been isolated from mouse (SCD1, 2, 3, and 4). While the basic biochemical role of SCD has been known in rats and mice since the 1970's (Jeffcoat, R. et al., Elsevier Science (1984), Vol. 4, pp. 85-112; de Antueno, R J, Lipids (1993), Vol. 28, No. 4, pp. 285-290), it has only recently been directly implicated in human disease processes. A single SCD gene, SCD1, has been characterized in humans. SCD1 is described in Brownlie et al, PCT published patent application, WO 01/62954, the disclosure of which is hereby incorporated by reference in its entirety. A second human SCD isoform has recently been identified, and because it bears little sequence homology to alternate mouse or rat isoforms it has been named human SCD5 or hSCD5 (PCT published patent application, WO 02/26944, incorporated herein by reference in its entirety). To date, no small-molecule, drug-like compounds are known that specifically inhibit or modulate SCD activity. Certain long-chain hydrocarbons have been used historically to study SCD activity. Known examples include thia-fatty acids, cyclopropenoid fatty acids, and certain conjugated linoleic acid isomers. Specifically, cis-12, trans-10 conjugated linoleic acid is believed to inhibit SCD enzyme activity and reduce the abundance of SCD1 mRNA while cis-9, trans-11 conjugated linoleic acid does not. Cyclopropenoid fatty acids, such as those found in stercula and cotton seeds, are also known to inhibit SCD activity. For example, sterculic acid (8-(2-octylcyclopropenyl)octanoic acid) and malvalic acid (7-(2-octylcyclopropenyl)heptanoic acid) are C18 and C16 derivatives of sterculoyl and malvaloyl fatty acids, respectively, having cyclopropene rings at their C9-C10 position. These agents are believed to inhibit SCD enzymatic activity by direct interaction with the enzyme, thus inhibiting delta-9 desaturation. Other agents that may inhibit SCD activity include thia-fatty acids, such as 9-thiastearic acid (also called 8-nonylthiooctanoic acid) and other fatty acids with a sulfoxy moiety. These known modulators of delta-9 desaturase activity are not useful for treating the diseases and disorders linked to SCD1 biological activity. None of the known SCD inhibitor compounds are selective for SCD or delta-9 desaturases, as they also inhibit other desaturases and enzymes. The thia-fatty acids, conjugated linoleic acids and cyclopropene fatty acids (malvalic acid and sterculic acid) are neither useful at reasonable physiological doses, nor are they specific inhibitors of SCD1 biological activity, rather they demonstrate cross inhibition of other desaturases, in particular the delta-5 and delta-6 desaturases by the cyclopropene fatty acids. The absence of small molecule inhibitors of SCD enzyme activity is a major scientific and medical disappointment because evidence is now compelling that SCD activity is directly implicated in common human disease processes: See e.g., Attie, A. D. et al., “Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia”, J. Lipid Res. (2002), Vol. 43, No. 11, pp. 1899-907; Cohen, P. et al., “Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss”, Science (2002), Vol. 297, No. 5579, pp. 240-3, Ntambi, J. M. et al., “Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity”, Proc. Natl. Acad. Sci. USA. (2002), Vol. 99, No. 7, pp. 11482-6. The present invention solves this problem by presenting new classes of compounds that are useful in modulating SCD activity and regulating lipid levels, especially plasma lipid levels, and which are useful in the treatment of SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, especially diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like. Related Literature PCT Published Patent Applications, WO 03/075929, WO 03/076400 and WO 03/076401 disclose compounds having histone deacetylase inhibiting enzymatic activity. BRIEF SUMMARY OF THE INVENTION The present invention provides pyridazine derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed. Accordingly, in one aspect, the invention provides methods of inhibiting human stearoyl-CoA desaturase (hSCD) activity comprising contacting a source of hSCD with a compound of formula (I): wherein: x and y are each independently 1, 2 or 3; W is —O—, —C(O)O—, —N(R1)—, —S(O)t— (where t is 0, 1 or 2), —N(R1)S(O)2—, —OC(O)— or —C(O)—; V is —C(O_—, —C(S)—, —C(O)N(R1)—, —C(O)O—, —S(O)2—, —S(O)2N(R1)— or —C(R11)H—; each R1 is independently selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12hydroxyalkyl, C4-C12cycloalkylalkyl and C7-C19aralkyl; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; or R3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R13)2; R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each independently selected from hydrogen or C1-C3alkyl; or R7 and R7a together, or R8 and R8a together, or R9 and R9a together, or R6 and R6a together are an oxo group, provided that when V is —C(O)—, R7 and R7a together or R8 and R8a together do not form an oxo group, while the remaining R7, R7a, R8, R8a, R9, R9a, R6 and R6a are each independently selected from hydrogen or C1-C3alkyl; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remaining R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or C1-C3alkyl; R11 is hydrogen or C1-C3alkyl; and each R13 is independently selected from hydrogen or C1-C6alkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof. In another aspect, this invention provides methods of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I) as set forth above. In another aspect, this invention provides compounds of formula (I) having the following formula (Ia) wherein: x and y are each independently 1, 2 or 3; W is —O—, —C(O)O—, —N(R1)—, —S(O)t— (where t is 0, 1 or 2), —N(R1)S(O)2—, —OC(O)— or —C(O)—; V is —C(O), —C(S)—, —C(O)N(R1)—, —C(O)O—, —S(O)2—, —S(O)2N(R1)— or —C(R11)H—; each R1 is independently selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12hydroxyalkyl, C4-C12cycloalkylalkyl and C7-C19aralkyl; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl, provided that, when W is —C(O)—, R2 can not be C1-C6alkyl substituted by —S(O)tR14 where R14 is hydrogen, C1-C6alkyl, C7-C12aralkyl, pyrazinyl, pyridinonyl, pyrrolidionyl or imidazolyl; or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; or R3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or, all of the rings may be fused to each other; R4 and R5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R13)2; R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each independently selected from hydrogen or C1-C3alkyl; or R7 and R7a together, or R8 and R8a together, or R9 and R9a together, or R6 and R6a together are an oxo group, provided that when V is —C(O)—, R7 and R7a together or R8 and R8a together do not form an oxo group, while the remaining R7, R7a, R8, R8a, R9, R9a, R6 and R6a are each independently selected from hydrogen or C1-C3alkyl; or one of R6, R6a, R7, and R7a together with one of R8, R8a, R9 and R9a form an alkylene bridge, while the remaining R6, R6a, R7, R7a, R8, R8a, R9, and R9a are each independently selected from hydrogen or C1-C3alkyl; R11 is hydrogen or C1-C3alkyl; and each R13 is independently selected from hydrogen or C1-C6alkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof. In another aspect, the invention provides methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, wherein the methods comprise administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention as set forth above. In another aspect, the invention provides compounds or pharmaceutical compositions useful in treating, preventing and/or diagnosing a disease or condition relating to SCD biological activity such as the diseases encompassed by cardiovascular disorders and/or metabolic syndrome (including dyslipidemia, insulin resistance and obesity). In another aspect, the invention provides methods of preventing or treating a disease or condition related to elevated lipid levels, such as plasma lipid levels, especially elevated triglyceride or cholesterol levels, in a patient afflicted with such elevated levels, comprising administering to said patient a therapeutically or prophylactically effective amount of a composition as disclosed herein. The present invention also relates to novel compounds having therapeutic ability to reduce lipid levels in an animal, especially triglyceride and cholesterol levels. In another aspect, the invention provides pharmaceutical compositions comprising the compounds of the invention as set forth above, and pharmaceutically acceptable excipients. In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level, or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient. In an embodiment of such composition, the patient has an elevated lipid level, such as elevated plasma triglycerides or cholesterol, before administration of said compound and said compound is present in an amount effective to reduce said lipid level. In another aspect, the invention provides methods for treating a patient for, or protecting a patient from developing, a disease or condition mediated by stearoyl-CoA desaturase (SCD), which methods comprise administering to a patient afflicted with such disease or condition, or at risk of developing such disease or condition, a therapeutically effective amount of a compound that inhibits activity of SCD in a patient when administered thereto. In another aspect, the invention provides methods for treating a range of diseases involving lipid metabolism utilizing compounds identified by the methods disclosed herein. In accordance therewith, there is disclosed herein a range of compounds having said activity, based on a screening assay for identifying, from a library of test compounds, a therapeutic agent which modulates the biological activity of said SCD and is useful in treating a human disorder or condition relating to serum levels of lipids, such as triglycerides, VLDL, HDL, LDL, and/or total cholesterol. DETAILED DESCRIPTION OF THE INVENTION Definitions Certain chemical groups named herein are preceded by a shorthand notation indicating the total number of carbon atoms that are to be found in the indicated chemical group. For example; C7-C12alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms, and C4-C12cycloalkylalkyl describes a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described. Accordingly, as used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated: “Methoxy” refers to the —OCH3 radical. “Cyano” refers to the —CN radical. “Nitro” refers to the —NO2 radical. “Trifluoromethyl” refers to the —CF3 radical. “Oxo” refers to the ═O substituent. “Thioxo” refers to the ═S substituent. “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to twelve carbon atoms, preferably one to eight carbon atoms or one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl(isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl(t-butyl), and the like. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, —OR14, —OC(O)—R14, —N(R14)2, —C(O)R14, —C(O)OR14, —C(O)N(R14)2, —N(R14)C(O)OR16, —N(R14)C(O)R16, —N(R14)(S(O)tR16) (where t is 1 to 2), —S(O)tOR16 (where t is 1 to 2), —S(O)tR16 (where t is 0 to 2), and —S(O)tN(R14)2 (where t is 1 to 2) where each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl; and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted unless otherwise indicated. “C1-C3alkyl” refers to an alkyl radical as defined above containing one to three carbon atoms. The C1-C3alkyl radical may be optionally substituted as defined for an alkyl group. “C1-C6alkyl” refers to an alkyl radical as defined above containing one to six carbon atoms. The C1-C6alkyl radical may be optionally substituted as defined for an alkyl group. “C1-C12alkyl” refers to an alkyl radical as defined above containing one to twelve carbon atoms. The C1-C12alkyl radical may be optionally substituted as defined for an alkyl group. “C2-C6alkyl” refers to an alkyl radical as defined above containing two to six carbon atoms. The C2-C6alkyl radical may be optionally substituted as defined for an alkyl group. “C3-C6alkyl” refers to an alkyl radical as defined above containing three to six carbon atoms. The C3-C6alkyl radical may be optionally substituted as defined for an alkyl group. “C3-C12alkyl” refers to an alkyl radical as defined above containing three to twelve carbon atoms. The C3-C12alkyl radical may be optionally substituted as defined for an alkyl group. “C6-C12alkyl” refers to an alkyl radical as defined above containing six to twelve carbon atoms. The C6-C12alkyl radical may be optionally substituted as defined for an alkyl group. “C7-C12alkyl” refers to an alkyl radical as defined above containing seven to twelve carbon atoms. The C7-C12alkyl radical may be optionally substituted as defined for an alkyl group. “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted by one of the following groups: alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —OR14, —OC(O)R14, —N(R14)2, —C(O)R14, —C(O)OR14, —C(O)N(R14)2, —N(R14)C(O)OR16, —N(R14)C(O)R16, —N(R14)(S(O)tR16) (where t is 1 to 2), —S(O)tOR16 (where t is 1 to 2), —S(O)tR16 (where t is 0 to 2), and —S(O)tN(R14)2 (where t is 1 to 2) where each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocylylalkyl, heteroaryl or heteroarylalkyl; and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted. “C3-C12alkenyl” refers to an alkenyl radical as defined above containing three to 12 carbon atoms. The C3-C12alkenyl radical may be optionally substituted as defined for an alkenyl group. “C2-C12alkenyl” refers to an alkenyl radical as defined above containing two to 12 carbon atoms. The C2-C12alkenyl radical may be optionally substituted as defined above for an alkenyl group. “Alkylene” and “alkylene chain” refer to a straight or branched divalent hydrocarbon chain, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain may be attached to the rest of the molecule and to the radical group through one carbon within the chain or through any two carbons within the chain. “Alkenylene” and “alkenylene chain” refer to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, e.g., ethenylene, propenylene, n-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. “Alkylene bridge” refers to a straight or branched divalent hydrocarbon bridge, linking two different carbons of the same ring structure, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene bridge may link any two carbons within the ring structure. “Alkoxy” refers to a radical of the formula —ORa where Ra is an alkyl radical as defined above. The alkyl part of the alkoxy radical may be optionally substituted as defined above for an alkyl radical. “C1-C6alkoxy” refers to an alkoxy radical as defined above containing one to six carbon atoms. The alkyl part of the C1-C6alkoxy radical may be optionally substituted as defined above for an alkyl group. “C1-C12alkoxy” refers to an alkoxy radical as defined above containing one to twelve carbon atoms. The alkyl part of the C1-C12alkoxy radical may be optionally substituted as defined above for an alkyl group. “C3-C12alkoxy” refers to an alkoxy radical as defined above containing three to twelve carbon atoms. The alkyl part of the C3-C12alkoxy radical may be optionally substituted as defined above for an alkyl group. “Alkoxyalkyl” refers to a radical of the formula —Ra—O—Ra where each Ra is independently an alkyl radical as defined above. The oxygen atom may be bonded to any carbon in either alkyl radical. Each alkyl part of the alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group. “C2-C12alkoxyalkyl” refers to an alkoxyalkyl radical as defined above containing two to twelve carbon atoms. Each alkyl part of the C2-C12alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group. “C3alkoxyalkyl” refers to an alkoxyalkyl radical as defined above containing three carbon atoms. Each alkyl part of the C3alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group. “C3-C12alkoxyalkyl” refers to an alkoxyalkyl radical as defined above containing three to twelve carbon atoms. Each alkyl part of the C3-C12alkoxyalkyl radical may be optionally substituted as defined above for an alkyl group. “Alkylsulfonyl” refers to a radical of the formula —S(O)2Ra where Ra is an alkyl group as defined above. The alkyl part of the alkylsulfonyl radical may be optionally substituted as defined above for an alkyl group. “C1-C6alkylsulfonyl” refers to an alkylsulfonyl radical as defined above having one to six carbon atoms. The C1-C6alkylsulfonyl group may be optionally substituted as defined above for an alkylsulfonyl group. “Aryl” refers to aromatic monocyclic or multicyclic hydrocarbon ring system consisting only of hydrogen and carbon and containing from 6 to 19 carbon atoms, preferably 6 to 10 carbon atoms, where the ring system may be partially or fully saturated. Aryl groups include, but are not limited to groups such as fluorenyl, phenyl and naphthyl. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R15—OR14, —R15—OC(O)—R14, —R15—N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR16, —R15—N(R14)C(O)R16, —R15—N(R14)(S(O)tR16) (where t is 1 to 2), —R15—S(O)tOR16 (where t is 1 to 2), —R15—S(O)tR16 (where t is 0 to 2), and —R15—S(O)tN(R14)2 (where t is 1 to 2) where each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted. “Aralkyl” refers to a radical of the formula —RaRb where Ra is an alkyl radical as defined above and Rb is one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl and the like. The aryl part of the aralkyl radical may be optionally substituted as described above for an aryl group. The alkyl part of the aralkyl radical may be optionally substituted as defined above for an alkyl group. “C7-C12aralkyl” refers to an aralkyl group as defined above containing seven to twelve carbon atoms. The aryl part of the C7-C12aralkyl radical may be optionally substituted as described above for an aryl group. The alkyl part of the C7-C12aralkyl radical may be optionally substituted as defined above for an alkyl group. “C7-C19aralkyl” refers to an aralkyl group as defined above containing seven to nineteen carbon atoms. The aryl part of the C7-C12aralkyl radical may be optionally substituted as described above for an aryl group. The alkyl part of the C7-C12aralkyl radical may be optionally substituted as defined above for an alkyl group. “C13-C19aralkyl” refers to an aralkyl group as defined above containing thirteen to nineteen carbon atoms. The aryl part of the C13-C19aralkyl radical may be optionally substituted as described above for an aryl group. The alkyl part of the C13-C19aralkyl radical may be optionally substituted as defined above for an alkyl group. “Aralkenyl” refers to a radical of the formula —RcRb where Rc is an alkenyl radical as defined above and Rb is one or more aryl radicals as defined above, which may be optionally substituted as described above. The aryl part of the aralkenyl radical may be optionally substituted as described above for an aryl group. The alkenyl part of the aralkenyl radical may be optionally substituted as defined above for an alkenyl group. “Aryloxy” refers to a radical of the formula —ORb where Rb is an aryl group as defined above. The aryl part of the aryloxy radical may be optionally substituted as defined above. “Aryl-C1-C6alkyl” refers to a radical of the formula —Rh—Ri where Rh is an unbranched alkyl radical having one to six carbons and Ri is an aryl group attached to the terminal carbon of the alkyl radical. “Cycloalkyl” refers to a stable non-aromatic monocyclic or bicyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, preferably having from three to twelve carbon atoms, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl and the like. Unless otherwise stated specifically in the specification, the term “cycloalkyl” is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R15—OR14, —R15—OC(O)—R14, —R15N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR16, —R15—N(R14)C(O)R16, —R15—N(R14)(S(O)tR16) (where t is 1 to 2), —R15—S(O)tOR16 (where t is 1 to 2), —R15—S(O)tR16 (where t is 0 to 2), and —R15—S(O)tN(R14)2 (where t is 1 to 2) where each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted. “C3-C6cycloalkyl” refers to a cycloalkyl radical as defined above having three to six carbon atoms. The C3-C6cycloalkyl radical may be optionally substituted as defined above for a cycloalkyl group. “C3-C12cycloalkyl” refers to a cycloalkyl radical as defined above having three to twelve carbon atoms. The C3-C12cycloalkyl radical may be optionally substituted as defined above for a cycloalkyl group. “Cycloalkylalkyl” refers to a radical of the formula —RaRd where Ra is an alkyl radical as defined above and Rd is a cycloalkyl radical as defined above. The cycloalkyl part of the cycloalkyl radical may be optionally substituted as defined above for an cycloalkyl radical. The alkyl part of the cycloalkyl radical may be optionally substituted as defined above for an alkyl radical. “C4-C12cycloalkylalkyl” refers to a cycloalkylalkyl radical as defined above having four to twelve carbon atoms. The C4-C12cycloalkylalkyl radical may be optionally substituted as defined above for a cycloalkylalkyl group. “Halo” refers to bromo, chloro, fluoro or iodo. “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. The alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group. “Haloalkenyl” refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 2-bromoethenyl, 3-bromoprop-1-enyl, and the like. The alkenyl part of the haloalkenyl radical may be optionally substituted as defined above for an alkyl group. “Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R15—OR14, —R15—OC(O)—R14, —R15—N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR16, —R15—N(R14)C(O)R16, —R15—N(R14)(S(O)tR16) (where t is 1 to 2), —R15—S(O)tOR16 (where t is 1 to 2), —R15—S(O)tR16 (where t is 0 to 2), and —R15—S(O)tN(R14)2 (where t is 1 to 2) where each R14 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R16 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted. “C3-C12heterocyclyl” refers to a heterocyclyl radical as defined above having three to twelve carbons. The C3-C12heterocyclyl may be optionally substituted as defined above for a heterocyclyl group. “Heterocyclylalkyl” refers to a radical of the formula —RaRe where Ra is an alkyl radical as defined above and Re is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkyl radical at the nitrogen atom. The alkyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for an alkyl group. The heterocyclyl part of the heterocyclylalkyl radical may be optionally substituted as defined above for a heterocyclyl group. “C3-C12heterocyclylalkyl” refers to a heterocyclylalkyl radical as defined above having three to twelve carbons. The C3-C12heterocyclylalkyl radical may be optionally substituted as defined above for a heterocyclylalkyl group. “Heteroaryl” refers to a 5 to 18-membered aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R15 OR14, —R15—OC(O)—R14, —R15—N(R14)2—R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR16, —R15—N(R14)C(O)R16, —R15—N(R14)(S(O)tR16) (where t is 1 to 2), —R15—S(O)tOR16 (where t is 1 to 2), —R15—S(O)tR16 (where t is 0 to 2), and —R15—S(O)tN(R14)2 (where t is 1 to 2) where each R14 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R15 is independently a direct bond or a straight or branched alkylene or alkenylene chain; and each R16 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, and where each of the above substituents is unsubstituted. “C1-C12heteroaryl” refers to a heteroaryl radical as defined above having one to twelve carbon atoms. The C1-C12heteroaryl group may be optionally substituted as defined above for a heteroaryl group. “C5-C12heteroaryl” refers to a heteroaryl radical as defined above having five to twelve carbon atoms. The C5-C12heteroaryl group may be optionally substituted as defined above for a heteroaryl group. “Heteroarylalkyl” refers to a radical of the formula —RaRf where Ra is an alkyl radical as defined above and Rf is a heteroaryl radical as defined above. The heteroaryl part of the heteroarylalkyl radical may be optionally substituted as defined above for a heteroaryl group. The alkyl part of the heteroarylalkyl radical may be optionally substituted as defined above for an alkyl group. “C3-C12heteroarylalkyl” refers to a heteroarylalkyl radical as defined above having three to twelve carbon atoms. The C3-C12heteroarylalkyl group may be optionally substituted as defined above for a heteroarylalkyl group. “Heteroarylcycloalkyl” refers to a radical of the formula —RdRf where Rd is a cycloalkyl radical as defined above and Rf is a heteroaryl radical as defined above. The cycloalkyl part of the heteroarylcycloalkyl radical may be optionally substituted as defined above for a cycloalkyl group. The heteroaryl part of the heteroarylcycloalkyl radical may be optionally substituted as defined above for a heteroaryl group. “Heteroarylalkenyl” refers to a radical of the formula —RbRf where Rb is an alkenyl radical as defined above and Rf is a heteroaryl radical as defined above. The heteroaryl part of the heteroarylalkenyl radical may be optionally substituted as defined above for a heteroaryl group. The alkenyl part of the heteroarylalkenyl radical may be optionally substituted as defined above for an alkenyl group. “Hydroxyalkyl” refers to a radical of the formula —Ra—OH where Ra is an alkyl radical as defined above. The hydroxy group may be attached to the alkyl radical on any carbon within the alkyl radical. The alkyl part of the hydroxyalkyl group may be optionally substituted as defined above for an alkyl group. “C2-C12hydroxyalkyl” refers to a hydroxyalkyl radical as defined above containing two to twelve carbon atoms. The alkyl part of the C2-C12hydroxyalkyl radical may be optionally substituted as defined above for an alkyl group. “C3-C12hydroxyalkyl” refers to a hydroxyalkyl radical as defined above containing three to twelve carbon atoms. The alkyl part of the C3-C12hydroxyalkyl radical may be optionally substituted as defined above for an alkyl group. “C7-C12hydroxyalkyl” refers to a hydroxyalkyl radical as defined above containing seven to twelve carbon atoms. The alkyl part of the C7-C12hydroxyalkyl radical may be optionally substituted as defined above for an alkyl group. “Hydroxyalkenyl” refers to a radical of the formula —Rc—OH where Rc is an alkenyl radical as defined above. The hydroxy group may be attached to the alkenyl radical on any carbon within the alkenyl radical. The alkenyl part of the hydroxyalkenyl group may be optionally substituted as defined above for an alkenyl group. “C2-C12hydroxyalkenyl” refers to a hydroxyalkenyl radical as defined above containing two to twelve carbon atoms. The alkenyl part of the C2-C12hydroxyalkenyl radical may be optionally substituted as defined above for an alkenyl group. “C3-C12hydroxyalkenyl” refers to a hydroxyalkenyl radical as defined above containing three to twelve carbon atoms. The alkenyl part of the C3-C12hydroxyalkenyl radical may be optionally substituted as defined above for an alkenyl group. “Hydroxyl-C1-C6-alkyl” refers to a radical of the formula —Rh—OH where Rh is an unbranched alkyl radical having one to six carbons and the hydroxy radical is attached to the terminal carbon. “Trihaloalkyl” refers to an alkyl radical, as defined above, that is substituted by three halo radicals, as defined above, e.g., trifluoromethyl. The alkyl part of the trihaloalkyl radical may be optionally substituted as defined above for an alkyl group. “C1-C6trihaloalkyl” refers to a trihaloalkyl radical as defined above having one to six carbon atoms. The C1-C6trihaloalkyl may be optionally substituted as defined above for a trihaloalkyl group. “Trihaloalkoxy” refers to a radical of the formula —ORg where Rg is a trihaloalkyl group as defined above. The trihaloalkyl part of the trihaloalkoxy group may be optionally substituted as defined above for a trihaloalkyl group. “C1-C6trihaloalkoxy” refers to a trihaloalkoxy radical as defined above having one to six carbon atoms. The C1-C6trihaloalkoxy group may be optionally substituted as defined above for a trihaloalkoxy group. “A multi-ring structure” refers to a multicyclic ring system comprised of two to four rings wherein the rings are independently selected from cycloalkyl, aryl, heterocyclyl or heteroaryl as defined above. Each cycloalkyl may be optionally substituted as defined above for a cycloalkyl group. Each aryl may be optionally substituted as defined above for an aryl group. Each heterocyclyl may be optionally substituted as defined above for a heterocyclyl group. Each heteroaryl may be optionally substituted as defined above for a heteroaryl group. The rings may be attached to other through direct bonds or some or all of the rings may be fused to each other. Examples include, but are not limited to a cycloalkyl radical substituted by aryl group; a cycloalkyl group substituted by an aryl group, which, in turn, is substituted by another aryl group; and so forth. “Prodrugs” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term “prodrug” refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. The term “prodrug” is also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the compounds of the invention and the like. “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. “Mammal” includes humans and domestic animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like. “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution. “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. “Pharmaceutically acceptable salt” includes both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like. “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. Often crystallizations produce a solvate of the compound of the invention. As used herein, the term “solvate” refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms. The compound of the invention may be true solvates, while in other cases, the compound of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent. A “pharmaceutical composition” refers to a formulation of a compound of the invention and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor. “Therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to a mammal, preferably a human, is sufficient to effect treatment, as defined below, of an SCD-mediated disease or condition in the mammal, preferably a human. The amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure. “Treating” or “treatment” as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or disorder of interest, and includes: (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, i.e., arresting its development; or (iii) relieving the disease or condition, i.e., causing regression of the disease or condition. As used herein, the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians. The compounds of the invention, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S) or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using a chiral column. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another. A “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any said compounds. The chemical naming protocol and structure diagrams used herein employ and rely the chemical naming features as utilized by Chemdraw version 7.0.1 (available from Cambridgesoft Corp., Cambridge, Mass.). For complex chemical names employed herein, a substituent group is named before the group to which it attaches. For example, cyclopropylethyl comprises an ethyl backbone with cyclopropyl substituent. In chemical structure diagrams, all bonds are identified, except for some carbon atoms which are assumed to be bonded to sufficient hydrogen atoms to complete the valency. For example, a compound of formula (I), as set forth above in the Summary of the Invention, wherein x and y are each 1; W is —N(R1)—; V is —C(O)—; R1 is methyl, R4 and R5 are each hydrogen; R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each hydrogen; R2 is 2-phenylethyl(phenethyl); R3 is 2-trifluoromethylphenyl; i.e., a compound of the following formula: is named herein as {-[6-Methyl-phenethyl-amino)-pyridazin-3-yl]-piperazin-1-yl}-(2-trifluoromethyl-phenyl)-methanone. Certain radical groups of the compounds of the invention are depicted herein as linkages between two parts of the compounds of the invention. For example, in the following formula (I): W is described, for example, as being —N(R1)S(O)2—; and V is described, for example, as being —C(O)N(R1)—. This description is meant to describe a W group attached to the R2 group as follows: R2—N(R1)S(O)r; and meant to describe a V group attached to the R3 group as follows: —C(O)N(R1)—R3. In other words, the description of the W and V linkage groups are meant to be read from left to right in view of formula (I) as depicted above. Embodiments of the Invention In one embodiment of the invention, compounds of formula (Ia), as set forth above in the Summary of the Invention, are directed to compounds wherein x and y are each 1; W is —O—; V is —C(Ok or —C(S)—; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each hydrogen. One embodiment of this embodiment are compounds wherein V is —C(O)—; R2 is C7-C12aralkyl optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl and C1-C6trihaloalkoxy; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. One embodiment of this embodiment are compounds wherein R2 is C7-C12aralkyl optionally substituted by one or more substituents selected from halo, C1-C6alkyl, C1-C6trihaloalkyl and C1-C6trihaloalkoxy; and R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6trihaloalkyl and C1-C6trihaloalkoxy. Another embodiment of this embodiment are compounds wherein V is —C(O)—; R2 is C1-C12alkyl or C2-C12alkenyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. Another embodiment of this embodiment are compounds wherein V is —C(O)—; R2 is C3-C12cycloalkyl or C4-C12cycloalkylalkyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. One embodiment of this embodiment are compounds wherein R2 is C4-C12cycloalkylalkyl; and R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6trihaloalkyl and C1-C6trihaloalkoxy. In another embodiment of the invention, compounds of formula (Ia), as set forth above in the Summary of the Invention, are directed to compounds wherein x and y are each 1; W is —S(O)t— (where t is 0, 1 or 2); V is —C(O)— or —C(S)—; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C1-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each hydrogen. One embodiment of this embodiment are compounds wherein V is —C(O)—; R2 is C7-C12aralkyl optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl and C1-C6trihaloalkoxy; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. A further embodiment of this embodiment are compounds wherein R2 is C7-C12aralkyl optionally substituted by one or more substituents selected from halo, C1-C6alkyl, C1-C6trihaloalkyl and C1-C6trihaloalkoxy; and R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6trihaloalkyl and C1-C6trihaloalkoxy. Another embodiment of the above embodiment are compounds wherein V is —C(O)—; R2 is C1-C12alkyl or C2-C12alkenyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. One embodiment of this embodiment are compounds wherein R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6trihaloalkyl and C1-C6trihaloalkoxy. In another embodiment of the invention, compounds of formula (Ia), as set forth above in the Summary of the Invention, are directed to compounds wherein x and y are each 1; W is —N(R1)—; V is —C(O)— or —C(S)—; R1 is hydrogen or C1-C6alkyl; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each hydrogen. One embodiment of this embodiment are compounds wherein V is —C(O)—; R1 is hydrogen or C1-C6alkyl; R2 is C7-C12aralkyl optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl and C1-C6trihaloalkoxy; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. One embodiment of this embodiment are compounds wherein R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6trihaloalkyl and C1-C6trihaloalkoxy. Another embodiment of the above embodiment are compounds wherein V is —C(O)—; R1 is hydrogen or C1-C6alkyl; R2 is C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl or C4-C12cycloalkylalkyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R2)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. In another embodiment of the invention, compounds of formula (Ia), as set forth above in the Summary of the Invention, are directed to compounds wherein x and y are each 1; W is —N(R1)S(O)2—; V is —C(O)— or —C(S)—; R1 is hydrogen or C1-C6alkyl; R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl; R3 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C12aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl; R4 and R5 are each hydrogen; and R6, R6a, R7, R7a, R8, R8a, R9 and R9a are each hydrogen. One embodiment of this embodiment are compounds wherein V is —C(O)—; R1 is hydrogen or C1-C6alkyl; R2 is C1-C12alkyl, C2-C12alkenyl, C3-C12cycloalkyl or C4-C12cycloalkylalkyl; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R2)2, —OC(O)R12, —C(O)OR12, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12 is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. One embodiment of this embodiment are compounds wherein R2 is C1-C12alkyl; and R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C1-C6trihaloalkyl and C1-C6trihaloalkoxy. Another embodiment of the above embodiment are compounds wherein V is —C(O)—; R1 is hydrogen or C1-C6alkyl; R2 is C7-C12aralkyl optionally substituted by one or more substituents selected from halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl and C1-C6trihaloalkoxy; R3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C1-C6alkyl, C1-C6trihaloalkyl, C1-C6trihaloalkoxy, C1-C6alkylsulfonyl, —N(R12)2, —OC(O)R2, —C(O)OR2, —S(O)2N(R12)2, cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and each R12′ is independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkyl, aryl or aralkyl. Specific embodiments of the compounds of the invention are disclosed herein in the following Reaction Schemes and Examples. In another embodiment, the methods of the invention are directed towards methods of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (Ia) as described above. In another embodiment, the pharmaceutical compositions of the invention are directed towards pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of formula (Ia) as described above. In another embodiment, the methods of the invention are directed towards the treatment and/or prevention of diseases mediated by stearoyl-CoA desaturase (SCD), especially human SCD (hSCD), preferably diseases related to dyslipidemia and disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like by administering an effective amount of a compound of the invention. The present invention also relates to pharmaceutical composition containing the compounds of the invention. In one embodiment, the invention relates to a composition comprising compounds of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient. In an embodiment of such composition, the patient has an elevated lipid level, such as elevated triglycerides or cholesterol, before administration of said compound of the invention and the compound of the invention is present in an amount effective to reduce said lipid level. Utility and Testing of the Compounds of the Invention The present invention relates to compounds, pharmaceutical compositions and methods of using the compounds and pharmaceutical compositions for the treatment and/or prevention of diseases mediated by stearoyl-CoA desaturase (SCD), especially human SCD (hSCD), preferably diseases related to dyslipidemia and disorders of lipid metabolism, and especially a disease related to elevated plasma lipid levels, especially cardiovascular disease, diabetes, obesity, metabolic syndrome and the like, by administering to a patient in need of such treatment an effective amount of an SCD-modulating, especially inhibiting, agent. In general, the present invention provides a method for treating a patient for, or protecting a patient from developing, a disease related to dyslipidemia and/or a disorder of lipid metabolism, wherein lipid levels in an animal, especially a human being, are outside the normal range (i.e., abnormal lipid level, such as elevated plasma lipid levels), especially levels higher than normal, preferably where said lipid is a fatty acid, such as a free or complexed fatty acid, triglycerides, phospholipids, or cholesterol, such as where LDL-cholesterol levels are elevated or HDL-cholesterol levels are reduced, or any combination of these, where said lipid-related condition or disease is an SCD-mediated disease or condition, comprising administering to an animal, such as a mammal, especially a human patient, a therapeutically effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention wherein the compound modulates the activity of SCD, preferably human SCD1. The compounds of the invention modulate, preferably inhibit, the activity of human SCD enzymes, especially human SCD1. The general value of the compounds of the invention in modulating, especially inhibiting, the activity of SCD can be determined using the assay described below in Example 7. Alternatively, the general value of the compounds in treating disorders and diseases may be established in industry standard animal models for demonstrating the efficacy of compounds in treating obesity, diabetes or elevated triglyceride or cholesterol levels or for improving glucose tolerance. Such models include Zucker obese fa/fa rats (available from Harlan Sprague Dawley, Inc. (Indianapolis, Ind.)), or the Zucker diabetic fatty rat (ZDF/GmiCrl-fa/fa) (available from Charles River Laboratories (Montréal, Quebec)). The compounds of the instant invention are inhibitors of delta-9 desaturases and are useful for treating diseases and disorders in humans and other organisms, including all those human diseases and disorders which are the result of aberrant delta-9 desaturase biological activity or which may be ameliorated by modulation of delta-9 desaturase biological activity. As defined herein, an SCD-mediated disease or condition includes but is not limited to a disease or condition which is, or is related to, cardiovascular disease, dyslipidemias (including but not limited to disorders of serum levels of triglycerides, hypertriglyceridemia, VLDL, HDL, LDL, fatty acid Desaturation Index (e.g. the ratio of 18:1/18:0 fatty acids, or other fatty acids, as defined elsewhere herein), cholesterol, and total cholesterol, hypercholesterolemia, as well as cholesterol disorders (including disorders characterized by defective reverse cholesterol transport), familial combined hyperlipidemia, coronary artery disease, atherosclerosis, heart disease, cerebrovascular disease (including but not limited to stroke, ischemic stroke and transient ischemic attack (TIA)), peripheral vascular disease, and ischemic retinopathy. In a preferred embodiment, compounds of the invention will, in a patient, increase HDL levels and/or decrease triglyceride levels and/or decrease LDL or non-HDL-cholesterol levels. An SCD-mediated disease or condition also includes metabolic syndrome (including but not limited to dyslipidemia, obesity and insulin resistance, hypertension, microalbuminemia, hyperuricaemia, and hypercoagulability), Syndrome X, diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, diabetic complications, body weight disorders (including but not limited to obesity, overweight, cachexia and anorexia), weight loss, body mass index and leptin related diseases. In a preferred embodiment, compounds of the invention will be used to treat diabetes mellitus and obesity. As used herein, the term “metabolic syndrome” is a recognized clinical term used to describe a condition comprising combinations of Type II diabetes, impaired glucose tolerance, insulin resistance, hypertension, obesity, increased abdominal girth, hypertriglyceridemia, low HDL, hyperuricaemia, hypercoagulability and/or microalbuminemia. An SCD-mediated disease or condition also includes fatty liver, hepatic steatosis, hepatitis, non-alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, erythrohepatic protoporphyria, iron overload disorders, hereditary hemochromatosis, hepatic fibrosis, hepatic cirrhosis, hepatoma and conditions related thereto. An SCD-mediated disease or condition also includes but is not limited to a disease or condition which is, or is related to primary hypertriglyceridemia, or hypertriglyceridemia secondary to another disorder or disease, such as hyperlipoproteinemias, familial histiocytic reticulosis, lipoprotein lipase deficiency, apolipoprotein deficiency (such as ApoCII deficiency or ApoE deficiency), and the like, or hypertriglyceridemia of unknown or unspecified etiology. An SCD-mediated disease or condition also includes a disorder of polyunsaturated fatty acid (PUFA) disorder, or a skin disorder, including but not limited to eczema, acne, psoriasis, keloid scar formation or prevention, diseases related to production or secretions from mucous membranes, such as monounsaturated fatty acids, wax esters, and the like. An SCD-mediated disease or condition also includes inflammation, sinusitis, asthma, pancreatitis, osteoarthritis, rheumatoid arthritis, cystic fibrosis, and pre-menstrual syndrome. An SCD-mediated disease or condition also includes but is not limited to a disease or condition which is, or is related to cancer, neoplasia, malignancy, metastases, tumours (benign or malignant), carcinogenesis, hepatomas and the like. An SCD-mediated disease or condition also includes a condition where increasing lean body mass or lean muscle mass is desired, such as is desirable in enhancing performance through muscle building. Myopathies and lipid myopathies such as carnitine palmitoyltransferase deficiency (CPT I or CPT II) are also included herein. Such treatments are useful in humans and in animal husbandry, including for administration to bovine, porcine or avian domestic animals or any other animal to reduce triglyceride production and/or provide leaner meat products and/or healthier animals. An SCD-mediated disease or condition also includes a disease or condition which is, or is related to, neurological diseases, psychiatric disorders, multiple sclerosis, eye diseases, and immune disorders. An SCD-mediated disease or condition also includes a disease or condition which is, or is related to, viral diseases or infections including but not limited to all positive strand RNA viruses, coronaviruses, SARS virus, SARS-associated coronavirus, Togaviruses, Picornaviruses, Coxsackievirus, Yellow Fever virus, Flaviviridae, ALPHAVIRUS (TOGAVIRIDAE) including Rubella virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Sindbis virus, Semliki forest virus, Chikungunya virus, O'nyong'nyong virus, Ross river virus, Mayaro virus, Alphaviruses; ASTROVIRIDAE including Astrovirus, Human Astroviruses; CALICIVIRIDAE including Vesicular exanthema of swine virus, Norwalk virus, Calicivirus, Bovine calicivirus, Pig calcivirus, Hepatitis E; CORONAVIRIDAE including Coronavirus, SARS virus, Avian infectious bronchitis virus, Bovine coronavirus, Canine coronavirus, Feline infectious peritonitis virus, Human coronavirus 299E, Human coronavirus OC43, Murine hepatitis virus, Porcine epidemic diarrhea virus, Porcine hemagglutinating encephalomyelitis virus, Porcine transmissible gastroenteritis virus, Rat coronavirus, Turkey coronavirus, Rabbit coronavirus, Berne virus, Breda virus; FLAVIVIRIDAE including Hepatitis C virus, West Nile virus, Yellow Fever virus, St. Louis encephalitis virus, Dengue Group, Hepatitis G virus, Japanese B encephalitis virus, Murray Valley encephalitis virus, Central European tick-borne encephalitis virus, Far Eastern tick-borne encephalitis virus, Kyasanur forest virus, Louping ill virus, Powassan virus, Omsk hemorrhagic fever virus, Kumilinge virus, Absetarov anzalova hypr virus, llheus virus, Rocio encephalitis virus, Langat virus, Pestivirus, Bovine viral diarrhea, Hog cholera virus, Rio Bravo Group, Tyuleniy Group, Ntayp Group, Uganda S Group, Modoc Group; PICORNAVIRIDAE including Coxsackie A virus, Rhinovirus, Hepatitis A virus, Encephalomyocarditis virus, Mengovirus, ME virus, Human poliovirus 1, Coxsackie B; POTYVIRIDAE including Potyvirus, Rymovirus, Bymovirus. Additionally it can be a disease or infection caused by or linked to Hepatitis viruses, Hepatitis B virus, Hepatitis C virus, human immunodeficiency virus (HIV) and the like. Treatable viral infections include those where the virus employs an RNA intermediate as part of the replicative cycle (hepatitis or HIV); additionally it can be a disease or infection caused by or linked to RNA negative strand viruses such as influenza and parainfluenza viruses. The compounds identified in the instant specification inhibit the desaturation of various fatty acids (such as the C9-C10 desaturation of stearoyl-CoA) which is accomplished by delta-9 desaturases, such as stearoyl-CoA desaturase 1 (SCD1). As such these compounds inhibit the formation of various fatty acids and downstream metabolites thereof. This may lead to an accumulation of stearoyl-CoA or palmitoyl-CoA and other upstream precursors of various fatty acids; which may possibly result in a negative feedback loop causing an overall change in fatty acid metabolism. Any of these consequences may ultimately be responsible for the overall therapeutic benefit provided by these compounds. Typically, a successful SCD inhibitory therapeutic agent will meet some or all of the following criteria. Oral availability should be at or above 20%. Animal model efficacy is less than about 2 mg/Kg, 1 mg/Kg, or 0.5 mg/Kg and the target human dose is between 50 and 250 mg/70 Kg, although doses outside of this range may be acceptable. (“mg/Kg” means milligrams of compound per kilogram of body mass of the subject to whom it is being administered). The therapeutic index (or ratio of toxic dose to therapeutic dose) should be greater than 100. The potency (as expressed by IC50 value) should be less than 10 μM, preferably below 1 μM and most preferably below 50 nM. The IC50 (“Inhibitory Concentration—50%”) is a measure of the amount of compound required to achieve 50% inhibition of SCD activity, over a specific time period, in an SCD biological activity assay. Any process for measuring the activity of SCD enzymes, preferably mouse or human SCD enzymes, may be utilized to assay the activity of the compounds useful in the methods of the invention in inhibiting said SCD activity. Compounds of the invention demonstrate an IC50 in a 15 minute microsomal assay of preferably less than 10 μM, less than 5 μM, less than 2.5 μM, less than 1 μM, less than 750 nM, less than 500 nM, less than 250 nM, less than 100 nM, less than 50 nM, and most preferably less than 20 nM. The compound of the invention may show reversible inhibition (i.e., competitive inhibition) and preferably does not inhibit other iron binding proteins. The required dosage should preferably be no more than about once or twice a day or at meal times. The identification of compounds of the invention as SCD inhibitors was readily accomplished using the SCD enzyme and microsomal assay procedure described in Brownlie et al, supra. When tested in this assay, compounds of the invention had less than 50% remaining SCD activity at 10 μM concentration of the test compound, preferably less than 40% remaining SCD activity at 10 μM concentration of the test compound, more preferably less than 30% remaining SCD activity at 10 μM concentration of the test compound, and even more preferably less than 20% remaining SCD activity at 10 μM concentration of the test compound, thereby demonstrating that the compounds of the invention are potent inhibitors of SCD activity. These results provide the basis for analysis of the structure-activity relationship (SAR) between test compounds and SCD. Certain R groups tend to provide more potent inhibitory compounds. SAR analysis is one of the tools those skilled in the art may now employ to identify preferred embodiments of the compounds of the invention for use as therapeutic agents. Other methods of testing the compounds disclosed herein are also readily available to those skilled in the art. Thus, in addition, said contacting may be accomplished in vivo. In one such embodiment, said contacting in step (a) is accomplished by administering said chemical agent to an animal afflicted with a triglyceride (TG)- or very low density lipoprotein (VLDL)-related disorder and subsequently detecting a change in plasma triglyceride level in said animal thereby identifying a therapeutic agent useful in treating a triglyceride (TG)- or very low density lipoprotein (VLDL)-related disorder. In such embodiment, the animal may be a human, such as a human patient afflicted with such a disorder and in need of treatment of said disorder. In specific embodiments of such in vivo processes, said change in SCD1 activity in said animal is a decrease in activity, preferably wherein said SCD1 modulating agent does not substantially inhibit the biological activity of a delta-5 desaturase, delta-6 desaturase or fatty acid synthetase. The model systems useful for compound evaluation may include, but are not limited to, the use of liver microsomes, such as from mice that have been maintained on a high carbohydrate diet, or from human donors, including persons suffering from obesity. Immortalized cell lines, such as HepG2 (from human liver), MCF-7 (from human breast cancer) and 3T3-L1 (from mouse adipocytes) may also be used. Primary cell lines, such as mouse primary hepatocytes, are also useful in testing the compounds of the invention. Where whole animals are used, mice used as a source of primary hepatocyte cells may also be used wherein the mice have been maintained on a high carbohydrate diet to increase SCD activity in mirocrosomes and/or to elevate plasma triglyceride levels (i.e., the 18:1/18:0 ratio); alternatively mice on a normal diet or mice with normal triglyceride levels may be used. Mouse models employing transgenic mice designed for hypertriglyceridemia are also available as is the mouse phenome database. Rabbits and hamsters are also useful as animal models, especially those expressing CETP (cholesteryl ester transfer protein). Another suitable method for determining the in vivo efficacy of the compounds of the invention is to indirectly measure their impact on inhibition of SCD enzyme by measuring a subject's Desaturation Index after administration of the compound. “Desaturation Index” as employed in this specification means the ratio of the product over the substrate for the SCD enzyme as measured from a given tissue sample. This may be calculated using three different equations 18:1 n-9/18:0 (oleic acid over stearic acid); 16:1n-7/16:0 (palmitoleic acid over palmitic acid); and/or 16:1n-7+18:1n-7/16:0 (measuring all reaction products of 16:0 desaturation over 16:0 substrate). Desaturation Index is primarily measured in liver or plasma triglycerides, but may also be measured in other selected lipid fractions from a variety of tissues. Desaturation Index, generally speaking, is a tool for plasma lipid profiling. A number of human diseases and disorders are the result of aberrant SCD1 biological activity and may be ameliorated by modulation of SCD1 biological activity using the therapeutic agents of the invention. Inhibition of SCD expression may also affect the fatty acid composition of membrane phospholipids, as well as production or levels of triglycerides and cholesterol esters. The fatty acid composition of phospholipids ultimately determines membrane fluidity, while the effects on the composition of triglycerides and cholesterol esters can affect lipoprotein metabolism and adiposity. In carrying out the procedures of the present invention it is of course to be understood that reference to particular buffers, media, reagents, cells, culture conditions and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to be able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein. Pharmaceutical Compositions of the Invention and Administration The present invention also relates to pharmaceutical composition containing the compounds of the invention disclosed herein. In one embodiment, the present invention relates to a composition comprising compounds of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient. In an embodiment of such composition, the patient has an elevated lipid level, such as elevated triglycerides or cholesterol, before administration of said compound of the invention and the compound of the invention is present in an amount effective to reduce said lipid level. The pharmaceutical compositions useful herein also contain a pharmaceutically acceptable carrier, including any suitable diluent or excipient, which includes any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity. Pharmaceutically acceptable carriers include, but are not limited to, liquids, such as water, saline, glycerol and ethanol, and the like. A thorough discussion of pharmaceutically acceptable carriers, diluents, and other excipients is presented in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., N.J. current edition). Those skilled in the art know how to determine suitable doses of the compounds for use in treating the diseases and disorders contemplated herein. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side-effects for the patient. The preferred dosage range for an animal is 0.001 mg/Kg to 10,000 mg/Kg, including 0.5 mg/Kg, 1.0 mg/Kg and 2.0 mg/Kg, though doses outside this range may be acceptable. The dosing schedule may be once or twice per day, although more often or less often may be satisfactory. Those skilled in the art are also familiar with determining administration methods (oral, intravenous, inhalation, sub-cutaneous, etc.), dosage forms, suitable pharmaceutical excipients and other matters relevant to the delivery of the compounds to a subject in need thereof. In an alternative use of the invention, the compounds of the invention can be used in in vitro or in vivo studies as exemplary agents for comparative purposes to find other compounds also useful in treatment of, or protection from, the various diseases disclosed herein. Preparation of the Compounds of the Invention It is understood that in the following description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds. It will also be appreciated by those skilled in the art that in the process described below the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include —C(O)—R″ (where R″ is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. The protecting group may also be a polymer resin such as a Wang resin or a 2-chlorotrityl-chloride resin. It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this invention may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All prodrugs of compounds of this invention are included within the scope of the invention. Although anyone skilled in the art is capable of preparing the compounds of the invention according to the general techniques disclosed above, more specific details on synthetic techniques for compounds of the invention are provided elsewhere in this specification for convenience. Again, all reagents and reaction conditions employed in synthesis are known to those skilled in the art and are available from ordinary commercial sources. The following Reaction Schemes illustrate methods to make compounds of this invention. It is understood that one of those skilled in the art would be able to make these compounds by similar methods or by methods known to one skilled in the art. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described in this invention. In the following Reaction Schemes x, y, R1, R2, R3, R4, R6, R6a, R7, R7a, R8, R8a, R9 and R9a are as defined as in the Specification unless specifically defined otherwise; X is selected from Cl or Br; and PG is a protecting group, such as BOC, benzyl and the like. In general, the compounds of formula (I) of this invention where W is S and V is —C(O)—, —S(O)2— or —C(R11)H— can be synthesized following the general procedure as described in Reaction Scheme 1. The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows: Compound 103. To a stirred solution of the amine of formula (101) (1 equivalent) in a solvent such as dichloromethane or toluene is added the solution of a compound of formula (102) (1 equivalent) in a solvent such as dichloromethane or toluene in the presence of a base such as triethylamine or Hunigs base. The resulting mixture is stirred at ambient temperature for an adequate time period and then quenched with water. The organic phase is washed with H2O, brine, dried over and then concentrated in vacuo to afford the product of formula (103). Compound 104. A solution of compound of formula of (103) obtained above is dissolved in an adequate solvent and the protecting group PG is removed under standard deprotection conditions such as hydrolysis or hydrogenation to obtain the amine of formula (104). Compound 106. The mixture of a pyridazine compound of formula (105) (1 equivalent) and the compound of formula (104) obtained above (1.5 equivalent) in an adequate solvent is heated at reflux for 4-24 hours. To the reaction mixture is added a basic solution such as NaOH solution. The aqueous layer is extracted by an organic solvent such as dichloromethane or ethyl acetate. The combined organic phase is dried, then evaporated to dryness. The crude compound is purified by column chromatography or crystallization to afford the compound of formula (106). Compound of formula (I). A mixture of compound (106) (1 equivalent), a thiol compound of formula (107) (1 equivalent) and a base, such as, but not limited to, sodium hydroxide (1 equivalent) in an anhydrous solvent, such as, but not limited to, tetrahydrofuran, 1,4-dioxane, is refluxed for 8-12 h. The reaction mixture is cooled, diluted with water, acidified, then extracted with an organic solvent, such as, but not limited to, dichloromethane. The organic layer is separated and dried over anhydrous MgSO4 to yield compound of formula (I) where W is —S— and V is —C(O)—, —S(O)2— or —C(R11)H—. Alternatively, the compounds of formula (I) of this invention where W is —O— and V is —C(O)—, —S(O)2— or —C(R11)H— can be synthesized following the general procedure as described in Reaction Scheme 2. The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows: Compound of formula (I). To a mixture of compound (106) (1 equivalent) and an alcohol of formula (108) (1 equivalent) in an anhydrous solvent, such as, but not limited to, benzene or toluene is added 60% NaH (1 equivalent). The reaction mixture is refluxed for 1-4 h with stirring, then cooled to ambient temperature, diluted with water and extracted with an organic solvent, such as, but not limited to, ethyl acetate or dichloromethane. The organic layer is separated, washed with water, dried over anhydrous MgSO4, filtered and concentrated. Purification by column chromatography affords the compound of formula (I) where W is —O— and V is —C(O)—, —S(O)2— or —C(R11)H— Alternatively, the compounds of formula (I) of this invention where W is —NR1— and V is —C(O)—, —S(O)2— or —C(R11)H— can be synthesized following the general procedure as described in Reaction Scheme 3. The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows: Compound of formula (I). To a stirred solution of compound (106) (1 equivalent) and an amine of formula (109) (1.5-2 equivalent) in an organic solvent, such as, but not limited to, acetone or n-butanol is added 2-3 equivalent of acid in water. The reaction is refluxed for 8-16 h while stirring, then cooled to ambient temperature and the solvent is removed in vacuo. Purification by purified by column chromatography affords the compound of formula (I) where W is —NR1— and V is —C(O)—, —S(O)2— or —C(R11)H—. Alternatively, the compounds of formula (I) of this invention where W is —S(O)t— (where t=1 or 2) and V is —C(O)—, —S(O)2— or —C(R11)H— can be synthesized following the general procedure as described in Reaction Scheme 4. The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows: Compound (110). To a solution of sodium periodate (1 equivalent) in an appropriate solvent, such as, but not limited to, MeOH and water mixture is added the thioether compound (1 equvalent). The reaction mixture is stirred in an ice-bath for 4-8 hours and then diluted with an organic solvent, such as, but not limited to, dichloromethane. The organic layer is separated and washed with water, dried over anhydrous Na2SO4, concentrated in vacuo. Purification by column chromatography affords the compound (110). Compound (111). A mixture of the thioether compound (1 equivalent) and an oxidizing agent, such as, but not limited to, m-CPBA (2-4 equivalent) in an appropriate solvent, such as, but not limited to, dichloromethane is stirred in an ice-bath for 2-4 h, and the stirring is continued for another 12-24 hours. The reaction mixture is diluted with an organic solvent such as dichloromethane, washed with a basic solution, such as NaOH solution, and brine. Organic layer is separated and dried over anhydrous Na2SO4, then concentrated in vacuo. Purification by column chromatography yields the compound (111). Alternatively, the compounds of formula (I) of the invention where W is —NH— and V is —C(O)—, —S(O)2— or —C(R11)H— can be synthesized following the general procedure as described in Reaction Scheme 5. The starting materials for the above reaction scheme are commercially available or can be prepared according to methods known to one skilled in the art or by methods disclosed herein. In general, the compounds of the invention are prepared in the above reaction scheme as follows: Compound 114. To a stirred solution of the amine of formula (112) (1 equivalent) in a solvent such as dichloromethane or toluene is added the solution of a chloride of formula (113) (1 equivalent) in a solvent such as dichloromethane or toluene in the presence of a base such as triethylamine or Hunigs base. The resulting mixture is stirred at ambient temperature for an adequate time period and then quenched with water. The organic phase is washed with H2O, brine, dried over and then concentrated in vacuo to afford the product of formula (114). Compound 115. A solution of compound of formula of (114) obtained above is dissolved in an adequate solvent and the protection group PG is removed under standard deprotection conditions such as hydrolysis or hydrogenation to obtain the amine of formula (115). Compound 117. The mixture of a pyridine compound of formula (115) (1 equivalent) and the compound of formula (116) (1.5 equivalent) in an adequate solvent is heated at reflux for 4-24 hours. To the reaction mixture is added a basic solution such as NaOH solution. The aqueous layer is extracted by an organic solvent such as dichloromethane or ethyl acetate. The combined organic phase is dried, then evaporated to dryness. The crude compound is purified by column chromatography or crystallization to afford the compound of formula (117). Compound 118. The nitro compound of formula (117) can be reduced to the corresponding amine compound of formula (118) using a standard hydrogenation process known to one skilled in the art. Compound of formula (I). Reaction of amine (118) with an appropriate aldehyde of formula (119) in the presence of a reducing agent such as, but not limited to, sodium borohydride in a solvent such as, but not limited, ethanol affords the compound of formula (I) where W is —NH— and V is —C(O)—, —S(O)2— or —C(R11)H—. Alternatively, the compounds of formula (I) of the invention where W is —O— and V is —C(O)—, —S(O)2— or —C(R11)H— can be synthesized following the general procedure as described in Reaction Scheme 6. Reaction of amine (118) with sodium nitrite in the presence of a Lewis acid such as, but not limited to, boron trifluoride diethyl ehterate in a solvent such as, but not limited to, N,N-dimethylformamide, generates a diazonium intermediate that can be converted into the acetoxy compound (120) by quenching the above reaction mixture with acetic anhydride. Hydrolysis of the ester compound (120) in the presence of a base such as, but not limited to, sodium hydroxide, produces a hydroxy intermediate that can be converted into the desired product of formula (I) (W=—O—) with an appropriate R2X in the presence of a base such as, but not limited to, sodium hydride in a solvent such as, but not limited to, tetrahydrofuran or N,N-dimethylformamide. Alternatively, the compounds of formula (I) of the invention where W is —S(O)t— (where t is 0, 1 or 2) and V is —C(O), —S(O)2— or —C(R11)H— can be synthesized following the general procedure as described in Reaction Scheme 7. Reaction of amine (118) with sodium nitrite in the presence of a Lewis acid such as, but not limited to, boron trifluoride diethyl etherate in a solvent such as, but not limited to, N,N-dimethylformamide, generates a diazonium intermediate that can be converted into compound (121) by quenching the above reaction mixture with acetyl sulfide. Hydrolysis of the thioester compound (121) in the presence of a base such as, but not limited to, sodium hydroxide, produces a thiol intermediate that can be converted into the desired sulfide product (122) (formula (I), W=—S—) with an appropriate R2X in the presence of a base such as, but not limited to, sodium hydride in a solvent such as, but not limited to, tetrahydrofuran, 1,4-dioxane or N,N-dimethylformamide. Treatment of compound (122) with an oxidizing agent such as, but not limited to, sodium periodate in a mixture of methanol and water affords the sulfoxide compound (110) (formula (I), W=—S(O)—). Alternatively, the sulfide compound (122) can be treated with trifluoro acetic anhydride and hydrogen peroxide in a solvent such as, but not limited to, dichloromethane to give the sulfone product (111) (formula (I), W=—S(O)2—). Preparation 1 15 SYNTHESIS OF [4-(6-CHLOROPYRIDAZIN-3-YL)PIPERAZIN-1-YL](2-TRIFLUOROMETHYLPHENYL)METHANONE A. To a stirred solution of 1-Boc-piperazine (1.96 g, 10.5 mmol) in dichloromethane (50 mL) was added 2-trifluoromethylbenzoyl chloride (2.09 g, 10.0 mmol) as a dichloromethane solution in the presence of triethylamine (3 mL) at 0° C. The resulting mixture was stirred at ambient temperature for 18 hours and then quenched with water (25 mL). The organic phase was washed with water, saturated NaCl, dried over MgSO4 and then concentrated in vacuo to afford the desired product as a pall yellow solid used for next step reaction without further purification. B. A solution of the compound obtained above (10 mmol) in 50 mL of a 1:4 mixture of trifluoroacetic acid and dichloromethane was stirred at ambient temperature for 5 h. After concentration in vacuo the residue was dissolved in dichloromethane (100 mL) and washed sequentially with 1 N NaOH (10 mL), water, saturated NaCl, and then dried over MgSO4, filtered and concentrated in vacuo to yield piperazin-1-yl-(2-trifluoromethylphenyl)methanone as a light yellow oil. This oil was converted into HCl salt by the addition of 10 mL of 2 N HCl in ether and 100 mL of anhydrous ether to the solution of the compound in 10 mL of dichloromethane. The white solid formed was filtered and dried to yield the HCl salt. C. A mixture of 3,6-dichloropyridazine (0.25 g, 1.678 mmol), piperazin-1-yl-(2-trifluoromethylphenyl)methanone (1.483 g, 5.034 mmol) obtained above, water (0.85 mL) and hydrochloric acid (37%, 0.035 mL) was heated to 80-100° C. for 36 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, diluted with water. The pH of the mixture was brought to pH 11 with 2 N NaOH solution and the mixture was then extracted with diethyl ether (3×15 mL). The organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography to yield a white solid (0.236 g, 38% yield). EXAMPLE 1 SYNTHESIS OF {4-[6-(METHYLPHENETHYLAMINO)PYRIDAZIN-3-YL]PIPERAZIN-1-YL}-(2-TRIFLUOROMETHYLPHENYL)METHANONE A mixture of [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.072 g, 0.194 mmol), N-methyl-2-phenylethylamine (0.052 g, 0.388 mmol), ammonium chloride (0.01 g, 0.194 mmol) in n-butanol (4 mL) was refluxed for 48 hours. The reaction mixture was cooled to room temperature, then added 10% potassium carbonate solution, and extracted with ethyl acetate. The organic extract was dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (10 mg, 11% yield). 1H NMR (400 MHz, CDCl3) δ 7.73, 7.61-7.64, 7.53-7.56, 7.36, 7.26-7.29, 7.19-7.21, 6.91, 6.75, 3.95, 3.75, 3.30-3.50, 0.92. MS (ES+) m/z 470.3 (M+1). Example 1.1 SYNTHESIS OF [4-(6-PHENETHYLAMINOPYRIDAZIN-3-YL)PIPERAZIN-1-YL]-(2-TRIFLUOROMETHYLPHENYL)METHANONE Following the procedure set forth above in Example 1, only making variations using 2-phenylethylamine to replace N-methyl-2-phenylethylamine to react with [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (11.8 mg, 15% yield). 1H NMR (CDCl3, 400 MHz) δ 7.74, 7.62-7.68, 7.52-7.57, 7.33-7.37, 7.28-7.32, 7.40-7.46, 6.83, 6.18, 3.95, 3.68-3.70, 3.30-3.50, 2.96. MS (ES+) m/z 456.4 (M+1). EXAMPLE 2 SYNTHESIS OF PROPANE-1-SULFONIC ACID {6-[4-(2-TRIFLUOROMETHYLBENZOYL)PIPERAZIN-1-YL]PYRIDAZIN-3-YL}AMIDE To a mixture of [4-(6-amino pyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (0.10 g, 0.285 mmol) and triethyl amine (0.037 g, 0.371 mmol) in 10 mL of dichloromethane at 0° C. was added n-propylsulphonyl chloride (0.044 g, 0.313 mmol). The reaction mixture was stirred at room temperature for 4 hours and then dilute hydrochloric acid solution was added (20 mL). The mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulphate, the concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (46.3 mg, 35.5% yield). 1H NMR (400 MHz, CDCl3) δ 7.75, 7.63-7.66, 7.56-7.59, 7.37, 7.25, 6.99, 4.04-4.07, 3.85-3.89, 3.71-3.78, 3.35, 1.96-2.00, 1.1. EXAMPLE 3 SYNTHESIS OF {4-[6-(2-PHENYLETHANESULFONYL)PYRIDAZIN-3-YL]PIPERAZIN-1-YL}-(2-TRIFLUOROMETHYL-PHENYL)METHANONE A mixture of m-CPBA (0.044 g, 0.26 mmol) and [4-(6-phenethylsulfanylpyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone in 2.5 mL of dichloromethane was stirred at room temperature over night. The reaction mixture was washed with 1N NaOH solution, extracted with dichloromethane. The residue obtained after removal of solvent was purified by column chromatography to yield the title compound as a white solid (21 mg, 16.2% yield). 1H NMR (400 MHz, CDCl3) δ 7.83, 7.76, 7.64-7.66, 7.57-7.59, 7.38, 7.23-7.25, 7.215-7.20, 6.94, 4.07-4.10, 3.74-3.93, 3.30-3.40, 3.12-3.15. EXAMPLE 4 SYNTHESIS OF {4-[6-(2-PHENYLETHANESULFINYL)PYRIDAZIN-3-YL]PIPERAZIN-1-YL}-(2-TRIFLUOROMETHYLPHENYL)METHANONE To an ice-cold solution of sodium periodate (0.025 g, 0.12 mmol) in 1:1 mixture of water and methanol was added [4-(6-phenethylsulfanylpyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone. The reaction mixture was stirred at room temperature over night, diluted with water and then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous MgSO4 and then concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (41 mg, 69.2%). 1H NMR (400 MHz, CDCl3) δ 7.86, 7.75, 7.63-7.66, 7.56-7.59, 7.37, 7.25-7.28, 7.21-7.17, 7.07-7.09, 4.04-4.10, 3.83-3.91, 3.70-3.80, 3.45-3.35, 3.26-3.30, 3.2-3.15. EXAMPLE 5 SYNTHESIS OF [4-(6-PHENETHYLOXYPYRIDAZIN-3-YL)PIPERAZIN-1-YL]-(2-TRIFLUOROMETHYL-PHENYL)METHANONE A mixture of [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.075 g, 0.202 mmol), 2-phenylethanol (0.025 g, 0.202 mmol) and sodium hydride (0.010 g) in 5 mL of toluene was stirred at room temperature for 1 hour, and then refluxed overnight. The reaction mixture was cooled to room temperature, added 20 mL of water, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid (58 mg, 62.9%). 1H NMR (400 MHz, CDCl3) δ 7.73, 7.61-7.64, 7.53-7.56, 7.36, 7.22-7.30, 7.20-7.24, 7.02, 6.86, 4.64, 3.91-3.98, 3.57, 3.48-3.52, 3.32, 3.11. Example 5.1 SYNTHESIS OF {4-[6-(2-CYCLOPROPYLETHOXY)PYRIDAZIN-3-YL]PIPERAZIN-1-YL}-(2-TRIFLUOROMETHYLPHENYL)METHANONE Following the procedure set forth above in Example 5, only making variations using 2-cyclopropylethanol to replace 2-phenylethanol to react with [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (56 mg, 74.8% yield). 1H NMR (400 MHz, CDCl3) δ 7.72, 7.60-7.63, 7.52-7.56, 7.35, 7.03, 6.87, 4.46, 3.91-3.98, 3.55, 3.46-3.50, 3.31, 1.68, 0.79-0.84, 0.43-0.46, 0.11-−0.79. EXAMPLE 6 SYNTHESIS OF [4-(6-PHENETHYLSULFANYLPYRIDAZIN-3-YL)PIPERAZIN-1-YL](2-TRIFLUOROMETHYLPHENYL)METHANONE A mixture of [4-(6-chloro pyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)-methanone (0.089 g, 0.240 mmol), 2-phenylethanethiol (0.049 g, 0.36 mmol) and sodium hydroxide (9.6 mg) in 5 mL 1,4-dioxane was heated at 100-110° C. overnight. The reaction mixture was cooled to room temperature, diluted with 20 mL of water, and then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulphate, then concentrated in vacuo. The residue was pirified by column chromatography to yield the title compound as a white solid (50 mg, 43.7% yield). 1H NMR (400 MHz, CDCl3) δ 7.65, 7.52-7.55, 7.47-7.48, 7.27, 7.12-7.22, 7.03, 6.76, 3.89-3.94, 3.79-3.84, 3.54-3.61, 3.49-3.51, 3.45, 3.17-3.25, 2.97. Example 6.1 SYNTHESIS OF {4-[6-(3-METHYLBUTYLSULFANYL)PYRIDAZIN-3-YL]PIPERAZIN-1-YL}-(2-TRIFLUOROMETHYL-PHENYL)METHANONE Following the procedure set forth above in Example 6, only making variations using 3-methylbutane-1-thiol to replace 2-phenylethanethiol to react with [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (24.3 mg, 26.4% yield). 1H NMR (400 MHz, CDCl3) δ 8.04, 7.98, 6.99, 3.79, 3.56, 3.45-3.47, 3.40, 1.85-1.87, 1.52, 0.72-0.80, 0.46-0.48, 0.09-0.10. EXAMPLE 7 Measuring Stearoyl-CoA Desaturase Inhibition Activity of a Test Compound Using Mouse Liver Microsomes The identification of compounds of the invention as SCD inhibitors was readily accomplished using the SCD enzymes and microsomal assay procedure described in Brownlie et al, PCT published patent application, WO 01/62954. Preparation of Mouse Liver Microsomes: Male ICR mice, on a high-carbohydrate, low fat diet, under light halothane (15% in mineral oil) anesthesia are sacrificed by exsanguination during periods of high enzyme activity. Livers are immediately rinsed with cold 0.9% NaCl solution, weighed and minced with scissors. All procedures are performed at 4° C. unless specified otherwise. Livers are homogenized in a solution (1:3 w/v) containing 0.25 M sucrose, 62 mM potassium phosphate buffer (pH 7.0), 0.15 M KCl, 1.5 mM N-acetyleysteine, 5 mM MgCl2, and 0.1 mM EDTA using 4 strokes of a Potter-Elvehjem tissue homogenizer. The homogenate is centrifuged at 10,400×g for 20 min to eliminate mitochondria and cellular debris. The supernatant is filtered through a 3-layer cheesecloth and centrifuged at 105,000×g for 60 min. The microsomal pellet is gently resuspended in the same homogenization solution with a small glass/teflon homogenizer and stored at −70° C. The absence of mitochondrial contamination is enzymatically assessed. The protein concentration is measured using bovine serum albumin as the standard. Incubation of Mouse Liver Microsomes with Test Compounds: Reactions are started by adding 2 mg of microsomal protein to pre-incubated tubes containing 0.20 μCi of the substrate fatty acid (1-14C palmitic acid) at a final concentration of 33.3 μM in 1.5 ml of homogenization solution, containing 42 mM NaF, 0.33 mM niacinamide, 1.6 mM ATP, 1.0 mM NADH, 0.1 mM coenzyme A and a 10 μM concentration of test compound. The tubes are vortexed vigorously and after 15 min incubation in a shaking water bath (37° C.), the reactions are stopped and fatty acids are analyzed. Fatty acids are analyzed as follows: The reaction mixture is saponified with 10% KOH to obtain free fatty acids which are further methylated using BF3 in methanol. The fatty acid methyl esters are analyzed by high performance liquid chromatography (HPLC) using a Hewlett Packard 1090, Series II chromatograph equipped with a diode array detector set at 205 nm, a radioisotope detector (Model 171, Beckman, CA) with a solid scintillation cartridge (97% efficiency for 14C-detection) and a reverse-phase ODS (C-18) Beckman column (250 mm×4.6 mm i.d.; 5 μm particle size) attached to a pre-column with a μBondapak C-18 (Beckman) insert. Fatty acid methyl esters are separated isocratically with acetonitrile/water (95:5 v:v) at a flow rate of 1 mL/min and are identified by comparison with authentic standards. Alternatively, fatty acid methyl esters may be analyzed by capillary column gas-chromatography (GC) or Thin Layer Chromatography (TLC). Those skilled in the art are aware of a variety of modifications to this assay that can be useful for measuring inhibition of stearoyl-CoA desaturase activity in microsomes by test compounds. Representative compounds of the invention showed activity as inhibitors of SCD when tested in this assay. The activity was defined in terms of % SCD enzyme activity remaining at the desired concentration of the test compound. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

<SOH> BACKGROUND OF THE INVENTION <EOH>Acyl desaturase enzymes catalyze the formation of double bonds in fatty acids derived from either dietary sources or de novo synthesis in the liver. Mammals synthesize at least three fatty acid desaturases of differing chain length specificity that catalyze the addition of double bonds at the delta-9, delta-6, and delta-5 positions. Stearoyl-CoA desaturases (SCDs) introduce a double bond in the C9-C10 position of saturated fatty acids. The preferred substrates are palmitoyl-CoA (16:0) and stearoyl-CoA (18:0), which are converted to palmitoleoyl-CoA (16:1) and oleoyl-CoA (18:1), respectively. The resulting mono-unsaturated fatty acids are substrates for incorporation into phospholipids, triglycerides, and cholesteryl esters. A number of mammalian SCD genes have been cloned. For example, two genes have been cloned from rat (SCD1, SCD2) and four SCD genes have been isolated from mouse (SCD1, 2, 3, and 4). While the basic biochemical role of SCD has been known in rats and mice since the 1970's (Jeffcoat, R. et al., Elsevier Science (1984), Vol. 4, pp. 85-112; de Antueno, R J, Lipids (1993), Vol. 28, No. 4, pp. 285-290), it has only recently been directly implicated in human disease processes. A single SCD gene, SCD1, has been characterized in humans. SCD1 is described in Brownlie et al, PCT published patent application, WO 01/62954, the disclosure of which is hereby incorporated by reference in its entirety. A second human SCD isoform has recently been identified, and because it bears little sequence homology to alternate mouse or rat isoforms it has been named human SCD5 or hSCD5 (PCT published patent application, WO 02/26944, incorporated herein by reference in its entirety). To date, no small-molecule, drug-like compounds are known that specifically inhibit or modulate SCD activity. Certain long-chain hydrocarbons have been used historically to study SCD activity. Known examples include thia-fatty acids, cyclopropenoid fatty acids, and certain conjugated linoleic acid isomers. Specifically, cis-12, trans-10 conjugated linoleic acid is believed to inhibit SCD enzyme activity and reduce the abundance of SCD1 mRNA while cis-9, trans-11 conjugated linoleic acid does not. Cyclopropenoid fatty acids, such as those found in stercula and cotton seeds, are also known to inhibit SCD activity. For example, sterculic acid (8-(2-octylcyclopropenyl)octanoic acid) and malvalic acid (7-(2-octylcyclopropenyl)heptanoic acid) are C18 and C16 derivatives of sterculoyl and malvaloyl fatty acids, respectively, having cyclopropene rings at their C9-C10 position. These agents are believed to inhibit SCD enzymatic activity by direct interaction with the enzyme, thus inhibiting delta-9 desaturation. Other agents that may inhibit SCD activity include thia-fatty acids, such as 9-thiastearic acid (also called 8-nonylthiooctanoic acid) and other fatty acids with a sulfoxy moiety. These known modulators of delta-9 desaturase activity are not useful for treating the diseases and disorders linked to SCD1 biological activity. None of the known SCD inhibitor compounds are selective for SCD or delta-9 desaturases, as they also inhibit other desaturases and enzymes. The thia-fatty acids, conjugated linoleic acids and cyclopropene fatty acids (malvalic acid and sterculic acid) are neither useful at reasonable physiological doses, nor are they specific inhibitors of SCD1 biological activity, rather they demonstrate cross inhibition of other desaturases, in particular the delta-5 and delta-6 desaturases by the cyclopropene fatty acids. The absence of small molecule inhibitors of SCD enzyme activity is a major scientific and medical disappointment because evidence is now compelling that SCD activity is directly implicated in common human disease processes: See e.g., Attie, A. D. et al., “Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia”, J. Lipid Res . (2002), Vol. 43, No. 11, pp. 1899-907; Cohen, P. et al., “Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss”, Science (2002), Vol. 297, No. 5579, pp. 240-3, Ntambi, J. M. et al., “Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity”, Proc. Natl. Acad. Sci. USA . (2002), Vol. 99, No. 7, pp. 11482-6. The present invention solves this problem by presenting new classes of compounds that are useful in modulating SCD activity and regulating lipid levels, especially plasma lipid levels, and which are useful in the treatment of SCD-mediated diseases such as diseases related to dyslipidemia and disorders of lipid metabolism, especially diseases related to elevated lipid levels, cardiovascular disease, diabetes, obesity, metabolic syndrome and the like. Related Literature PCT Published Patent Applications, WO 03/075929, WO 03/076400 and WO 03/076401 disclose compounds having histone deacetylase inhibiting enzymatic activity.

<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>The present invention provides pyridazine derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed. Accordingly, in one aspect, the invention provides methods of inhibiting human stearoyl-CoA desaturase (hSCD) activity comprising contacting a source of hSCD with a compound of formula (I): wherein: x and y are each independently 1, 2 or 3; W is —O—, —C(O)O—, —N(R 1 )—, —S(O) t — (where t is 0, 1 or 2), —N(R 1 )S(O) 2 —, —OC(O)— or —C(O)—; V is —C(O_—, —C(S)—, —C(O)N(R 1 )—, —C(O)O—, —S(O) 2 —, —S(O) 2 N(R 1 )— or —C(R 11 )H—; each R 1 is independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl and C 7 -C 19 aralkyl; R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl; or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 13 ) 2 ; R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a together, or R 6 and R 6a together are an oxo group, provided that when V is —C(O)—, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 6 and R 6a are each independently selected from hydrogen or C 1 -C 3 alkyl; or one of R 6 , R 6a , R 7 , and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; R 11 is hydrogen or C 1 -C 3 alkyl; and each R 13 is independently selected from hydrogen or C 1 -C 6 alkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof. In another aspect, this invention provides methods of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I) as set forth above. In another aspect, this invention provides compounds of formula (I) having the following formula (Ia) wherein: x and y are each independently 1, 2 or 3; W is —O—, —C(O)O—, —N(R 1 )—, —S(O) t — (where t is 0, 1 or 2), —N(R 1 )S(O) 2 —, —OC(O)— or —C(O)—; V is —C(O), —C(S)—, —C(O)N(R 1 )—, —C(O)O—, —S(O) 2 —, —S(O) 2 N(R 1 )— or —C(R 11 )H—; each R 1 is independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl and C 7 -C 19 aralkyl; R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl, provided that, when W is —C(O)—, R 2 can not be C 1 -C 6 alkyl substituted by —S(O) t R 14 where R 14 is hydrogen, C 1 -C 6 alkyl, C 7 -C 12 aralkyl, pyrazinyl, pyridinonyl, pyrrolidionyl or imidazolyl; or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other; R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl; or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or, all of the rings may be fused to each other; R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 13 ) 2 ; R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a together, or R 6 and R 6a together are an oxo group, provided that when V is —C(O)—, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 6 and R 6a are each independently selected from hydrogen or C 1 -C 3 alkyl; or one of R 6 , R 6a , R 7 , and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; R 11 is hydrogen or C 1 -C 3 alkyl; and each R 13 is independently selected from hydrogen or C 1 -C 6 alkyl; a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof. In another aspect, the invention provides methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, wherein the methods comprise administering to the mammal in need thereof a therapeutically effective amount of a compound of the invention as set forth above. In another aspect, the invention provides compounds or pharmaceutical compositions useful in treating, preventing and/or diagnosing a disease or condition relating to SCD biological activity such as the diseases encompassed by cardiovascular disorders and/or metabolic syndrome (including dyslipidemia, insulin resistance and obesity). In another aspect, the invention provides methods of preventing or treating a disease or condition related to elevated lipid levels, such as plasma lipid levels, especially elevated triglyceride or cholesterol levels, in a patient afflicted with such elevated levels, comprising administering to said patient a therapeutically or prophylactically effective amount of a composition as disclosed herein. The present invention also relates to novel compounds having therapeutic ability to reduce lipid levels in an animal, especially triglyceride and cholesterol levels. In another aspect, the invention provides pharmaceutical compositions comprising the compounds of the invention as set forth above, and pharmaceutically acceptable excipients. In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the invention in a pharmaceutically acceptable carrier and in an amount effective to modulate triglyceride level, or to treat diseases related to dyslipidemia and disorders of lipid metabolism, when administered to an animal, preferably a mammal, most preferably a human patient. In an embodiment of such composition, the patient has an elevated lipid level, such as elevated plasma triglycerides or cholesterol, before administration of said compound and said compound is present in an amount effective to reduce said lipid level. In another aspect, the invention provides methods for treating a patient for, or protecting a patient from developing, a disease or condition mediated by stearoyl-CoA desaturase (SCD), which methods comprise administering to a patient afflicted with such disease or condition, or at risk of developing such disease or condition, a therapeutically effective amount of a compound that inhibits activity of SCD in a patient when administered thereto. In another aspect, the invention provides methods for treating a range of diseases involving lipid metabolism utilizing compounds identified by the methods disclosed herein. In accordance therewith, there is disclosed herein a range of compounds having said activity, based on a screening assay for identifying, from a library of test compounds, a therapeutic agent which modulates the biological activity of said SCD and is useful in treating a human disorder or condition relating to serum levels of lipids, such as triglycerides, VLDL, HDL, LDL, and/or total cholesterol. detailed-description description="Detailed Description" end="lead"?

20060130

20090407

20060914

65153.0

A61K31551

JAISLE, CECILIA M

PYRIDAZINE DERIVATIVES AND THEIR USE AS THERAPEUTIC AGENTS

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Communication System and Method of Operating the Communicating System

A communication system, for example UMTS (Universal Mobile Telecommunication System), comprises a base station and a plurality of mobile stations. In normal operation the mobile station continuously makes uplink transmissions on certain spread spectrum channels (DPDCH, DPCCH). The maximum allowed power (Pmax) for these uplink transmissions is specified. However there are occasions when for example receiving packet data from the base station, the receiving mobile station has to transmit an acknowledgement (ACK) or a Non-acknowledgement (NACK) at a power level specified by the base station. In order to keep the transmit power of the mobile station within the maximum allowed power, the total power required to transmit an ACK or NACK in parallel with the continuous uplink signals is determined and if this exceeds Pmax then at least the power DPDCH and DPCCH channels are scaled to allow sufficient power for the transmission of an ACK or NACK. The power scaling is carried-out based on the power required for whichever one of ACK or NACK requires the most power. This avoids reducing the amount of time available to a mobile whether an ACK or NACK should be transmitted.

1. A method of operating a communication system comprising a first station (BS) and a second station (MS), the first and second stations each having transceiving means (12, 38), the second station transmitting a first signal (DPCCH) to the first station, the power of the transmitted first signal not exceeding a predetermined maximum level (Pmax), wherein in response to the second station wishing to transmit any one of a set of possible additional signals, the transmit power of the first signal is scaled by an amount which takes into account the greater (or greatest) power requirement of all of the set of the possible additional signals to be transmitted subsequently. 2. A method as claimed in claim 1, characterised in that the set of the possible additional signals comprise a positive acknowledgement signal (ACK) and a negative acknowledgement signal (NACK), in that one of the ACK and NACK is transmitted at a mutually different power level than the other, and in that the scaling in the transmitted power of the first signal assumes that the higher power one of the ACK or NACK is to be transmitted. 3. A method as claimed in claim 1, wherein the first signal is transmitted in first frames or time slots and the additional signals are transmitted in second frames or time slots, wherein the boundaries between the first frames or time slots are not coincident with the boundaries between the second frames or time slots, characterised in that the transmit power of the first signal is scaled at the frame or time slot boundary immediately preceding the transmission of the additional signal. 4. A method as claimed in claim 1, characterised by the second station transmitting the first signals substantially continuously in successive first frames or time slots, by the first station transmitting to the second station a data packet requiring a response consisting of at least a selected one of the set of possible additional signals, in that the first station requires the response to be transmitted in a second frame or time slot whose boundaries are different from the boundaries of the first frames or time slots, and in that the power level of at least the first signal is scaled at the boundary of the first frame or time slot immediately preceding the occurrence of the second time slot. 5. A method as claimed in claim 1, characterised in that the second station determines if the combined power requirement of the first signal and all of the set of possible additional signals exceeds the predetermined maximum level, and, if so, it scales the power requirement of the first signal. 6. A method as claimed in claim 1, characterised in that the scaling results in a power reduction. 7. A method as claimed in claim 1 characterised in that in response to the scaling occurring coincidentally with a requirement to increase the power of the first signal, the scaling results in a smaller increase than the requirement. 8. A method as claimed in claim 7, characterised in that the requirement to increase power is due to a regular power control process. 9. A method as claimed in claim 8, characterised in that the regular power control process is a closed loop process and in that the second station receives commands to change power from the first station. 10. A method as claimed in claim 7, characterised in that the requirement to increase power is due at least in part to a change in parameters or in format of a data signal transmitted from the second station. 11. A method as claimed in claim 1, characterised in that the first signal and the possible additional signals are transmitted as spread spectrum signals. 12. A communication system comprising a first station (BS) and a second station (MS), the first station and second stations having transceiving means (12, 38), the second station having power control means (34) for controlling the transmitted power level of a first signal (DPCCH) to be transmitted to the first station, wherein the power control means is adapted, in response to determining that the second station wishes to transmit any one of a set of possible additional signals simultaneously with the first signals, to scale the transmit power of the first signal by an amount which takes into account the greater (or greatest) power requirement of all of the set of the possible additional signals to be transmitted subsequently. 13. A system as claimed in claim 12, characterised by the second station having power scaling means (36) which is adapted, in response to the power control means determining that the combined power requirement of the first signal and the set of possible additional signals exceeding the predetermined maximum level, to scale the power requirements of the first signal. 14. A system as claimed in claim 12, characterised in that the power scaling means is adapted, in response to the scaling occurring coincidentally with a requirement to increase the power of the first signal, to effect a smaller increase in the scaling than the requirement. 15. A system as claimed in claim 14, characterised by power control means in the first station for effecting a closed loop power control process with the second station and by means in the first station for generating commands instructing the second station to change power. 16. A system as claimed in claim 15, characterised in that power control means in the first station is adapted to generate a command to increase power due at least in part to a change in parameters or in format of a data signal transmitted from the second station. 17. A system as claimed in claim 12 characterised in that the transceiving means are spread spectrum transceiving means. 18. A second station (MS) for use in a communication system comprising a first station and a second station, the second station including transceiving means (38) for communication with the first station, and power control means (34) for controlling the transmitted power level of a first signal (DPCCH) to be transmitted to the first station, wherein the power control means is adapted, in response to determining that the second station wishes to transmit any one of a set of possible additional signals (ACK or NACK) simultaneously with the first signals, to scale the transmit power of the first signal by an amount which takes into account the greater (or greatest) power requirement of all of the set of the possible additional signals to be transmitted subsequently. 19. A second station as claimed in claim 18, characterised by power scaling means (36) which is adapted, in response to the power control means determining that the combined power requirement of the first signal and the set of possible additional signals exceeding the predetermined maximum level, to scale the power requirements of the first signal. 20. A second station as claimed in claim 19, characterised in that the power scaling means is adapted, in response to the scaling occurring coincidentally with a requirement to increase the power of the first signal, to effect a smaller increase in the scaling than the requirement. 21. A second station as claimed in claim 20, characterised in that power control means in the second station is responsive to commands generated by the first station for effecting a change in power. 22. A second station as claimed in claim 18, characterised in that the transceiving means is a spread spectrum transceiving means.

The present invention relates to a communication system, to a station for use in a communication system, and to a method of operating a communication system. The present invention has particular, but not exclusive, application to spread spectrum systems such as UMTS (Universal Mobile Telecommunication System). Terminals in mobile communication systems usually have a maximum transmit power limit, which may be set by physical constraints or in response to an instruction received from a controller. In a communication system while a terminal is transmitting a first signal, it is sometimes necessary to transmit simultaneously additional signals which would require the terminal's maximum transmit power limit to be exceeded. In such cases, a variety of approaches may be taken, including reducing the transmit power of the first signal in order to allow sufficient power for the additional signal(s) to be transmitted without breaching the maximum power limit or switching-off part or all of the first signal in order to allow the additional signal(s) to be transmitted. In some systems, it is only possible to execute the reduction in transmit power of the first signal at particular time instants, such as a frame- or timeslot-boundary. These time instants may not correspond to the times at which the transmission of the additional signal(s) must commence. A method of overcoming this problem is to execute a reduction in transmit power in advance of the transmission of the additional signal(s). In such situations, the exact nature of the additional signal(s) may not yet be known at the time when the reduction in transmit power of the first signal has to be executed because, for example, there is insufficient time for the terminal to evaluate a critical feature, such as a CRC (cyclic redundancy check) in a received signal. Different types of additional signal may have different transmit power requirements. An object of the present invention is to be able to transmit an additional signal in a timely manner whilst not exceeding a predetermined maximum power limit. According to a first aspect of the present invention there is provided a method of operating a communication system comprising a first station and a second station, the first and second stations each having transceiving means, the second station transmitting a first signal to the first station, the power of the transmitted first signal not exceeding a predetermined maximum level, wherein in response to the second station wishing to transmit any one of a set of possible additional signals, the transmit power of the first signal is scaled by an amount which takes into account the greater (or greatest) power requirement of all of the set of the possible additional signals to be transmitted subsequently. According to a second aspect of the present invention there is provided a communication system comprising a first station and a second station, the first station and second stations having transceiving means, the second station having power control means for controlling the transmitted power level of a first signal to be transmitted to the first station, wherein the power control means is adapted, in response to determining that the second station wishes to transmit any one of a set of possible additional signals simultaneously with the first signals, to scale the transmit power of the first signal by an amount which takes into account the greater (or greatest) power requirement of all of the set of the possible additional signals to be transmitted subsequently. According to a third aspect of the present invention there is provided a second station for use in a communication system comprising a first station and a second station, the second station including transceiving means for communication with the first station, and power control means for controlling the transmitted power level of a first signal to be transmitted to the first station, wherein the power control means is adapted, in response to determining that the second station wishes to transmit any one of a set of possible additional signals simultaneously with the first signals, to scale the transmit power of the first signal by an amount which takes into account the greater (or greatest) power requirement of all of the set of the possible additional signals to be transmitted subsequently. The method in accordance with the present invention avoids setting a requirement on the terminal to make an earlier decision about which type of additional signal is to be transmitted, or to make a reduction in power of the first signal at some time other than the most convenient or required instant. The present invention will now be described, by way of example, with reference to the accompanying drawings, wherein: FIG. 1 is a block schematic diagram of an UMTS communication system, FIG. 2 is a simplified block schematic diagram illustrating the downlink and uplink signals, FIG. 3 is a timing diagram showing individually the uplink signals, FIG. 4 is a timing diagram showing the combination of the uplink signals, and FIG. 5 is a flow chart illustrating an embodiment of the method in accordance with the present invention. In the drawings the same reference numbers have been used to indicate corresponding features. The UMTS communication system comprises at least one base station BS and a plurality of mobile stations MS, one of which is shown in FIG. 1. The mobile stations are able to roam within the radio coverage of the base station(s) and maintain radio communication by way of spread spectrum signalling on downlinks from the base station(s) and uplinks from the mobile stations. As is customary with spread spectrum signalling several signals can be transmitted simultaneously each signal having its own signature or spreading code selected from a set of signatures. Additionally power control has to be effected to prevent weaker signals being swamped by more powerful signals. Accordingly a base station can specify the maximum power at which a mobile station can transmit on the uplink. Referring to FIG. 1, the base station BS is controlled by a controller 10 which carries out the many functions involved in the maintenance of the system and the sending and receiving of signals. A transceiver 12 is coupled to an antenna 14 for the transmission and reception of spread spectrum signals. An external source of data 16 is coupled to a base band stage 18 in which data is formatted into packets. The data packets are prepared for transmission by multiplying them in a multiplier 20 with a signature, for example a pseudo random code, obtained from a code store 22 under the control of the controller 10. The spread spectrum signal is passed to the transceiver for modulation and transmission. In the case of a signal received at the antenna it is demodulated and despread by multiplying the demodulated signal with the appropriate signature. Thereafter the despread signal is passed to the base band stage 18. The mobile station MS is controlled by a controller 30 which carries out the many functions involved in the operation of the mobile station, including the sending and receiving of signals. For convenience of illustration and to facilitate an understanding of the present invention the controller 30 is shown as comprising a microprocessor 32, a transmit power controller 34 and a power scaler 36. A transceiver 38 is coupled to an antenna 40 for the transmission and reception of spread spectrum signals from the base station BS. A man/machine interface 42, which includes a base band data formatting and deformatting stage, means for inputting data and means for outputting data, is coupled to a multiplier 44 to which is supplied a signature, for example a pseudo random code, obtained from a code store 46 under the control of the microprocessor 32. A signal to be transmitted on the uplink is spread and is passed to the transceiver 38 for modulation and transmission. In the case of a downlink signal received at the antenna 40 it is demodulated and despread by multiplying the demodulated signal with the appropriate signature. Thereafter the despread signal is passed to the man/machine interface 42. In the case of UMTS the operating standard requires each mobile station to transmit spread spectrum uplink signals substantially continuously. These signals are formatted into successive frames or time slots whose duration is specified by the system. Two signals are often transmitted continuously and these are a dedicated physical data channel DPDCH and dedicated physical control channel DPCCH, these signals are shown in FIG. 1. Only DPCCH is transmitted when there is no data. The relative transmission power levels PD and PC of the DPDCH and DPCCH channels are regulated so as to maintain a fixed power ratio for a given data type and their combined powers are controlled so as not to exceed an allowable maximum power level Pmax. Further while maintaining the fixed power ratio, the power level PC of the DPCCH is adjusted periodically by a closed-loop power control mechanism. Referring to FIG. 2, which is a simplified version of FIG. 1, from time to time the base station BS uses the downlink to transmit packet data to an identified mobile station using High-Speed Downlink Packet Access HSDPA. Under the UMTS standard, the mobile station MS must transmit a positive (ACK) or negative (NACK) acknowledgement for each HSDPA packet received, depending for example on the outcome of a cyclic redundancy check (CRC) evaluation. Referring to FIG. 3 the ACKs and NACKs are transmitted as spread spectrum signals on a so-called High-Speed Dedicated Physical Control Channel (HS-DPCCH), whose time slots are not aligned with the time slots on the other uplink channels carrying the continuous uplink signals DPDCH and DPCCH. The relative transmit powers of the ACKs and NACKs are different and the respective transmit powers are determined by the base station BS and notified to the mobile station MS. If the transmission of an ACK or NACK in parallel with the continuous uplink signals would require more transmit power than is allowed, the transmit power must be reduced. If the adjustment of the respective signal powers is delayed until the CRC in the HSDPA packet is evaluated, in the case of a large packet it would be difficult, if not impossible, to make the adjustment at a DPCCH slot boundary as specified in the UMTS standard. To avoid this problem the method in accordance with the present invention causes the transmit power of the other uplink channels, that is, the DPDCH and DPCCH, to be reduced at the timeslot boundary immediately preceding the start of the ACK or NACK transmission. However, as mentioned above, the transmit power for ACKs is required to be different from the transmit power for NACKS. Consequently, if the mobile station MS was to know by how much to reduce the power of the continuous signals DPDCH and DPCCH in time for the slot boundary prior to the start of the ACK or NACK transmission, it would need to complete the CRC evaluation process more quickly than the time allowed by the timing of the ACK/NACK transmission. Since this is not possible, the mobile station MS reduces the transmit power at the time slot prior to the start of the ACK/NACK transmission by an amount corresponding to whichever of ACK or NACK has the higher power requirement PA or PN, respectively. In this way, the mobile station MS can ensure that enough transmit power is available for the ACK/NACK transmission regardless of the final outcome of the CRC evaluation process. The principle is illustrated in FIGS. 3 and 4. In FIG. 3 the mobile station MS is initially transmitting at its maximum allowed power, Pmax=PC1+PD1. Suppose that PA is defined to be 2PC and PN is defined to be equal to PC. Then the powers of the DPDCH and DPCCH must be reduced to PD2 and PC2, respectively, such that PC2+PD2+PA=Pmax That is, PC2+PD2+2PC2=Pmax. The power ratio between the control and data channels is maintained, such that PD2/PC2=PD1/PC1. Thus   P C   2 = P C   1 + P D   1 - P A 1 + P D   1 / P C   1   or   P C   2 = P C   1 + P D   1 3 + P D   1 / P C   1 and   P D   2 = P C   1 + P D   1 - P A 1 + P C   1 / P D   1    or   P D   2 = P C   1 + P D   1 1 + 3   P C   1 / P D   1 .  In FIG. 4 the broken horizontal line illustrates the maximum allowed transmit power Pmax. When there is not ACK or NACK to be transmitted then the combined maximum amplitudes of PD1 and PC1 equal Pmax. However at the boundary of the frame or time slot immediately preceding the sending of an ACK or NACK, these amplitudes are adjusted by for example reducing DPCCH whilst maintaining the power ratio PD/PC constant. Thus capacity is left for the transmission of the higher power one of ACK or NACK, even though the lower power one may be transmitted thereby making the combined transmit power lower than Pmax. The flow chart shown in FIG. 5 summarises the operations carried out by the secondary station in implementing the method in accordance with the present invention. Block 50 relates to the mobile station MS continuously transmitting the DPDCH and DPCCH signals at a combined transmit power level equal to or less than the maximum allowable power level Pmax. Block 52 relates to the mobile station receiving packet data in a downlink HSDPA packet data signal. Block 54 denotes the mobile station determining the power levels for the ACK or NACK signal and the greater one of the two levels. Block 56 denotes checking if Pmax would be exceeded by an uplink signal comprising DPDCH, DPCCH and the higher power of the ACK or NACK signals. If the answer is yes (Y) then in block 58 the scaling stage 36 (FIG. 1) of the mobile station scales the power of at least the DPCCH channel so that Pmax will not be exceeded. The flow chart proceeds to block 60. If the answer in the block 56 is no (N) the flow chart proceeds to the block 60. The block 60 denotes the power control stage 34 (FIG. 1) of the mobile station reducing the power of the DPDCH and DPCCH channels at the frame or time slot boundary preceding the transmission of the ACK or NACK. Block 62 relates to the mobile station MS transmitting the ACK or NACK. When implementing the method in accordance with the present invention the scaling of the DPCCH power may coincide with a requested power increase, for example due to a closed loop power control process or a change in data format on the DPDCH. In this case, the result of the scaling process in accordance with the present invention may in fact be to increase the DPCCH (+DPDCH) transmit power, but by a smaller amount than was requested by the closed loop power control process and/or change in DPDCH data format. This situation may arise where the sum of PC1 and PD1 is less than Pmax, but the sum of PC2+PD2+the greater of PA and PN would be greater than Pmax if the scaling were not applied. In another embodiment, the additional signals may carry information other than ACK/NACK signalling; for example, they may carry packet data (as in the proposed enhanced uplink in UMTS) or other signalling information. In a further non-illustrated embodiment the base station may be required to implement the method in accordance with the present invention rather than the mobile station. Although the method in accordance with the present invention has been described with reference to a spread spectrum communication system, its teachings may be applied to other systems having transmitter power control. In the present specification and claims the word “a” or “an” preceding an element does not exclude the presence of a plurality of such elements. Further, the word “comprising” does not exclude the presence of other elements or steps than those listed. From reading the present disclosure, other modifications will be apparent to persons skilled in the art. Such modifications may involve other features which are already known in the design, manufacture and use of telecommunication systems and component parts therefor and which may be used instead of or in addition to features already described herein.

20060202

20101109

20080626

62639.0

H04B7005

PEREZ, ANGELICA

COMMUNICATION SYSTEM AND METHOD OF OPERATING THE COMMUNICATING SYSTEM

UNDISCOUNTED

ACCEPTED

H04B

ACCEPTED

Supply Unit for a Driver Circuit and Method for Operating Same

A power supply and method of operating the same. The method includes the steps of: operating first and second switches to an “On” position; operating said first switch to a “Off” position, causing a flow of a first free-wheeling current through a first free-wheeling current path; measuring a value of said free-wheeling current; controlling the switching of said second switch responsive to said value of said free-wheeling current; and regulating power from said power supply unit. The power supply includes: an inductive converter; a first free-wheeling current path comprising: a first switch connected in series with said inductive converter and a first means for measuring a first free-wheeling current flowing through said first free-wheeling current path; and a second free-wheeling current path comprising: a second switch connected in series with said inductive converter and a second means for measuring a second free-wheeling current flowing through said second free-wheeling current path.

1-20. (canceled) 21. A method of operating a power supply unit, the method comprising the steps of: operating a first and a second switch to an “On” position; operating said first switch to a “Off” position and causing a flow of a first free-wheeling current through a first free-wheeling current path; measuring a value of said first free-wheeling current; controlling the switching of said second switch responsive to said value of said first free-wheeling current; and regulating power from said power supply unit. 22. The method of claim 21, further comprising the steps of: operating said first and said second switch to the “On” position; operating said second switch to a “Off” position and causing the flow of a second free-wheeling current through a second free-wheeling current path; measuring a value of said second free-wheeling current; and controlling the switching of said first switch responsive to said value of said second free-wheeling. 23. The method of claim 21, further comprising the steps of: designating said first free-wheeling current as faulty when the value of said first free-wheeling current is less than a first prescribed threshold value; and designating said second free-wheeling current as faulty when the value of said second free-wheeling current is less than a second prescribed threshold value. 24. The method of claim 23, comprising the step of maintaining said second switch in the “On” position when said first free-wheeling current is faulty. 25. The method of claim 23, comprising the step of maintaining said first and said second switch in the “Off” position when said first free-wheeling current is faulty. 26. The method of claim 23, comprising the step of maintaining said first switch in the “On” position when said second free-wheeling current is faulty. 27. The method of claim 23, comprising the step of maintaining said first and said second switch in the “Off” position when said second free-wheeling current is faulty. 28. The method of claim 21, further comprising the steps of: generating a first control signal for operating said second switch; and generating a second control signal for operating said first switch. 29. The method of claim 28, comprising the steps of: generating said first control signal from a first periodic signal; and generating said second control signal from a second periodic signal. 30. The method of claim 28, comprising the steps of: generating said first control signal from a first clock signal; and generating said second control signal from a second clock signal. 31. The method of claim 28, comprising the step of synchronizing said first and said second control signals to a clock signal. 32. The method of claim 28, further comprising the steps of: generating said first control signal when said first free-wheeling current is not faulty; and generating said second control signal when said second free-wheeling current is not faulty. 33. The method of claim 21 operating a power electronics circuit. 34. The method of claim 33 providing power to said power electronics circuit. 35. The method of claim 21 operating an electric motor. 36. The method of claim 21 providing power to an inductive converter, said method further comprising the steps of: operating said first switch between said “On” and said “Off” positions; and operating said second switch between said “On” and said “Off” positions. 37. A power supply unit comprising: an inductive converter; a first free-wheeling current path comprising: a first switch connected in series with said inductive converter, said first switch operable between an “On” position and a “Off” position; and a first means for measuring a first free-wheeling current flowing through said first free-wheeling current path; and a second free-wheeling current path comprising: a second switch connected in series with said inductive converter, said second switch operable between an “On” position and a “Off” position; and a second means for measuring a second free-wheeling current flowing through said second free-wheeling current path. 38. The power supply unit of claim 37, wherein: said first means for measuring said first free-wheeling current includes a first current sensor; and said second means for measuring said second free-wheeling current includes a second current sensor. 39. The power supply unit of claim 37, further comprising: a first control circuit measuring said first free-wheeling current and operating said first switch between said “On” and “Off” positions; and a second control circuit measuring said second free-wheeling current and operating said second switch between said “On” and “Off” positions. 40. The power supply unit of claim 39, wherein said second control circuit receives a first signal from said first control circuit; and said first control circuit receives a second signal from said second control circuit. 41. The power supply unit of claim 40, wherein said first signal is a first periodic or clock signal generated by said first control circuit and wherein said second signal is a second periodic or clock signal generated by said second control circuit. 42. The power supply unit of claim 40, wherein said first signal is generated by said first control circuit from a first periodic signal or a clock signal and wherein said second signal is generated by said second control circuit from a second periodic signal or a clock signal. 43. The power supply unit of claim 37, configured to operate a power electronics circuit. 44. The power supply unit of claim 43, configured to provide power to said power electronics circuit. 45. The power supply unit of claim 37, configured to operate an electric motor. 46. The power supply unit of claim 37, wherein said inductive converter provides power in response to operating said first switch and said second switch between said “On” and “Off” positions. 47. The power supply unit of claim 37, configured to generate said first free-wheeling current in response to operating said first switch to said “Off” position; and said second free-wheeling current in response to operating said second switch to said “Off” position. 48. The power supply unit of claim 37, wherein said inductive converter is a transformer. 49. The power supply unit of claim 37, wherein said first switch does not operate when said first free-wheeling current is less than a first prescribed value. 50. The power supply unit of claim 37, wherein said second switch does not operate when said second free-wheeling current is less than a second prescribed value. 51. The power supply unit of claim 37, wherein said first free-wheeling current path further comprises a first free-wheeling diode. 52. The power supply unit of claim 37, wherein said second free-wheeling current path further comprises a second free-wheeling diode. 53. The power supply unit of claim 37, wherein said first switch is a first field effect transistor. 54. The power supply unit of claim 37, wherein said second switch is a second field effect transistor.

The invention relates to a method for operating a supply unit for a driver circuit for a power stage, particularly for a power circuit for an electric motor. The invention also relates to a supply unit for a power supply in a driver circuit for a power stage. Electrical driver units generally comprise an electric motor and a power electronics circuit. The power electronics circuit draws power from a supply system at a fixed frequency and voltage and converts this power to produce a rotating field in a motor. The speed and torque of the motor are regulated by the power electronics circuit. The power electronics circuit generally comprises a servo amplifier or, in an unregulated drive system, a frequency converter. The servo amplifier and the frequency converter are normally together called an inverter and are actuated by means of the driver circuit provided in the power electronics circuit. When electric drive units are being used, it is necessary for them to be immediately turned off and safely stopped in the event of faults or risks. That is to say that the motor must under no circumstances move on account of electrical actuation. Normally, this is done by turning off the power supply for the power electronics circuit, as is known, by way of example, from the document BIA Report May, 2003 “Sichere Antriebssteuerung mit Frequenzumrichtern” [Safe drive control using frequency converters], ISBN 3-88383-645-1 or from the document Antriebstechnik 33 (1994), No. 10, “Vermeidung von unerwartetem Anlauf bei stromrichtergespeisten Antrieben” [Avoiding unexpected starting in inverter-powered drives], Erwin Zinken, BIA St Augustin. This allows the motor to be reliably stopped, since no further power is supplied to the motor. However, when it is started again the entire power electronics circuit needs to be turned on again, which takes a considerable amount of time. A further option is to isolate the motor from the power electronics circuit using an electromechanical switch, e.g. a contactor. However, the sudden switching can easily damage the power electronics circuit on account of overvoltages. In addition, the loading is also very high for the contactor, since high current levels need to be switched. A further solution for safely turning off the rotating field is to suppress the ignition pulse. Ignition pulses are equivalent to control signals generated by the driver circuit in the power electronics circuit, which actuates the power stage in the power electronics circuit. The power stage has six electronic switches which are controlled by means of control signals, so that the internal DC voltage is converted into a three-phase alternating current. The ignition pulse can be suppressed in various ways. It is usual—as known from the aforementioned document BIA Report May, 2003—to interrupt the supply voltage at the driver circuit. The voltage is usually turned off by a relay in the event of a fault. Safe stopping through ignition pulse suppression, i.e. by not producing the control signals, leaves all the other components in the power electronics circuits in a full standby state. For the ongoing application, it is thus possible to put the electrical drive system into the safe state and to activate it again without this being noticed. Delays when the driver circuit is turned on again do not arise in essence. The switching of the supply voltage at the driver circuit has to date been effected by a mechanical relay, which is subject to wear. Such a mechanical switching relay does not allow the power electronics circuit to be designed for “single-fault safety”. “Single-fault safety” means that if a fault occurs in one of the safety-related components used the actuation of the motor is stopped immediately. It is therefore an object of the present invention to provide a method for operating a power stage in a power electronics circuit for an electric motor which is designed for “single-fault safety” in particular. It is also an object of the present invention to provide a supply unit for a driver circuit, particularly for actuating a motor, which is designed for “single-fault safety”. This object is achieved by the method in accordance with claim 1 and by the supply unit in accordance with claim 11. Further advantageous refinements of the invention are specified in the dependent claims. A first aspect of the present invention provides a method for operating a supply unit for a driver circuit, particularly in a power electronics circuit for an electric motor. A control current is switched by an inductive converter using a first and a second switch on the basis of a first control signal and a second control signal in order to generate a power supply for the driver circuit. Turning off the first and second switches allows a free-wheeling current to flow through a first or a second free-wheeling current path. Actuating the power stage involves first of all turning on the first and second switches on the basis of the first and second control signals and then, e.g. on the basis of an actuation value, turning off the first switch in a turnoff operation using the first control signal. The turnoff operation prompts measurement of the free-wheeling current through the first free-wheeling current path. The second switch is then switched, or not, using the second control signal on the basis of the measured first freewheeling current. The inventive method has the advantage that in a supply unit a switching operation taking place in a normal mode involves the operation of the first switch being checked by using the measured free-wheeling current to identify whether the first switch has actually interrupted the current path on the basis of the first control signal and is thus operating correctly. Since generating the power supply requires both switches to be turned on and off constantly, essentially at the same time, the generation of the power supply can be interrupted immediately by preventing one of the switches from switching. In line with a first alternative, the second switch is prevented from being turned off if measurement of the free-wheeling current through the first free-wheeling path detects a fault. Since, when a fault is identified in this manner, the turn-off operation for the first switch has not actually turned said switch off, the circuit thus remains closed via the inductive converter. As a result of the switching of the second switch being prevented, however, no further switching operation takes place, which means that no power can be transmitted by the inductive converter. In line with a further alternative, the first and second switches can be prevented from being turned on again if measurement of the free-wheeling current through the first free-wheeling current path detects a fault. In this case, the second switch is turned off after the fault is identified. This has the advantage over the first alternative that a continuous direct current cannot flow through the inductive converter, which current can sometimes result in destruction thereof. Provision can be made for a further switching operation to involve first of all turning on the first and second switches again on the basis of the first and second control signals and then turning off the second switch in a further turn-off operation using the second control signal. As a result, the free-wheeling current through the second free-wheeling current path is measured and the first switch is switched using the first control signal on the basis of the measured free-wheeling current through the second free-wheeling current path. This also allows the operation of the second switch to be checked. In particular, one of the two switches can be checked alternately in each switching cycle to determine whether it is operating correctly, i.e. to determine whether it is being turned off correctly. If one of the two switches does not interrupt the respective current path correctly, the subsequent check on the switching behavior prevents further switching of the respective other switch, which means that no further voltage or current change takes place on the inductive converter in order to stop further power transmission and hence the power supply immediately. Actuation of the power stage in the power electronics circuit is stopped such that no power is provided for generating a rotating field for a downstream electric motor which needs to be stopped. If measurement of the free-wheeling current through the second free-wheeling current path detects a fault, the first and second switches can firstly be prevented from being turned on again and/or the first switch can be prevented from being turned off, in a similar manner to the procedure when checking the first free-wheeling current path. Provision may be made for the first and/or the second control signal to be generated using a periodic signal. The periodic signal can be blocked for generating the first and/or the second control signal if measurement of the free-wheeling current through the first and/or the second free-wheeling current path detects a fault. Blocking the periodic signal required for generating the control signals is one way of immediately stopping the switching operations for the first and second switches. A further aspect of the present invention provides a supply unit for a driver circuit for a power stage, particularly in a power electronics circuit for an electric motor. The driver circuit has an inductive converter which is connected in series with a first and a second switch in order to provide a power supply by switching the switches. The first and second switches can be actuated by a first and a second signal, respectively. The power supply can be produced in the inductive converter by turning on and off the first and second switches. The first switch has a first free-wheeling current path connected to it in order to accept a freewheeling current in a turn-off operation for the first switch. The second switch is connected to a second freewheeling current path in order to accept a free-wheeling current in a turn-off operation for the second switch. The driver circuit has a control device in order, in a turn-on operation, to turn on the first and second switches on the basis of the first and second control signals and in order, in a turn-off operation, first of all to turn off the first switch and to measure a freewheeling current through the first free-wheeling current path, and in order to switch the second switch on the basis of the measured free-wheeling current path. The supply unit based on the invention is used for operating a driver circuit for a power stage with a power supply which is produced by turning on and off a supply voltage on an inductive converter. The turning-on and turning-off are effected using two switches which need to be switched essentially at the same time. The control device first of all turns on the two switches at the same time and then, e.g. on the basis of an actuation value, turns off the first switch. If the first switch is faulty and does not interrupt the current path through the inductive converter, this is detected by the measurement of the free-wheeling current through the first freewheeling current path, and the second switch is prevented from being switched again. If it is detected that the first circuit is switched correctly, the second switch is likewise turned off, so that the period of time between turning off the first switch and turning off the second switch is as short as possible. The first free-wheeling current path can have a first current sensor and/or a first free-wheeling diode. The second free-wheeling current path can have a second current sensor and/or a second free-wheeling diode. The control device can be designed so that, in a further turn-off operation, it first of all turns off the second switch and measures a free-wheeling current through the second free-wheeling current path in order to switch the first switch on the basis of the measured free-wheeling current. The effect which can be achieved by this is that first the first and then the second switch are alternately turned off first in each turn-on/turn-off operation so as thus to check the operation of the first and second switches in succession. In line with a further embodiment, the supply unit comprises a first control circuit and a second control circuit, which is separate from the latter, with the first control circuit controlling the switching of the first switch and measuring the current through the first free-wheeling current path. The second control circuit accordingly controls the switching of the second switch and measures the current through the second free-wheeling current path. The first control circuit and the second control circuit are coupled to one another such that the first control circuit generates the first control signal on the basis of a second Active signal which is applied by the second control circuit, and the second control circuit conversely generates the second control signal on the basis of an Active signal which is applied by the first control circuit. This makes it possible to achieve single-fault safety, which interrupts the generation of control signals and hence the provision of the power supply as soon as a fault occurs in one of the switches, in one of the freewheeling paths or in one of the control circuits. As soon as the control circuit identifies the fault in the respective associated switch, it checks the operability of the switch. By virtue of the control circuit generating the Active signal which is required by the respective other control circuit in order to actuate the associated switch, provision of the power supply is interrupted even if one of the control circuits fails. This means that the driver circuit based on the invention has “single-fault safety”, since provision of the power supply is interrupted immediately when a fault occurs in one of the components. So that the first and second Active signals cannot be generated incorrectly, said signals are provided as a periodic signal or as a signal sequence from the respective control circuit, so that in the event of a fault the periodic Active signal continues to be produced. The periodic signal or the signal sequence has the advantage that in the event of a fault in the respective control circuit which would result in a permanent state of the Active signal this state does not result in the respective control signal continuing to be generated in the duplicate other control circuit. Preferably, the inductive converter is in the form of a transformer. In line with one embodiment of the invention, the control device is designed to generate the first and/or the second control signal using a provided clock signal. If a fault occurs, the clock signal can be interrupted, which means that generation of the first and second control signals is interrupted. Preferred embodiments of the invention are explained in more detail below with reference to the appended drawings, in which: FIG. 1 shows a block diagram to illustrate a drive system; FIG. 2 shows a block diagram of the inventive driver circuit; and FIG. 3 shows a signal flowchart to illustrate the actuation of the switches in the driver circuit. FIG. 1 shows a block diagram of the actuation of an electric motor in a drive system. A control system 1 generates actuation values, with an electric motor 2 being intended to be actuated on the basis of the actuation values. The electric motor 2 is usually actuated using a power electronics circuit 3 which comprises a power stage 4. In the example shown, the power stage 4 generates three phase currents and for this purpose typically has 6 electronic switches (not shown) which are actuated by means of respective switching signals from a driver circuit 5. The electric motor 2 is preferably in the form of a synchronous or asynchronous motor, particularly in the form of an electric motor which can be operated using an electrical rotating field and has no separate commutation. The power stage 4 is used to provide the rotating field at the necessary current level for operating the electric motor 2. The switching signals which are used to actuate the power stage 4 are provided by the driver circuit 5. In some fields of application, it is necessary for the electric motor 3 to be stopped immediately when a fault occurs so that the electric motor 2 does not continue to run uncontrolled. This is done by virtue of the driver circuit 5 in the power electronics circuit 3 immediately interrupting the generation of the respective switching signal as soon as a fault has been identified. To generate the rotating field for the electric motor 2, a particular sequence of switching signals is required. If the driver circuit stops these switching signals, it is not possible to produce the rotating field. This allows the electric motor 2 to be stopped. Generation of the switching signals in the driver circuit 5 is interrupted, in particular, by interrupting the power supply to the driver circuit 5. The power supply is provided by a supply unit 6 which is connected to the driver circuit 5. FIG. 2 shows a circuit diagram of an inventive supply unit 6 for a driver circuit 5. The power supply in the form of a supply voltage is provided for the driver circuit 5, which generates switching signals which are forwarded to the electronic switches in the power stage 4. The switching signals are DC isolated and are in a voltage range which is appropriate for an electronic switch in a downstream power stage. Typically, the gate input of a power field effect transistor is inbuilt in the power stage. The switching signal is essentially a pulse-width-modulated signal which transmits on and off states to the power stage. The power stage (not shown) then turns on or off a coil winding in the electric motor on the basis of the switching signal. The supply unit 6 which is shown in FIG. 2 generates a supply voltage as a power supply, said supply voltage being produced in a secondary coil 12 on the basis of a signal being switched on a primary coil 10 in a transformer 11. Since turning on and off the flow of current through the primary coil produces positive and negative voltages in the secondary coil 12, this resultant voltage signal is rectified by means of a rectifier diode 13 and is preferably smoothed by a capacitor (not shown), so that essentially a positive voltage is applied to the driver circuit 5. The primary coil 10 is connected in series with a first switch 14 and a second switch 15 between a high supply voltage potential VDD and a low supply voltage potential, preferably a ground potential GND. The first and/or the second switch 14, 15 are preferably in the form of field effect transistors, these each being able to be actuated by means of a control signal via an appropriate gate connection. To switch the transformer 11, the first and second switches 14, 15 are usually turned on and off at the same time, so that the switching operations in the primary coil 10 induce the corresponding voltage signal in the secondary coil 12 of the transformer 11. Particularly in the turn-off operation, the inductance of the primary coil 10 produces a free-wheeling current which is in the opposite direction to the flow of current when the primary coil 10 is in the turned-on state. So that this current does not result in harmful overvoltages on the field effect transistors and other components of the driver circuit, each of the switches 14, 15 is provided with a free-wheeling current path 16, 17. The first switch 14 is arranged between the high supply potential VDD and a first connection of the primary coil 10. The first connection of the primary coil 10 is connected via the first free-wheeling current path 16 to the ground potential, so that a free-wheeling current when the first switch is turned off can drain to the ground potential GND. The second switch 15 is arranged between a second connection of the primary coil 10 and the ground potential GND. The second connection of the primary coil 10 is likewise connected via a second freewheeling current path 17 to the high supply voltage potential VDD. So that turning on the switches does not produce a short between the high supply potential VDD and the ground potential GND, the first free-wheeling current path 16 contains a first free-wheeling diode 18 and the second free-wheeling current path 17 contains a second freewheeling diode 19 such that a voltage which is negative with respect to the ground potential and which is applied to the first connection of the primary coil 10 is drained via the first free-wheeling current path 16, and a voltage which is higher than the high supply potential VDD and which is applied to the second connection of the primary coil 10 is drained via the second free-wheeling current path 17, since the respective free-wheeling diode 18, 19 becomes conductive in this direction. The first free-wheeling current path 16 has a first current sensor 20, and the second free-wheeling current path 17 has a second current sensor 21, in order to measure the respective free-wheeling currents through the free-wheeling current paths 16, 17. The current sensors 20, 21 may be designed, by way of example, using a measuring resistor, e.g. a shunt, or may have a magnetic field current sensor in which the resistor in the respective free-wheeling current path is not affected by a measuring resistor. To measure a free-wheeling current, it is also possible to detect the free-wheeling current by measuring the current through the corresponding switch. A first control circuit 22 and a second control circuit 23 are provided for generating the control signals for the switches 14, 15. The first control circuit 22 is connected to the first current sensor 20, so that a measured free-wheeling current in the first free-wheeling current path 16 is provided in the first control circuit 22. The first control circuit 22 is connected to a first control connection of the first switch 14, particularly to the gate connection of the field effect transistor. The second control circuit 22 is connected to the second current sensor 23, so that the measured free-wheeling current in the second free-wheeling current path 17 is available in the second control circuit. The second control circuit 23 is connected to a control input of the second switch 15, i.e. to the gate connection of the second field effect transistor. The first control circuit 22 is connected to the second control circuit 23 via a first Active signal line 24 in order to transmit an Active signal to the second control circuit 23. A second Active signal line 25 is provided, so that the second control circuit 23 can transmit a second Active signal to the first control circuit 22. The control circuits 22, 23 receive, via a signal line 26, an externally prescribed enable signal which permits or prevents actuation of the electric motor 2. In addition, each of the control circuits 22, 23 has an input for a clock signal CLK. The control circuits are synchronized to this clock. The text below describes the mode of operation of the first control circuit 22 with regard to the first switch 14 and the first free-wheeling current path 16, the second control circuit 23 operating in essentially similar fashion with regard to the second switch and the second free-wheeling current path 17. The first and second control circuits 22, 23 receive the enable value via the data line 26 and, at the start of the period duration, generate a respective turn-on signal as a first or second control signal, which is supplied to the first switch 14 or the second switch 15, respectively, e.g. a high level. The respective turn-on signal turns on the switches 14 and 15, so that the high supply potential VDD is connected to the first connection of the primary coil 10 and the low supply potential GND is connected to the second connection of the primary coil 10. When a turned-on period has elapsed, the first control signal is switched such that the first switch 15 is turned off, e.g. by changing to a low level. The turnoff operation produces a free-wheeling voltage on the primary coil 10 of the transformer 11, said voltage being reduced via the first free-wheeling current path 16. The free-wheeling current in the first free-wheeling current path 16 is measured using the first current sensor 20, and the measured value is made available to the first control device 22. The latter compares the measured current value with a threshold current value which is chosen such that it is possible to detect that a significant free-wheeling current is flowing. This allows the switching behavior of the first switch 14 to be checked. This is because if the first switch 14 is not interrupted on the basis of the control signal, the current path through the primary coil 10 is not interrupted and a free-wheeling voltage which would need to be reduced via the first free-wheeling current path 16 does not arise. This is detected as a fault in the first control circuit 22, and further generation of a control signal to turn on the switch 14 is stopped. If a free-wheeling current in the first free-wheeling current path is measured which exceeds the threshold current value, the first control circuit 22 generates an Active signal on the first Active signal line 24, as a result of which the Active signal is transmitted to the second control circuit 23. When the corresponding Active signal is received, the second control circuit 23 immediately turns off the second switch 15, so that for the entire period duration of the control signals only a short time delay arises between turning off the first switch and turning off the second switch, and this time delay has no significant effects on the generation of the switching signal. The first and second control circuits 22, 23 operate essentially in sync, which means that it is advantageous if the same clock signal CLK is applied to both control circuits 22, 23. The two control circuits 22, 23 are tuned to one another such that during a clock cycle only one of the two control circuits ever generates the control signal for turning off the respective switch 14, 15 independently without receiving the Active signal beforehand. Preferably, the two control circuits operate out of sync with regard to the turn-off signal, and particularly in a first clock cycle the first control circuit generates the first control signal for turning off the first switch 14 independently and the second control circuit 23 makes the control signal for turning off the second switch 15 dependent on the first switch 14 having been turned off. In a second clock cycle, the second control circuit 23 then generates the control signal for turning off the second switch 15 independently of the Active signal, and the first control circuit 22 on the basis of the Active signal generated by the second control circuit 23 when the second switch 15 is successfully turned off. The respective Active signal indicates to the respective control circuit 22, 23 that the control signal for turning off the respective switch 14, 15 now needs to be generated. That the respective switch has been turned off is preferably indicated by a suitable edge of the Active signal, since this edge needs to be generated actively by the respective control circuit. It is also possible for faults which occur in one of the control circuits to result in immediate interruption of the generation of the switching signal, since the Active signal can be produced only by a correctly operating control circuit 22, 23. This provides the presented supply unit 6 with “single-fault safety”, i.e. when a fault occurs in one of the components used the generation of the switching signal is immediately interrupted, so that the rotating field is no longer produced to actuate the electric motor 2. The proposed supply unit is thus in a form such that faults when one of the switches 14, 15 is turned off immediately result in an appropriate switching signal no longer being generated. Since the relevant control circuit 22, 23 may also have faults and then might no longer identify a relevant fault when the respective switch is switched, the control circuit must actively generate an Active signal when the switch connected to it is detected to have been turned off. This signal would not be generated in a faulty control circuit, which means that the respective other control circuit does not generate a turn-off signal. In the subsequent clock cycle too, no control signals would be generated which result in one of the switches 14, 15 being switched. Hence, by way of example, a fault in the first switch 14 which involves the first switch 14 no longer switching from its turned-on state to its turned-off state results in the second switch 15 no longer being turned off either, since the Active signal required by the second control device 23 would no longer be generated by the first control circuit 22. The current path through the primary coil 10 is thus maintained. Since there is no longer a change of current in the primary coil 10, no power is transmitted to the secondary coil 12 either, which means that the supply voltage is turned off. Alternatively, provision may also be made for the occurrence of a fault which is identified by one of the control circuits and is indicated to the others by the absence of the correct Active signal to result in the control circuit generating a control signal to turn off the switch which is connected to it, in order to interrupt the current path through the primary coil 10 in every case, since otherwise a very high direct current would flow through the primary coil 10 which might destroy it. However, this results in a further switching operation in which power briefly continues to be transmitted to the secondary coil 12 and thus produces a further edge in the switching signal, so that the turnoff operation for the rotating field for actuating the electric motor 2 would continue to be produced. Depending on the application in which the electric motor 2 is being operated, this is a negligibly short period in the range of a few μsec, however. Similarly, faults in one of the free-wheeling diodes 18, 19 can be identified. If one of the free-wheeling diodes 18, 19 starts to conduct in the reverse direction, there is a short between the high supply potential VDD and the ground potential GND, and the safe state is reached. The circuit would then not operate. If the diode in question starts not to conduct in the forward direction, however, this failure does not prevent operation but is relevant to safety if a transistor with a short fails. The fault that the respective free-wheeling diode 18, 19 starts not to conduct in the forward direction results in the current sensor 20, 21 measuring no free-wheeling current, which means that the respective control circuit does not generate an Active signal, since it cannot detect that the respective switch 14, 15 has turned off. Hence, a faulty diode results either in a short being produced in the circuit which stops the electric motor or in the generation of the control signal in question being prevented. A significant advantage of such a supply unit is that diagnostic intervals are just one cycle of the clock signal CLK, which means that they can be carried out at short intervals of time of 50 μsec, for example. In addition, a superordinate control system (not shown) is connected to the control units 22 and 23. If one were no longer to operate correctly, the control system blocks the enable signal, so that the control units 22, 23 generate no more control signals. FIG. 3 shows a signal diagram to illustrate the profiles of the clock signal and the first and second control signals. It can be seen that the first and second control circuits 22, 23 indicate that the respective switch has been turned on upon the rising edge of the clock signal by means of a likewise rising edge of the control signal. For a particular period, the two control signals remain at the high levels. It can be seen that the first control signal ST1 turns off the first switch 14 with a rising edge. A suitable Active signal is then generated in the control circuit 22 if the switching operation was successful and no other fault has occurred. This signal is transmitted to the second control circuit 23, which generates the falling edge for the second control signal ST2 in order to turn off the second switch. Up to the next rising edge of the clock signal CLK, the control signals remain at a low level. Upon the next rising edge of the clock signal CLK, the two control signals ST1, ST2 change to a high level, with the second control circuit now generating a falling edge of the second control signal ST2. The falling edge of the second control signal ST2 turns off the second switch 15, with an Active signal being generated if the second switch 15 has been turned off and no further fault has occurred. The Active signal then likewise turns off the first switch 14, with a negligible time delay, in line with a falling edge of the first control signal ST1. It is thus possible for the operation of the switches 14, 15 or of the components in the respective free-wheeling current path to be checked alternately, with generation of the control signals being stopped immediately if a fault is identified.

20070726

20100420

20071129

78622.0

G05G112

HAN, YOUNGHUIE JESSICA

SUPPLY UNIT FOR A DRIVER CIRCUIT AND METHOD FOR OPERATING SAME

UNDISCOUNTED

ACCEPTED

G05G

ACCEPTED

Reproducing apparatus, method, method and program

The present invention relates to a playback apparatus, a playback method, and a program for the same that increase the level of convenience of a recording medium and thereby, for example, enable a user to perform playback control processing and the like more easily. An information acquisition unit 353 in a playback control unit 334 allows a holding unit 354 to hold an acquired an LTC change point table 361. An input acceptance processing unit 352 supplies an accepted cue-up instruction to a cue-up processing unit 355. The cue-up processing unit 355 identifies the FTC of a frame to be cued up, referring to the LTC change point table 361 held in the holding unit 354, and supplies this information to a control unit 351. Based on the information, the control unit 351 creates cue-up command information, and supplies it through a command processing unit 356 to a disk recording/playback apparatus which displays a frame image of a frame to be cued up onto a monitor. The invention can be applied to an editing system.

1. A playback apparatus for playing back video data, comprising: identifying means for identifying second position information which is relative position information, relative to a starting frame of the video data, of a playback frame which is a frame corresponding to a frame playback instruction using first position information which is absolute position information as to each frame of the video data; and playback means for playing back the playback frame corresponding to the second position information identified by the identifying means. 2. The playback apparatus according to claim 1, wherein the first position information is a time code indicating an absolute position of the frame, using a real time. 3. The playback apparatus according to claim 1, wherein the first position information is a time code indicating an absolute position of the frame, using time information relative to a predetermined time. 4. The playback apparatus according to claim 1, wherein the second position information is a time code indicating a relative position of the frame, using a frame number indicating the number of frames counted from the starting frame of the video data. 5. The playback apparatus according to claim 1, wherein the identifying means identifies the second position information as to the playback frame, based on table information that associates the first position information with the second position information and has an element of a correlation between the first position information and the second position information at a change point which is a frame where a type of change pattern of a value of the first position information changes. 6. The playback apparatus according to claim 5, wherein each element of the table information includes status information indicating a type of change pattern of a value of the first position information as to a frame after the change point. 7. The playback apparatus according to claim 5, wherein in each status section which is grouped by the change point in the table information and composed of a plurality of consecutive frames having the same status information, the identifying means performs determination whether the first position information of the playback instruction exists, and identifies the second position information as to the playback frame, based on a result of the determination. 8. The playback apparatus according to claim 7, wherein the identifying means performs the determination in turn for consecutive status sections in a direction that increases the second position information if a value of the first position information of the playback instruction is larger than a value of the first position information as to a frame that is currently played back, and the identifying means performs the determination in turn for consecutive status sections in a direction that decreases the second position information if a value of the first position information of the playback instruction is smaller than a value of the first position information as to a frame that is currently played back. 9. A playback method for playing back video data, comprising: accepting a playback instruction to play back a frame, using first position information which is absolute position information as to each frame of the video data; identifying second position information which is relative position information, relative to a starting frame of the video data, of a playback frame; and playing back a frame corresponding to the second position information identified. 10. A program for allowing a computer to execute processing for playing back video data, comprising: accepting a playback instruction to play back a frame, using first position information which is absolute position information as to each frame of the video data; identifying second position information which is relative position information, relative to a starting frame of the video data, of a playback frame; and playing back a frame corresponding to the second position information identified.

TECHNICAL FIELD The present invention relates to a playback apparatus, a playback method, and a program for the same, and in particular, to a playback apparatus, a playback method, and a program for the same that increase the level of convenience of a recording medium and thereby, for example, enable a user to perform playback control processing and the like more easily. BACKGROUND ART In recent years, there has become widespread a method by which when video data and audio data acquired by shooting or the like are recorded onto a recording medium, additional information as editing information is added to the video data and the audio data (e.g., see patent document 1). For example, in the case where video data and audio data are recorded onto videotape by a VCR or the like, as shown in FIG. 1A, the audio data and the video data (skewed black rectangular portions in FIG. 1A) are in turn recorded in an essence data recording area 11 which is a predetermined recording area on videotape 10, and also LTC (Linear Time Code), associated with the video data, which is a time code of each frame of the video data is recorded in an additional-information recording area 13 which is a predetermined recording area. In the case of FIG. 1A, three clips (clips 12-1 to 12-3) including the video data and the audio data are recorded in the essence data recording area 11 on the videotape 10, and LTC, associated with the clips, is recorded in the additional-information recording area 13. The values of the first LTCs 14-1 to 14-3 of LTCs associated with the clips 12-1 to 12-3 are “00:10:20:00”, “12:34:56:10”, and “00:00:30:15”, respectively. LTCs are continuous in each clip. However, there are cases where LTCs are discontinuous over clips, or there are cases where LTCs having the same value exist in a plurality of clips. In recent years, a method of non-linear editing (NLE) to perform editing with a personal computer or the like has been employed as a method for editing video data and audio data. In the non-linear editing, as shown in FIG. 1B, video data and audio data are recorded, as files in units of clips for example, on a hard disk (HDD) 20 or the like in a personal computer used as a data editing apparatus. In the case of FIG. 1B, essence data which is data to be edited including video data and audio data is recorded on the hard disk 20, as files 21-1 and 21-2. In this case, it is possible to specify essence data in units of frames for example, and each frame has a frame number assigned thereto in each file. This frame number is managed as FTC (File Time Code), and a user who edits essence data can directly specify a necessary part in a necessary file using the FTC. The FTC (frame number) is relative position information in which, the number of the first frame of each file being “0”, FTC is assigned to each frame in order from the first frame. Therefore, there are cases where FTC (frame number) of the same value exists in a plurality of files. [Patent document 1] Japanese Patent Application Laid-Open No. 2001-29241 (pages 14 and 15, FIG. 8) DISCLOSURE OF THE INVENTION However, for example, in the case of FIG. 1A, LTC which is a time code associated with a frame represents a time when video data is created by shooting or the like, but is not for the purpose of managing recording positions of the corresponding essence data on the videotape. Therefore, since LTCs are not always continuous over clips as described above, there is a problem that a user cannot directly retrieve essence data of a desired frame using LTC. In the case of FIG. 1A, when the user retrieves a desired frame, it is necessary to output essence data in order from the first to use a displayed LTC. Further, for example, in the case of FIG. 1B, the user can directly retrieve essence data of a desired frame using FTC indicating a frame number. However, since, as described above, FTC is a value indicating a relative position from the first frame of each file and is independent data for each file, there is a problem that the user cannot easily grasp the correlation between times of video data creation by shooting or the like in a plurality of files. Further, for example, in the case of performing an edit in which a plurality of clips are combined and thereby having a plurality of clips in one file, the user cannot easily grasp the correlation between times of video data creation by shooting or the like in clips included in the file. Therefore, for example, in the case of performing cue-up processing for directly specifying a frame to be displayed using FTC at the time of playing back such a file, it is difficult for the user to grasp which clip includes a frame displayed after cued up and judge whether the frame is before or after a frame before cued up. The present invention has been made in view of the above circumstances and an object of the invention is to increase the level of convenience of a recording medium, such as enabling a user to perform playback control processing more easily. A playback apparatus according to the present invention includes an identifying device for identifying second position information which is relative position information, relative to a starting frame of video data, of a playback frame which is a frame corresponding to a frame playback instruction using first position information which is absolute position information as to each frame of the video data; and a playback device for playing back the playback frame corresponding to the second position information identified by the identifying device. The first position information can be a time code indicating an absolute position of the frame, using a real time. The first position information can be a time code indicating an absolute position of the frame, using time information relative to a predetermined time. The second position information can be a time code indicating a relative position of the frame, using a frame number indicating the number of frames counted from the starting frame of the video data. The identifying device can identify the second position information as to the playback frame, based on table information that associates the first position information with the second position information and has an element of a correlation between the first position information and the second position information at a change point which is a frame where a type of change pattern of a value of the first position information changes. Each element of the table information can include status information indicating a type of change pattern of a value of the first position information as to a frame after the change point. In each status section which is grouped by the change point in the table information and composed of a plurality of consecutive frames having the same status information, the identifying device can perform determination whether the first position information of the playback instruction exists, and identify the second position information as to the playback frame, based on a result of the determination. The identifying device can perform the determination in turn for consecutive status sections in a direction that increases the second position information if a value of the first position information of the playback instruction is larger than a value of the first position information as to a frame that is currently played back, and the identifying device can perform the determination in turn for consecutive status sections in a direction that decreases the second position information if a value of the first position information of the playback instruction is smaller than a value of the first position information as to a frame that is currently played back. A playback method according to the invention includes accepting a playback instruction to play back a frame, using first position information which is absolute position information as to each frame of the video data; identifying second position information which is relative position information, relative to a starting frame of the video data, of a playback frame; and playing back a frame corresponding to the second position information identified. A program according to the invention includes accepting a playback instruction to play back a frame, using first position information which is absolute position information as to each frame of the video data; identifying second position information which is relative position information, relative to a starting frame of the video data, of a playback frame; and playing back a frame corresponding to the second position information identified. The playback apparatus, playback method, and the program for the same according to the invention, identify second position information which is relative position information, relative to a starting frame of video data, of a playback frame which is a frame corresponding to a frame playback instruction using first position information which is absolute position information as to each frame of the video data; and play back the playback frame corresponding to the second position information identified. According to the present invention, it is possible to process a signal. In particular, it is possible to increase the level of convenience of a recording medium and thereby enable a user to perform playback control processing and the like more easily. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1A is an illustration of assistance in explaining conventional LTC. FIG. 1B is an illustration of assistance in explaining conventional FTC. FIG. 2 is a block diagram showing an example of the structure of a disk recording/playback apparatus (disk drive) according to an embodiment of the invention. FIG. 3 is a block diagram showing an example of the detailed structure of a data conversion unit in FIG. 2. FIG. 4 is a block diagram showing an example of the detailed structure of an LTC data processing unit incorporated in a real-time metadata processing unit of FIG. 3. FIG. 5 is a block diagram showing an example of the detailed structure of an LTC data processing unit incorporated in a non-real-time metadata processing unit of FIG. 3. FIG. 6 is a flowchart of assistance in explaining recording processing by a control unit of FIG. 2. FIG. 7 is a flowchart of assistance in explaining audio data recording task initiated at step S3 in FIG. 6. FIG. 8 is a flowchart of assistance in explaining video data recording task initiated at step S4 in FIG. 6. FIG. 9 is a flowchart of assistance in explaining low-resolution data recording task initiated at step S5 in FIG. 6. FIG. 10 is a flowchart of assistance in explaining real-time metadata recording task initiated at step S6 in FIG. 6. FIG. 11 is a schematic diagram of assistance in explaining the data structure of KLV-encoded data. FIG. 12 is a flowchart of assistance in explaining LTC data generation processing. FIG. 13 is a flowchart of assistance in explaining LTC change point table creation processing. FIG. 14 is a flowchart of assistance in explaining LTC change point table creation processing, subsequent to FIG. 13. FIG. 15 is a flowchart of assistance in explaining LTC change point table creation processing, subsequent to FIG. 14. FIG. 16A is a diagram of assistance in explaining an example of a state of LTC change. FIG. 16B is a diagram of assistance in explaining an example of an element of an LTC change point table. FIG. 17A is a diagram of assistance in explaining another example of a state of LTC change. FIG. 17B is a diagram of assistance in explaining another example of an element of an LTC change point table. FIG. 18A is a diagram of assistance in explaining another example of a state of LTC change. FIG. 18B is a diagram of assistance in explaining another example of an element of an LTC change point table. FIG. 19A is a diagram of assistance in explaining another example of a state of LTC change. FIG. 19B is a diagram of assistance in explaining another example of an element of an LTC change point table. FIG. 20A is a diagram of assistance in explaining another example of a state of LTC change. FIG. 20B is a diagram of assistance in explaining another example of an element of an LTC change point table. FIG. 21A is a diagram of assistance in explaining another example of a state of LTC change. FIG. 21B is a diagram of assistance in explaining another example of an element of an LTC change point table. FIG. 22 is a schematic diagram showing an example of the structure of data recorded on an optical disk in FIG. 2. FIG. 23A is a schematic diagram of assistance in explaining an example of the structure of data recorded on an optical disk in FIG. 2. FIG. 23B is a schematic diagram of assistance in explaining another example of the structure of data recorded on an optical disk in FIG. 2. FIG. 24 is an illustration showing an example of a directory structure in an optical disk of FIG. 2. FIG. 25 is an illustration showing an example of a more detailed directory structure shown in FIG. 24. FIG. 26 is an illustration showing an example of an XML description of a non-real-time metadata file. FIG. 27 is a block diagram showing an example of the structure of a camcorder according to an embodiment of the invention. FIG. 28 is an illustration showing an example of the structure of an editing system according to an embodiment of the invention. FIG. 29 is a block diagram showing an example of the internal structure of an editing control apparatus in FIG. 28. FIG. 30 is a block diagram showing an example of the detailed structure of a playback control unit in FIG. 29. FIG. 31 is an illustration of assistance in explaining an example of a display by a monitor in FIG. 28. FIG. 32 is a flowchart of assistance in explaining playback control processing. FIG. 33 is a flowchart of assistance in explaining cue-up control processing. FIG. 34 is a flowchart of assistance in explaining cue-up control processing, subsequent to FIG. 33. FIG. 35 is a flowchart of assistance in explaining cue-up control processing, subsequent to FIG. 34. FIG. 36 is a diagram of assistance in explaining an example of a state of cue-up processing. FIG. 37 is a diagram of assistance in explaining another example of a state of cue-up processing. FIG. 38 is a diagram of assistance in explaining another example of a state of cue-up processing. FIG. 39 is a diagram of assistance in explaining another example of a state of cue-up processing. FIG. 40 is a diagram of assistance in explaining another example of a state of cue-up processing. DESCRIPTION OF REFERENCE NUMERALS 30: Disk recording/playback apparatus (disk drive) 31: Optical disk 32: Spindle motor 33: Pickup unit 34: RF amplifier 35: Servo control unit 36: Signal processing unit 37: Memory controller 38: Memory 39: Data conversion unit 40: Control unit 41: Operation unit 51: Signal input/output device 61: Demultiplexer 62: Data amount detection unit 63: Video signal conversion unit 64: Audio signal conversion unit 65: Low-resolution data generation unit 66: Real-time metadata processing unit 67: Non-real-time metadata processing unit 71: LTC data processing unit 72: LTC data processing unit 81: Video data conversion unit 82: Audio data conversion unit 83: Low-resolution data processing unit 84: Real-time metadata processing unit 85: Non-real-time metadata processing unit 86: Multiplexer 101: Control unit 102: LTC generation unit 103: Initial-value setting unit 104: Counter 105: Real-time clock 111: Acquisition control unit 112: Determination processing unit 113: Data management unit 114: Data holding unit 115: Section setting management unit 116: Section setting holding unit 117: Registration processing unit 121: LTC data 122: FTC data 123: Section name 124: LTC change point table 161: Audio annual-ring data 162: Video annual-ring data 163: Low-resolution annual-ring data 164: Real-time meta annual-ring data 165: Non-real-time metadata 282: Non-real-time metadata file 300: Camcorder 301: Disk recording/playback unit 310: Editing system 321: Disk recording/playback apparatus 322: Network 323: Disk recording/playback apparatus 324: Editing control apparatus 334: Playback control unit 335: Editing control unit 351: Control unit 352: Input acceptance processing unit 353: Information acquisition unit 354: Holding unit 355: Cue-up processing unit 356: Command processing unit 361: LTC change point table BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described below with reference to the accompanying drawings. FIG. 2 is a block diagram showing an example of the structure of a disk recording/playback apparatus (disk drive) 30 according to an embodiment of the invention. A spindle motor 32 rotationally drives an optical disk 31 at CLV (Constant Linear Velocity) or CAV (Constant Angular Velocity) based on a spindle motor drive signal from a servo control unit 35. A pickup unit 33 controls the output of laser light based on a record signal supplied from a signal processing unit 36 to record the record signal onto the optical disk 31. Further, the pickup unit 33 irradiates the optical disk 31 with laser light converged, and also generates a current signal by performing photoelectric conversion of reflected light from the optical disk 31 to supply the current signal to a radio frequency (RF) amplifier 34. An irradiation position of laser light is controlled so as to be a specified position by a servo signal supplied from the servo control unit 35 to the pickup unit 33. The RF amplifier 34 generates a focus error signal, a tracking error signal and a playback signal, based on the current signal from the pickup unit 33. The RF amplifier 34 supplies the tracking error signal and the focus error signal to the servo control unit 35 and supplies the playback signal to the signal processing unit 36. The servo control unit 35 controls a focus servo operation and a tracking servo operation. More specifically, based on the focus error signal and the tracking error signal from the RF amplifier 34, the servo control unit 35 generates a focus servo signal and a tracking servo signal respectively, and supplies them to an actuator (not shown) of the pickup unit 33. Further, the servo control unit 35 generates a spindle motor drive signal for driving the spindle motor 32 and controls a spindle servo operation for rotating the optical disk 31 at a predetermined rotational velocity. Furthermore, the servo control unit 35 performs thread control for changing an irradiation position of laser light by moving the pickup unit 33 radially. Further, a signal reading position on the optical disk 31 is set by a control unit 40. The pickup unit 33 is controlled in position so that a signal can be read from the set reading position. The signal processing unit 36 generates a record signal by modulating record data inputted from a memory controller 37 and supplies it to the pickup unit 33. The signal processing unit 36 also generates playback data by demodulating a playback signal from the RF amplifier 34 and supplies it to the memory controller 37. The memory controller 37 stores record data from a data conversion unit 39 in a memory 38 if necessary, as described later, and also reads out it and supplies it to the signal processing unit 36. Further, the memory controller 37 stores playback data from the signal processing unit 36 in the memory 38 if necessary, and also reads out it and supplies it to the data conversion unit 39. The data conversion unit 39 generates record data by compressing video and audio signals shot with a video camera (not shown) or a signal played back from a recording medium (not shown) that is supplied from a signal input/output device 51 based on a scheme such as MPEG (Moving Picture Experts Group) or JPEG (Joint Photographic Experts Group) as necessary, and supplies the record data to the memory controller 37. The data conversion unit 39 also decompresses playback data supplied from the memory controller 37 as necessary, converts the data into a predetermined format for output, and supplies it to the signal input/output device 51. The control unit 40 controls the servo control unit 35, the signal processing unit 36, the memory controller 37, and the data conversion unit 39 based on an operation signal or the like from an operation unit 41 so that these units perform recording/playback processing. The operation unit 41 is operated by a user for example, and supplies an operation signal corresponding to the operation to the control unit 40. In the disk recording/playback apparatus 30 thus configured, when the user instructs the disk recording/playback apparatus 30 to record data by operating the operation unit 41, data from the signal input/output device 51 is supplied through the data conversion unit 39, the memory controller 37, the signal processing unit 36 and the pickup unit 33 to the optical disk 31 and recorded. Further, when the user instructs the disk recording/playback apparatus 30 to play back data by operating the operation unit 41, data is read and played back from the optical disk 31 through the pickup unit 33, the RF amplifier 34, the signal processing unit 36, the memory controller 37 and the data conversion unit 39 and is supplied to the signal input/output device 51. FIG. 3 shows an example of the structure of the data conversion unit 39 in FIG. 2. In the case of recording data onto the optical disk 31, a signal to be recorded is supplied from the signal input/output device 51 to a demultiplexer 61. The demultiplexer 61 demultiplexes the signal supplied from the signal input/output device 51 into, for example, a moving video signal (e.g., baseband video signal), an audio signal (e.g., baseband audio signal) accompanying the video signal and metadata, as a plurality of associated data series, and supplies them to a data amount detection unit 62. In short, at the time of recording data onto the optical disk 31, the signal input/output device 51 outputs, for example, a signal obtained by the video camera (not shown), as described above. The signal obtained by the video camera contains a video signal and its accompanying audio signal which are obtained by shooting a subject, and also metadata about the video signal. The demultiplexer 61 demultiplexes such a signal into the video signal, the audio signal, and the metadata as well. The metadata includes real-time metadata (RT) containing data of which real-time performance is required in its reading processing and non-real-time metadata (NRT) containing data of which real-time performance is not required in its reading processing. The real-time metadata (RT) includes, for example, a linear time code (LTC) which identifies the position of the frame of a video signal using predetermined time information such as a date and time (year, month, day, hour, minute, and second) and is absolute position information (time code) of each frame, a file time code (FTC) which is each frame number and relative position information from the first frame of a file, a user bit (UB) which indicates signal characteristics of the video signal of the frame, a unique material identifier (UMID) which is an ID for identifying a frame, global positioning system (GPS) information which represents a position where shooting has been performed with a video camera, an essence mark which is information about the contents of essence data such as a video signal and an audio signal, ARIB (Association of Radio Industries and Businesses) metadata, and setting/control information of a video camera with which shooting has been performed. The ARIB metadata refers to metadata for a communication interface such as a serial digital interface (SDI) standardized by ARIB which is a standardizing body. Further, the setting/control information of a video camera refers to information such as an iris control value, a white balance/black balance mode, and lens information about a lens zoom and focus. The non-real-time metadata (NRT) includes, for example, a conversion table which relates LTC corresponding to each frame with a frame number (FTC), information about UMID and GPS, etc. The frame refers to the unit of video signals, namely to video data corresponding to video for one screen (or a various kinds of data corresponding to the video data). Further, a clip refers to a unit that indicates one shooting process which is performed from the start of shooting until the end of shooting. That is, a one-clip video signal is typically composed of video signals of multiple frames. Further, the clip does not only indicate one shooting process but also indicates the time of the shooting process from the start of shooting until the end of shooting. Furthermore, the clip also indicates the length of video data and the amount of video data obtained by one shooting process, the video data itself, the length of various kinds of data and the amount of various kinds of data obtained by one shooting process, and a set of various kinds of data itself. Further, real-time metadata and non-real-time metadata may beadded to video data expressed in any unit. In the description below, real-time metadata is added to video data for each frame, and non-real-time metadata is added to video data for each clip. That is, in the description below, the real-time metadata is frame metadata which is added to a video signal for each frame, and includes data corresponding to the frame. The non-real-time metadata is clip metadata which is added to a video signal for each clip, and includes data corresponding to the whole clip. In most cases, video data is filed for each clip and managed by a file system. In such a case, the non-real-time metadata may be metadata for each file including video data. Further, the real-time metadata and the non-real-time metadata may include data besides the foregoing. The real-time metadata and the non-real-time metadata may include the same content data. The non-real-time metadata may include the above-mentioned real-time metadata, and the real-time metadata may include the above-mentioned non-real-time metadata. For example, the non-real-time metadata and/or the real-time metadata may include an essence mark, ARIB metadata, and setting/control information of a video camera. The real-time metadata and/or the non-real-time metadata may include information about UMID and GPS. The data amount detection unit 62 supplies a video signal, an audio signal, real-time metadata, and non-real-time metadata supplied from the demultiplexer 61 to a video signal conversion unit 63, an audio signal conversion unit 64, a real-time metadata processing unit 66, and a non-real-time metadata processing unit 67 respectively without being processed. Further, the data amount detection unit 62 detects the amount of each data (a video signal, an audio signal, real-time metadata, and non-real-time metadata) and supplies them to the memory controller 37. That is, the data amount detection unit 62 detects the amount of each data (a video signal, an audio signal, real-time metadata, and non-real-time metadata supplied from the demultiplexer 61) for a predetermined playback time period for example, and supplies them to the memory controller 37. Further, the data amount detection unit 62 supplies a video signal supplied from the demultiplexer 61, and an audio signal if necessary, to a low-resolution data generation unit 65. The video signal conversion unit 63 encodes a video signal supplied from the data amount detection unit 62 into MPEG format for example, with all frames being I (Intra) pictures, and supplies the thereby obtained data series of video data to the memory controller 37. Further, the audio signal conversion unit 64 encodes an audio signal supplied from the data amount detection unit 62 into MPEG format for example, and supplies the thereby obtained data series of audio data to the memory controller 37. The real-time metadata processing unit 66 rearranges the components of real-time metadata through the data amount detection unit 62 if necessary, and supplies the thereby obtained data series of real-time metadata to the memory controller 37. Further, the real-time metadata processing unit 66 includes an LTC data processing unit 71 which generates LTC data corresponding to each frame in such a case where LTC data is not added to a signal supplied from the signal input/output device 51. Furthermore, the real-time metadata processing unit 66 supplies a data series of LTC data after being processed to the non-real-time metadata processing unit 67 if necessary. The non-real-time metadata processing unit 67 rearranges the components of non-real-time metadata through the data amount detection unit 62 if necessary, and supplies the thereby obtained data series of non-real-time metadata to the memory controller 37. Further, the non-real-time metadata processing unit 66 includes an LTC data processing unit 72. The LTC data processing unit 72 generates a conversion table which relates LTC data with a frame number (FTCdata) using the data series of LTCdata supplied from the real-time metadata processing unit 66. The low-resolution data generation unit 65 generates a data series of low-resolution data obtained by reducing the amount of data supplied thereto, and supplies it to the memory controller 37. That is, the low-resolution data generation unit 65 generates a fewer-pixel video signal which is a video signal composed of frames having a small number of pixels, by thinning out the pixels of each frame of a video signal supplied through the data amount detection unit 62. Further, the low-resolution data generation unit 65 encodes the fewer-pixel video signal with the MPEG4 standard for example, and outputs the encoded data as low-resolution data. Further, the low-resolution data generation unit 65 can output low-resolution data including an audio signal whose data amount is reduced by thinning out an audio signal supplied through the data amount detection unit 62 or a sample of the audio signal (e.g., in the form of multiplexing the audio signal into the fewer-pixel video signal in units of frames). In the description below, the low-resolution data includes an audio signal. While the data series of video data outputted from the video signal conversion unit 63 and the data series of audio data outputted from the audio signal conversion unit 64 have the same contents as the data series of low-resolution data outputted from the low-resolution data generation unit 65, video data outputted from the video signal conversion unit 63 and audio data outputted from the audio signal conversion unit 64 are originally supplied from a user; therefore, video data outputted from the video signal conversion unit 63 and audio data outputted from the audio signal conversion unit 64 are hereinafter referred to as main-line data where appropriate. The low-resolution data is video and audio data of the same content as that of the main-line data while having a small amount of data. Therefore, in the case of playing back data for a certain playback time period, the low-resolution data can be read from the optical disk 31 within a short time compared to the main-line data. It is possible to adopt a data rate of e.g., about 25 Mbps (Mega bit per second) for the main-line data. In this case, it is possible to adopt a data rate of e.g., about 3 Mbps for the low-resolution data. Further, in this case, assuming that a data rate of e.g., about 2 Mbps is adopted for metadata (real-time metadata and non-real-time metadata), the data rate of the whole data recorded onto the optical disk 31 amounts to about 30 (=25+3+2) Mbps. Therefore, it is possible to adopt a device that is adequate for practical use having a record rate of 35 Mbps for example, as the optical disk 31 (the disk recording/playback apparatus 30 which drives the optical disk 31). As described above, in the data conversion unit 39 of FIG. 3, the data series of real-time metadata, non-real-time metadata, and low-resolution data as well as the data series of main-line data (video data and audio data) are supplied to the memory controller 37. The main-line data, the real-time metadata, the non-real-time metadata, and the low-resolution data supplied to the memory controller 37 are supplied to the optical disk 31 and recorded. On the other hand, at the time of playing back data from the optical disk 31, main-line data, real-time metadata, non-real-time metadata, and low-resolution data are read out as necessary from the optical disk 31. Video data and audio data constituting the main-line data are supplied to a video data conversion unit 81 and an audio data conversion unit 82 respectively, where the video data and the audio data are decoded into a video signal and an audio signal, which are supplied to a multiplexer 86. The real-time metadata, the non-real-time metadata, and the low-resolution data are supplied to a real-time metadata processing unit 84, a non-real-time metadata processing unit 85, and a low-resolution data processing unit 83, respectively. The real-time metadata processing unit 84, as necessary, changes the arrangement of components of the real-time metadata supplied thereto and supplies it to the multiplexer 86. The non-real-time metadata processing unit 85, as necessary, changes the arrangement of components of the non-real-time metadata supplied thereto and supplies it to the multiplexer 86. The low-resolution data processing unit 83 decodes the low-resolution data supplied thereto into a video signal and an audio signal each having a small amount of data, and supplies them to the multiplexer 86. The video data conversion unit 81 performs, e.g., MPEG decoding on the data series of the video data supplied from the memory controller 37, and supplies the thereby obtained video signal to the multiplexer 86. Further, the audio data conversion unit 82 performs, e.g., MPEG decoding on the data series of the audio data supplied from the memory controller 37, and supplies the thereby obtained audio signal to the multiplexer 86. The multiplexer 86 supplies the video signal supplied from the video data conversion unit 81, the audio signal supplied from the audio data conversion unit 82, the real-time metadata supplied from the real-time metadata processing unit 84, and the non-real-time metadata supplied from the non-real-time metadata processing unit 85 to the signal input/output device 51. Further, the multiplexer 86 can multiplex and output the video signal supplied from the video data conversion unit 81, the audio signal supplied from the audio data conversion unit 82, the real-time metadata supplied from the real-time metadata processing unit 84, and the non-real-time metadata supplied from the non-real-time metadata processing unit 85, and the video signal and the audio signal each having a small amount of data supplied from the low-resolution data processing unit 83, or can output each signal (data) independently in parallel. FIG. 4 is a block diagram showing an example of the detailed structure of the LTC data processing unit 71 in FIG. 3. The real-time metadata processing unit 66 of FIG. 3 incorporating the LTC data processing unit 71 shown in FIG. 4 supplies a control signal and a synchronization signal to the LTC data processing unit 71 and requests the LTC data processing unit 71 to generate LTC if the supplied real-time metadata does not include LTC, for example, in such a case where a video signal and an audio signal shot with an imaging device connected to the signal input/output device 51 are supplied. Upon acquiring the control signal and the synchronization signal, a control unit 101 in the LTC data processing unit 71 controls each unit of the LTC data processing unit 71 to perform LTC generation processing, based on the control signal and the synchronization signal. In the case of generating LTC relative to a predetermined time and independent of a real time, the control unit 101 controls an LTC generation unit 102 which performs LTC generation processing, an initial-value setting unit 103 which performs initial-value setting processing, and a counter 104 which counts frames, to perform various kinds of processing. The initial-value setting unit 103, controlled by the control unit 101, performs initial-value setting processing. Further, the initial-value setting unit 103 supplies the set initial value to the LTC generation unit 102. The counter 104 counts the number of frames to be processed, based on the synchronization signal supplied to the control unit 101, and supplies the count value to the LTC generation unit 102. Furthermore, a real-time clock 105 holds time information regarding real times and supplies the time information to the LTC generation unit 102, controlled by the control unit 101. The LTC generation unit 102, controlled by the control unit 101, generates LTC data in synchronization with a frame, using e.g. an initial value supplied from the initial-value setting unit 103 and the count value supplied from the counter 104, and supplies the LTC data to the real-time metadata processing unit 66. Further, in the case of generating LTC using a real time, the control unit 101 controls the LTC generation unit 102 which performs LTC generation processing, the real-time clock 105 which supplies real time information to perform various kinds of processing. In this case, the LTC generation unit 102, controlled by the control unit 101, generates LTC data in synchronization with a frame, using time information supplied from the real-time clock 105, and supplies the LTC data to the real-time metadata processing unit 66. FIG. 5 is a block diagram showing an example of the detailed structure of the LTC data processing unit 72 in FIG. 3. In such a case where LTC data is supplied from the real-time metadata processing unit 66, the non-real-time metadata processing unit 67 of FIG. 3 incorporating the LTC data processing unit 72 shown in FIG. 5 supplies the LTC data to the LTC data processing unit 71 and allows it to detect a frame (change point) where the change pattern such as increase or decrease in LTC value changes and to create an LTC change point table which indicates the relationship between LTC and FTC at the change point. The LTC data processing unit 72 incorporates an acquisition control unit 111 which acquires LTC data and FTC data supplied from the outside, a determination processing unit 112 which performs various kinds of determination processing, a data management unit 113 which manages LTC data and FTC data supplied from the outside, a data holding unit 114 which holds LTC data 121 and FTC data 122, controlled by the data management unit 113, a section setting management unit 115 which manages the setting of a specified section in a clip, supplied from the determination processing unit 112 as described later, a section setting holding unit 116 which holds a set section name 123, controlled by the section setting management unit 115, and a registration processing unit 117 which supplies an LTC change point table supplied from the determination processing unit 112 to the memory 38 which stores the LTC change point table. The acquisition control unit 111 incorporates a cache (not shown) of a predetermined capacity. The acquisition control unit 111 temporarily stores LTC data and FTC data supplied from the real-time metadata processing unit 66 in the incorporated cache and supplies them to the determination processing unit 112 for each predetermined amount of data. The determination processing unit 112 performs various kinds of determination processing based on various kinds of data from units, allows each unit to store each data based on the determination result, and supplies elements of the generated LTC change point table to the registration processing unit 117. The data management unit 113 manages the input/output of LTC data 121 and FTC data 122 held in the data holding unit 114. For example, the data management unit 113 supplies LTC data and FTC data supplied from the determination processing unit 112 to the data holding unit 114 which holds the LTC data and the FTC data. Further, the data management unit 113 acquires LTC data 121 and FTC data 122 held in the data holding unit 114 and supplies them to the determination processing unit 112, based on a request from the determination processing unit 112. The data holding unit 114 is composed of a storage medium such as a hard disk. The data holding unit 114 supplies the LTC data 121 and the FTC data 122 held in the storage area to the data management unit 113 and stores the LTC data and the FTC data supplied from the data management unit 113, based on a request from the data management unit 113. The section setting management unit 115 acquires a section name 123 held in the section setting holding unit 116 and supplies it to the determination processing unit 112, based on a request from the determination processing unit 112. Further, the section setting management unit 115 supplies a section name supplied from the determination processing unit 112 to the section setting holding unit 116 which holds the section name. The section setting holding unit 116 is composed of a storage medium such as a hard disk. The section setting holding unit 116 supplies the section name 123 held in the storage area to the section setting management unit 115 and holds the section name supplied from the section setting management unit 115, based on a request from the section setting management unit 115. The term “section” refers to a section between adjacent LTC change points dividing a clip. As described above, the LTC change point refers to a frame where a change pattern of increase or decrease in LTC value (LTC change pattern) changes, or to a frame whose LTC change pattern differs from an LTC change pattern of the next frame, among the frames divided by a plurality of predetermined LTC change patterns, as described later. That is, the LTC change patterns of frames included in one section are all the same. In other words, the section refers to a set of consecutive frames having the same LTC change pattern when all frames included in a clip are divided by the LTC change patterns. In most cases, video data of a clip is composed of a plurality of frames and provided with a plurality of LTC change points. Since the section refers to a section between adjacent LTC change points, a clip can be divided into a section or a plurality of sections. As described later, an LTC change pattern is related to the LTC and FTC of the corresponding change point and is registered in the LTC change table, as a section status. LTC change patterns includes “increment” which denotes that the LTC value of the next frame is larger than the LTC value of the current frame by 1, “increase” which denotes that the LTC value of the next frame is larger than the LTC value of the current frame by 2 or more, “still” which denotes that the LTC value of the next frame is the same as the LTC value of the current frame, “decrease” which denotes that the LTC value of the next frame is smaller than the LTC value of the current frame by 1 or more, “end” which denotes that the next frame does not exist (the current frame is the last frame of a clip), and “over” which denotes that there is not enough free space in the memory 38 for creating the LTC change point table in which elements are accumulated. The section setting holding unit 116 holds the LTC change point table, i.e., the name of a section status, as the section name 123. The registration processing unit 117 supplies elements of the LTC change point table supplied from the determination processing unit 112 to the memory 38 through the memory controller 37. Next, referring to the flowchart of FIG. 6, a description will be made as to the recording processing by the control unit 40 in the case where the data conversion unit 39 is configured as shown in FIG. 3. When the user operates the operation unit 41 and the operation unit 41 supplies an operation signal for instructing the control unit 40 to start the recording processing, the control unit 40 starts the recording processing. First, at step S1, the control unit 40 sets an audio annual-ring size Tsa and a video annual-ring size Tsv, and further sets a low-resolution annual-ring size Tsl and a real-time meta annual-ring size Tsm. The audio annual-ring size Tsa is a variable for determining the amount of audio data to be collectively placed and recorded on the optical disk 31 and is represented, for example, by a playback time period of an audio signal. The video annual-ring size Tsv also is a variable for determining the amount of video data to be collectively placed and recorded on the optical disk 31 and is represented, for example, by a playback time period of a video signal. Further, the low-resolution annual-ring size Tsl is a variable for determining the amount of low-resolution data to be collectively placed and recorded on the optical disk 31, and is represented, for example, by a playback time period of a video signal (or an audio signal) from which the low-resolution data is generated, in the same way as in the audio annual-ring size Tsa and the video annual-ring size Tsv. The real-time meta annual-ring size Tsm also is a variable for determining the amount of real-time metadata to be collectively placed and recorded on the optical disk 31, and is represented, for example, by a playback time period of a video signal (or an audio signal) of which information (e.g., the date and time when the video was shot) is described by the real-time metadata, in the same way as in the audio annual-ring size Tsa and the video annual-ring size Tsv. The following is the reason why the audio annual-ring size Tsa, the video annual-ring size Tsv, the low-resolution annual-ring size Tsl, and the real-time meta annual-ring size Tsm are not represented by the amount of data itself such as the number of bits, the number of bytes, but are represented by a playback time period or represented indirectly. According to the recording processing of FIG. 6, as described later, audio annual-ring data which is a set of audio data for each data amount based on the audio annual-ring size Tsa extracted from a series of audio data A, video annual-ring data which is a set of video data for each data amount based on the video annual-ring size Tsv extracted from a series of video data V, low-resolution annual-ring data which is a set of low-resolution data for each data amount based on the low-resolution annual-ring size Tsl extracted from a data series of low-resolution data, and real-time meta annual-ring data which is a set of real-time metadata for each data amount based on the real-time meta annual-ring size Tsm extracted from a data series of real-time metadata are periodically placed and recorded on the optical disk 31. In the case where audio annual-ring data, video annual-ring data, low-resolution annual-ring data, and real-time meta annual-ring data are periodically placed and recorded on the optical disk 31 as described, both a video signal and its accompanying audio signal are necessary for playback of video and audio. In viewpoint of the playback, audio annual-ring data at a certain playback time slot and video annual-ring data at the playback time slot should be recorded in positions close to each other such as adjacent positions on the optical disk 31. Since low-resolution annual-ring data is obtained by reducing the amount of audio annual-ring data and video annual-ring data, audio annual-ring data and video annual-ring data at a certain playback time slot and low-resolution annual-ring data obtained by reducing the amount of audio annual-ring data and video annual-ring data at the playback time slot should be recorded in positions close to each other on the optical disk 31. Further, since real-time meta annual-ring data denotes information about audio annual-ring data and video annual-ring data, audio annual-ring data and video annual-ring data at a certain playback time slot and real-time meta annual-ring data denoting information about audio annual-ring data at the playback time slot also should be recorded in positions close to each other on the optical disk 31. However, when the amounts of data are compared between audio data and video data for the same playback time period, the amounts of data vary greatly between audio data and video data, in general. In other words, the amount of audio data for a certain playback time period is much smaller than that of video data. Further, there are cases where the data rates of audio data and video data are not fixed but variable. In the same way, when the data rates of audio data and video data are compared to the data rates of low-resolution data and real-time metadata for the same playback time period, the data rates of low-resolution data and real-time metadata are smaller than those of audio data and video data. If the audio annual-ring size Tsa and the video annual-ring size Tsv are represented by the amount of data, and audio annual-ring data and video annual-ring data for each data amount are extracted in sequence from series of audio data and video data respectively, audio annual-ring data at a playback time slot ahead of that of video annual-ring data is obtained, thereby making it difficult to place audio data and video data which should be played back at the same playback time slot, in positions close to each other on the optical disk 31. As in the case of representing the audio annual-ring size Tsa and the video annual-ring size Tsv by the amount of data, if the low-resolution annual-ring size Tsl and the real-time meta annual-ring size Tsm are represented by the amount of data, it becomes difficult to place audio data, video data, low-resolution data, and real-time metadata which should be played back at similar playback time slots, in positions close to each other on the optical disk 31. For this reason, the audio annual-ring size Tsa, the video annual-ring size Tsv, the low-resolution annual-ring size Tsl, and the real-time meta annual-ring size Tsm are represented by a playback time period, thereby making it possible to place audio data, video data, low-resolution data, and real-time metadata which should be played back at similar playback time slots, in positions close to each other on the optical disk 31. The audio annual-ring size Tsa, the video annual-ring size Tsv, the low-resolution annual-ring size Tsl, and the real-time meta annual-ring size Tsm which are set at step S1 may be predetermined fixed values or variable values. In the case where the audio annual-ring size Tsa, the video annual-ring size Tsv, the low-resolution annual-ring size Tsl, and the real-time meta annual-ring size Tsm are variable values, the variable values can be inputted by operating the operation unit 41, for example. After step S1, the processing goes to step S2, where the control unit 40 controls the data conversion unit 39 so that the data conversion unit 39 starts audio signal conversion processing and video signal conversion processing for compressing/encoding an audio signal and a video signal supplied from the signal input/output device 51 to the disk recording/playback apparatus 30 into a series of audio data and a series of video data, and also controls the memory controller 37 so that the memory controller 37 starts audio data storage processing and video data storage processing for supplying audio data and video data obtained at the data conversion unit 39 to the memory 18 which stores the audio data and the video data. Further, at step S2, the control unit 40 controls the data conversion unit 39 so that the data conversion unit 39 starts real-time metadata processing for processing a series of real-time metadata supplied from the signal input/output device 51 to the disk recording/playback apparatus 30 and low-resolution data generation processing for generating a series of low-resolution data from an audio signal and a video signal supplied from the signal input/output device 51 to the disk recording/playback apparatus 30, and also controls the memory controller 37 so that the memory controller 37 starts real-time metadata storage processing and low-resolution data storage processing for supplying real-time metadata and low-resolution data obtained at the data conversion unit 39 to the memory 38 which stores the real-time metadata and the low-resolution data. Furthermore, at step S2, the control unit 40 controls the data conversion unit 39 so that the data conversion unit 39 starts non-real-time metadata processing for processing a series of non-real-time metadata supplied from the signal input/output device 51 to the disk recording/playback apparatus 30 and for performing processing about LTC using LTC contained in non-real-time metadata obtained, and also controls the memory controller 37 so that the memory controller 37 starts non-real-time metadata storage processing for supplying non-real-time metadata obtained at the data conversion unit 39 to the memory 38 which stores the non-real-time metadata. At step S3, the control unit 40 starts an audio data recording task which is a control task for recording audio data onto the optical disk 31. At step 4, the control unit 40 starts a video data recording task which is a control task for recording video data onto the optical disk 31, and advances the processing to step S5. At step S5, the control unit 40 starts a low-resolution data recording task which is a control task for recording low-resolution data onto the optical disk 31. At step 6, the control unit 40 starts a real-time metadata recording task which is a control task for recording real-time metadata onto the optical disk 31, and advances the processing to step S7. Detailed description will be made later as to the audio data recording task at step S3, the video data recording task at step S4, the low-resolution data recording task at step S5, and the real-time metadata recording task at step S6. At step S7, the control unit 40 determines whether an operation signal of an instruction to end data recording is supplied from the operation unit 41. If the control unit 40 determines that an operation signal is not supplied from the operation unit 41, the processing goes to step S8, where the control unit 40 determines whether all recording tasks have ended. At step S8, if the control unit 40 determines that all recording tasks have not ended, the control unit 40 returns the processing to step S7 to repeat steps S7 and S8. On the other hand, at step S7, if the control unit 40 determines that an operation signal of an instruction to end data recording is supplied from the operation unit 41, that is, e.g., if the user operates the operation unit 41 so as to end the data recording, the processing goes to step S9, where the control unit 40 ends the audio signal conversion processing, the video signal conversion processing, the real-time metadata processing, the low-resolution data generation processing, the audio data storage processing, the video data storage processing, the real-time metadata storage processing, and the low-resolution data storage processing, which are initiated at step S2, and the processing goes to step S10. At step S10, as in the case of step S8, the control unit 40 determines whether all recording tasks have ended, and the processing remains at step 10 until the control unit 40 determines that all recording tasks have ended. At step S10, if the control unit 40 determines that all recording tasks have ended, that is, if all of the audio data recording task initiated at step S3, the video data recording task initiated at step S4, the low-resolution data recording task initiated at step S5, and the real-time metadata recording task initiated at step S6 end, the control unit 40 advances the processing to step S11. At step S8, if the control unit 40 determines that all recording tasks have ended, that is, if all of the audio data recording task initiated at step S3, the video data recording task initiated at step S4, the low-resolution data recording task initiated at step S5, and the real-time metadata recording task initiated at step S6 end, the control unit 40 advances the processing to step S11. At step S11, the control unit 40 controls the memory controller 37 to read non-real-time metadata stored in the memory 38, perform padding so that the amount of non-real-time metadata becomes an integral multiple of the amount of data in one sector and supply it to the signal processing unit 36, and thereby performs recording control so that the non-real-time metadata whose amount is an integral multiple of the amount of data in one sector is recorded in the corresponding number of sectors. The control unit 40 advances the processing to step S12, where the control unit 40 ends the non-real-time metadata processing and the non-real-time metadata storage processing to end the recording processing. Next, referring to the flowchart of FIG. 7, a description will be made of the audio data recording task initiated at step S3 in FIG. 6. When the audio data recording task starts, first at step S31 the control unit 40 initializes a variable Na which is incremented by 1 at step S37 (performed later) to e.g. 1, and the processing goes to step S32. At step S32, the control unit 40 determines whether Tsa×Na is equal to or less than Tsv×Nv, and further determines whether Tsa×Na is equal to or less than Tsl×Nl and is equal to or less than Tsm×Nm. Here, Tsa is an audio annual-ring size and represents a playback time period of an audio signal. The variable Na is incremented by 1 every time audio data (audio annual-ring data) whose amount is based on the audio annual-ring size Tsa is recorded onto the optical disk 31, as described later. In the same manner, Tsv is a video annual-ring size, and the variable Nv is incremented by 1 every time video data (video annual-ring data) whose amount is based on the audio annual-ring size Tsv is recorded onto the optical disk 31, as described later. Further, Tsl is a low-resolution annual-ring size, and the variable Nl is incremented by 1 every time low-resolution data (low-resolution annual-ring data) whose amount is based on the low-resolution annual-ring size Tse is recorded onto the optical disk 31, as described later. Furthermore, Tsm is a real-time meta annual-ring size, and the variable Nm is incremented by 1 every time real-time metadata (real-time meta annual-ring data) whose amount is based on the real-time meta annual-ring size Tsm is recorded onto the optical disk 31, as described later. Therefore, Tsa×Na corresponds to the last playback time of audio annual-ring data to be recorded onto the optical disk 31 in the case where audio data is recorded in units of the audio annual-ring size Tsa. Tsv×Nv corresponds to the last playback time of video annual-ring data to be recorded onto the optical disk 31 in the case where video data is recorded in units of the video annual-ring size Tsv. Tsl×Nl corresponds to the last playback time of low-resolution annual-ring data to be recorded onto the optical disk 31 in the case where low-resolution data is recorded in units of the low-resolution annual-ring size Tse. Tsm×Nm corresponds to the last playback time of real-time meta annual-ring data to be recorded onto the optical disk 31 in the case where real-time metadata is recorded in units of the real-time meta annual-ring size Tsm. Here, assume that audio annual-ring data, video annual-ring data, low-resolution annual-ring data, and real-time meta annual-ring data at similar playback time slots are periodically placed so as to be recorded in positions close to each other on the optical disk 31. Further, assume that audio annual-ring data, video annual-ring data, low-resolution annual-ring data, and real-time meta annual-ring data, in order of earliest playback time, are placed in forwarder positions (positions based on the order they are read/written) on the optical disk 31. Furthermore, assume that audio annual-ring data, video annual-ring data, low-resolution annual-ring data, and real-time meta annual-ring data at similar playback time slots are placed in forwarder positions on the optical disk 31, for example, in the order of the audio annual-ring data, the video annual-ring data, the low-resolution annual-ring data, and the real-time meta annual-ring data. In this case, audio annual-ring data of interest as audio annual-ring data to be recorded is audio annual-ring data at the latest (closest to the playback time Tsa×Na) playback time slot prior to the playback time Tsa×Na. The audio annual-ring data of interest needs to be recorded just before video annual-ring data, low-resolution annual-ring data, and real-time meta annual-ring data at the latest playback time slot prior to the playback time Tsa×Na are recorded, that is, just after video annual-ring data, low-resolution annual-ring data, and real-time meta annual-ring data at the second latest playback time slot prior to the playback time Tsa×Na are recorded. Video annual-ring data to be recorded is video annual-ring data at the latest playback time slot prior to Tsv×Nv. Low-resolution annual-ring data to be recorded is low-resolution annual-ring data at the latest playback time slot prior to Tsl×Nl. Real-time meta annual-ring data to be recorded is real-time meta annual-ring data at the latest playback time slot prior to Tsm×Nm. Regarding annual-ring data at similar playback time slots, the audio annual-ring data is placed in a forwarder position, as described above. Therefore, the audio annual-ring data of interest needs to be recorded with timing in which Tsa×Na (playback time of audio annual-ring data) is equal to or less than Tsv×Nv (playback time of video annual-ring data), is equal to or less than Tsl×Nl (playback time of low-resolution annual-ring data), and is equal to or less than Tsm×Nm (playback time of real-time meta annual-ring data). Accordingly, it is determined at step S32 whether Tsa×Na (playback time of audio annual-ring data) is equal to or less than Tsv×Nv (playback time of video annual-ring data), is equal to or less than Tsl×Nl (playback time of low-resolution annual-ring data), and is equal to or less than Tsm×Nm (playback time of real-time meta annual-ring data), as described above. Thus, it is determined whether the current timing is a timing for recording audio annual-ring data of interest. At step S32, if the control unit 40 determines that Tsa×Na (playback time of audio annual-ring data) is more than Tsv×Nv (playback time of video annual-ring data), Tsl×Nl (playback time of low-resolution annual-ring data), or Tsm×Nm (playback time of real-time meta annual-ring data), that is, the current timing is not a timing for recording audio annual-ring data of interest, the control unit 40 returns the processing to step S32 for repetition. Further, at step S32, if the control unit 40 determines that Tsa×Na (playback time of audio annual-ring data) is equal to or less than Tsv×Nv (playback time of video annual-ring data) Tsl×Nl (playback time of low-resolution annual-ring data), and Tsm×Nm (playback time of real-time meta annual-ring data), that is, the current timing is a timing for recording audio annual-ring data of interest, the control unit 40 advances the processing to step S33, where the control unit 40 determines whether audio data is supplied from the data conversion unit 39 through the memory controller 37 to the memory 38. At step S33, if the control unit 40 determines that audio data is supplied to the memory 38, the control unit 40 advances the processing to step S34. At step S34, the control unit 40 determines whether audio data of an audio signal necessary to playback for the audio annual-ring size Tsa×Na has been accumulatively stored in the memory 38. If the control unit 40 determines that the audio data for Tsa×Na has not been stored in the memory 38, the processing returns to step S32 to repeat the steps thereafter. Further, at step S34, if the control unit 40 determines that the audio data for the playback time period Tsa×Na has been stored in the memory 38, the control unit 40 advances the processing to step S35. When the data amount detection unit 62 in the data conversion unit 39 detects an accumulative audio signal necessary to playback for the playback time period Tsa×Na, the data amount detection unit 62 sends the detection information to the memory controller 37. Based on the detection information, the memory controller 37 determines whether audio data necessary to playback for the playback time period Tsa×Na has been accumulatively stored in the memory 38, and sends the determination result to the control unit 40. The control unit 40 performs the determination at step S34 based on the determination result from the memory controller 37. In this embodiment, video data obtained by compressing/encoding an audio signal is stored in the memory 38. However, an audio signal, without being compressed/encoded, can be stored in the memory 38 as audio data. At step S35, the control unit 40 controls the memory controller 37 so that the memory controller 37 reads and extracts, from audio data stored in the memory 38, in a first-in-first-out manner, audio data having the maximum amount of data readable from the memory 38 that is an integral multiple of (n times) the amount Su of data in a physical recording/playback unit (physical unit area) formed on the optical disk 31, for example, one sector. After that, the processing goes to step S36. Further, audio annual-ring data read from the memory 38 as audio data having the maximum amount of data readable from the memory 38 that is an integral multiple of the amount of data in one sector, is the above-described latest audio annual-ring data prior to the playback time Tsa×Na. At step S36, the control unit 40 allows the memory controller 37 to supply the audio annual-ring data of interest (obtained at step S35) having the amount of data that is an integral multiple of the amount of data in one sector to the signal processing unit 36, and thereby performs recording control so that the audio annual-ring data of interest having the amount of data that is an integral multiple of the amount of data in one sector is recorded in the corresponding number of sectors. After performing recording control of the audio annual-ring data of interest at step S36 as described above, the control unit 40 advances the processing to step S37. At step S37, the control unit 40 increments the variable Na by 1 and returns the processing to step S32 to repeat the steps thereafter. On the other hand, at step S33, if the control unit 40 determines that audio data is not supplied to the memory 38, that is, if the supply of audio data from the data conversion unit 39 to the memory controller 37 is stopped, the control unit 40 advances the processing to step S38. At step S38, the control unit 40 controls the memory controller 37 to read all audio data remaining in the memory 38 and add padding data to the audio data so that its amount becomes the minimum amount of data that is an integral multiple of the amount of data in one sector. Thus, the audio data read from the memory 38 is formed into audio annual-ring data having the amount of data that is an integral multiple of the amount of data in one sector. Further, the control unit 40 allows the memory controller 37 to supply the audio annual-ring data to the signal processing unit 36, and thereby performs recording control so that the audio annual-ring data having the amount of data that is an integral multiple of the amount of data in one sector is recorded in the corresponding number of sectors. Subsequently, the processing goes to step S39, where the control unit 40 sets the variable Na to a value corresponding to infinity (an extremely large value) and ends the audio data recording task. In the above case, the sector is used as a physical unit area of the optical disk 31. However, it is also possible to use, for example, an ECC (Error Correction Code) block in which unit data subjected to ECC processing is recorded, as a physical unit area of the optical disk 31. Further, it is possible to use, for example, a fixed number of sectors and a fixed number of ECC blocks as physical unit areas of the optical disk 31. The ECC processing is performed in units of ECC blocks in the signal processing unit 36 for example. A sector can be composed of one or more ECC blocks. Alternatively, at least one ECC block can be used. In the description below, one sector is used as a physical unit area of the optical disk 31. Assuming that one sector forms one ECC block, the result of recording data on the optical disk 31 is the same, regardless of whether a sector or an ECC block is used as a physical unit area. Next, referring to the flowchart of FIG. 8, a description will be made of the video data recording task initiated at step S4 in FIG. 6. When the video data recording task starts, first at step S51 the control unit 40 initializes the variable Nv which is incremented by 1 at step S57 (described later) to e.g. 1, and the processing goes to step S52. At step S52, the control unit 40 determines whether Tsv×Nv is less than Tsa×Na, and further determines whether Tsv×Nv is equal to or less than Tsl×Nl and is equal to or less than Tsm×Nm. As described above, assume that audio annual-ring data and video annual-ring data at similar playback time slots are periodically placed so as to be recorded in positions close to each other on the optical disk 31. Further, audio annual-ring data and video annual-ring data at similar playback time slots are recorded so that the audio annual-ring data is firstly placed and the video annual-ring data is subsequently placed. In the case where video annual-ring data to be recorded is referred to as “video annual-ring data of interest”, the video annual-ring data of interest is video annual-ring data at the latest (closest to the playback time Tsv×Nv) playback time slot prior to the playback time Tsv×Nv. The video annual-ring data of interest needs to be recorded just after audio annual-ring data at the latest playback time slot prior to the playback time Tsa×Na is recorded, and just before low-resolution annual-ring data, and real-time meta annual-ring data at the latest playback time slot prior to the playback time Tsa×Na are recorded. Therefore, the video annual-ring data of interest needs to be recorded with timing in which Tsv×Nv (playback time of video annual-ring data) is less than Tsa×Na (playback time of audio annual-ring data) and is equal to or less than Tsl×Nl (playback time of low-resolution annual-ring data) and Tsm×Nm (playback time of real-time meta annual-ring data). Accordingly, it is determined at step S52 whether Tsv×Nv (playback time of video annual-ring data) is less than Tsa×Na (playback time of audio annual-ring data) and is equal to or less than Tsl×Nl (playback time of low-resolution annual-ring data) and Tsm×Nm (playback time of real-time meta annual-ring data), as described above. Thus, it is determined whether the current timing is a timing for recording video annual-ring data of interest. Therefore, as described above, it is determined at step S52 whether Tsv×Nv (playback time of video annual-ring data) is less than Tsa×Na (playback time of audio annual-ring data). Thus, it is determined whether the current timing is a timing for recording video annual-ring data of interest. At step S52, if the control unit 40 determines that Tsv×Nv (playback time of video annual-ring data) is equal to or more than Tsa×Na (playback time of audio annual-ring data) or is more than Tsl×Nl (playback time of low-resolution annual-ring data) or Tsm×Nm (playback time of real-time meta annual-ring data), that is, the current timing is not a timing for recording video annual-ring data of interest, the control unit 40 returns the processing to step S52 for repetition. Further, at step S52, if the control unit 40 determines that Tsv×Nv (playback time of video annual-ring data) is less than Tsa×Na (playback time of audio annual-ring data) and is equal to or less than Tsl×Nl (playback time of low-resolution annual-ring data) and Tsm×Nm (playback time of real-time meta annual-ring data), that is, the current timing is a timing for recording video annual-ring data of interest, the control unit 40 advances the processing to step S53, where the control unit 40 determines whether video data is supplied from the data conversion unit 39 through the memory controller 37 to the memory 38. At step S53, if the control unit 40 determines that video data is supplied to the memory 38, the processing goes to step S54. At step S54, the control unit 40 determines whether video data of a video signal necessary to playback for the video annual-ring size Tsv×Nv has been accumulatively stored in the memory 38. If the control unit 40 determines that the video data for Tsv×Nv has not been stored in the memory 38, the processing returns to step S52 to repeat the steps thereafter. Further, at step S54, if the control unit 40 determines that the video data for the playback time period Tsv×Nv has been stored in the memory 38, the control unit 40 advances the processing to step S55. When the data amount detection unit 62 in the data conversion unit 39 detects an accumulative video signal necessary to playback for the playback time period Tsv×Nv, the data amount detection unit 62 sends the detection information to the memory controller 37. Based on the detection information, the memory controller 37 determines whether video data necessary to playback for the playback time period Tsv×Nv has been accumulatively stored in the memory 38, and sends the determination result to the control unit 40. The control unit 40 performs the determination at step S54 based on the determination result from the memory controller 37. In this embodiment, video data obtained by compressing/encoding a video signal is stored in the memory 38. However, a video signal, without being compressed/encoded, can be stored in the memory 38 as video data. At step S55, the control unit 40 controls the memory controller 37 so that the memory controller 37 reads and extracts, from video data stored in the memory 38, in a first-in-first-out manner, video data having the maximum amount of data readable from the memory 38 that is an integral multiple of (n times) the amount of data in a physical recording/playback unit (physical unit area) formed on the optical disk 31, for example, one sector. After that, the processing goes to step S56. Further, video annual-ring data read from the memory 38 as video data having the maximum amount of data readable from the memory 38 that is an integral multiple of the amount of data in one sector, is the above-described latest video annual-ring data prior to the playback time Tsv×Nv. At step S56, the control unit 40 allows the memory controller 37 to supply the video annual-ring data of interest (obtained at step S55) having the amount of data that is an integral multiple of the amount of data in one sector to the signal processing unit 36, and thereby performs recording control so that the video annual-ring data of interest having the amount of data that is an integral multiple of the amount of data in one sector is recorded in the corresponding number of sectors. After performing recording control of the video annual-ring data of interest at step S56 as described above, the control unit 40 advances the processing to step S57. At step S57, the control unit 40 increments the variable Nv by 1 and returns the processing to step S52 to repeat the steps thereafter. On the other hand, at step S53, if the control unit 40 determines that video data is not supplied to the memory 38, that is, if the supply of video data from the data conversion unit 39 to the memory controller 37 is stopped, the control unit 40 advances the processing to step S58. At step S58, the control unit 40 controls the memory controller 37 to read all video data remaining in the memory 38 and add padding data to the video data so that its amount becomes the minimum amount of data that is an integral multiple of the amount of data in one sector. Thus, the video data read from the memory 38 is formed into video annual-ring data having the amount of data that is an integral multiple of the amount of data in one sector. Further, the control unit 40 allows the memory controller 37 to supply the video annual-ring data to the signal processing unit 36, and thereby performs recording control so that the video annual-ring data having the amount of data that is an integral multiple of the amount of data in one sector is recorded in the corresponding number of sectors. After the completion of step S58, the control unit 40 advances the processing to step S59, where the control unit 40 sets the variable Nv to a value corresponding to infinity and ends the video data recording task. Next, referring to the flowchart of FIG. 9, a description will be made of the low-resolution data recording task initiated at step S5 in FIG. 6. When the low-resolution data recording task starts, first at step S71 the control unit 40 initializes the variable Nl which is incremented by 1 at step S77 (described later) to e.g. 1, and the processing goes to step S72. At step S72, the control unit 40 determines whether Tsl×Nl is less than Tsa×Na and Tsv×Nv and is equal to or less than Tsm×Nm. As in the case of step S52 in FIG. 8, a state in which Tsl×Nl is less than Tsa×Na is a condition for recording low-resolution annual-ring data of interest as low-resolution annual-ring data to be recorded just after audio annual-ring data at the latest playback time slot prior to the playback time Tsl×Nl is recorded. Further, as in the case of step S52 in FIG. 8, a state in which Tsl×Nl is less than Tsv×Nv is a condition for recording low-resolution annual-ring data of interest as low-resolution annual-ring data to be recorded just after video annual-ring data at the latest playback time slot prior to the playback time Tsl×Nl is recorded. Furthermore, as in the case of step S32 in FIG. 7, a state in which Tsl×Nl is equal to or less than Tsm×Nm is a condition for recording low-resolution annual-ring data of interest as low-resolution annual-ring data to be recorded, that is, low-resolution annual-ring data at the latest (closest to the playback time Tsl×Nl) playback time slot prior to the playback time Tsl×Nl, just before real-time meta annual-ring data at the latest playback time slot prior to the playback time Tsl×Nl is recorded, that is, just after real-time meta annual-ring data at the second latest playback time slot prior to the playback time Tsl×Nl is recorded. At step S72, if the control unit 40 determines that Tsl×Nl (playback time of low-resolution annual-ring data) is equal to or more than Tsa×Na (playback time of audio annual-ring data) or Tsv×Nv (playback time of video annual-ring data) or is more than Tsm×Nm (playback time of real-time meta annual-ring data), that is, the current timing is not a timing for recording low-resolution annual-ring data of interest, the control unit 40 returns the processing to step S72 for repetition. Further, at step S72, if the control unit 40 determines that Tsl×Nl (playback time of low-resolution annual-ring data) is less than Tsa×Na (playback time of audio annual-ring data) and Tsv×Nv (playback time of video annual-ring data) and is equal to or less than Tsm×Nm (playback time of real-time meta annual-ring data), that is, the current timing is a timing for recording low-resolution annual-ring data of interest, the processing goes to step S73, where the control unit 40 determines whether low-resolution data is supplied from the data conversion unit 19 through the memory controller 17 to the memory 18. At step S73, if the control unit 40 determines that low-resolution data is supplied to the memory, the processing goes to step S74. At step S74, the control unit 40 determines whether low-resolution data necessary to playback for the low-resolution annual-ring size Tsl×Nl has been accumulatively stored in the memory 38. If the control unit 40 determines that the low-resolution data for Tsl×Nl has not been stored in the memory 38, the processing returns to step S72 to repeat the steps thereafter. Further, at step S74, if the control unit 40 determines that the low-resolution data for the playback time period Tsl×Nl has been stored in the memory 38, the processing goes to step S75. When the data amount detection unit 42 in the data conversion unit 39 detects an accumulative video signal and audio signal necessary to playback for the playback time period Tsl×Nl, the data amount detection unit sends the detection information to the memory controller 37. Based on the detection information, the memory controller 37 determines whether low-resolution data necessary to playback for the playback time period Tsl×Nl has been accumulatively stored in the memory 38, and sends the determination result to the control unit 40. The control unit 40 performs the determination at step S74 based on the determination result from the memory controller 37. In this embodiment, low-resolution data is generated by compressing/encoding a video signal etc. whose data amount is reduced. However, a video signal etc. whose data amount is reduced can be low-resolution data without being compressed/encoded. At step S75, the control unit 40 controls the memory controller 37 so that the memory controller 37 reads and extracts, from low-resolution data stored in the memory 38, in a first-in-first-out manner, low-resolution data having the maximum amount of data readable from the memory 38 that is an integral multiple of (n times) the amount of data in a physical recording/playback unit (physical unit area) formed on the optical disk 31, for example, one sector. After that, the processing goes to step S76. Further, low-resolution annual-ring data read from the memory 38 as low-resolution data having the maximum amount of data readable from the memory 38 that is an integral multiple of the amount of data in one sector, is the above-described latest low-resolution annual-ring data prior to the playback time Tsl×Nl. Further, low-resolution data that has not been read out at step S75 remains in the memory 38. At step S76, the control unit 40 allows the memory controller 37 to supply the low-resolution annual-ring data of interest (obtained at step S75) having the amount of data that is an integral multiple of the amount of data in one sector to the signal processing unit 36, and thereby performs recording control so that the low-resolution annual-ring data of interest having the amount of data that is an integral multiple of the amount of data in one sector is recorded in the corresponding number of sectors. Thereby, the low-resolution annual-ring data having the amount of data that is an integral multiple of the amount of data in one sector is recorded in the corresponding number of sectors in such a way that the boundaries of low-resolution annual-ring data coincide with the boundaries of sectors of the optical disk 31. Subsequently, the processing goes to step S77, where the control unit 40 increments the variable Nl by 1 and returns the processing to step S72 to repeat the steps thereafter. On the other hand, at step S73, if the control unit 40 determines that low-resolution data is not supplied to the memory 38, that is, if the supply of low-resolution data from the data conversion unit 39 to the memory controller 37 is stopped, the processing goes to step S78. At step S78, the control unit 40 controls the memory controller 37 to read all low-resolution data remaining in the memory 38 and add padding data to the low-resolution data so that its amount becomes the minimum amount of data that is an integral multiple of the amount of data in one sector. Thus, the low-resolution data read from the memory 38 is formed into low-resolution annual-ring data having the amount of data that is an integral multiple of the amount of data in one sector. Further, the control unit 40 allows the memory controller 37 to supply the low-resolution annual-ring data to the signal processing unit 36, and thereby performs recording control so that the low-resolution annual-ring data having the amount of data that is an integral multiple of the amount of data in one sector is recorded in the corresponding number of sectors. Subsequently, the processing goes to step S79, where the control unit 40 sets the variable Nl to a value corresponding to infinity and ends the low-resolution data recording task. Next, referring to the flowchart of FIG. 10, a description will be made of the real-time metadata recording task initiated at step S5 in FIG. 6. When the real-time metadata recording task starts, first at step S91 the control unit 40 initializes the variable Nl which is incremented by 1 at step S97 (described later) to e.g. 1, and the processing goes to step S92. At step S92, the control unit 40 determines whether Tsm×Nm is less than Tsa×Na, Tsv×Nv, and Tsl×Nl. As in the case of step S52 in FIG. 8, a state in which Tsm×Nm is less than Tsa×Na is a condition for recording real-time meta annual-ring data of interest as real-time meta annual-ring data to be recorded just after audio annual-ring data at the latest playback time slot prior to the playback time Tsm×Nm is recorded. Further, as in the case of step S72 in FIG. 9, a state in which Tsm×Nm is less than Tsv×Nv is a condition for recording real-time meta annual-ring data of interest as real-time meta annual-ring data to be recorded just after video annual-ring data at the latest playback time slot prior to the playback time Tsm×Nm is recorded. Furthermore, a state in which Tsm×Nm is less than Tsl×Nl is a condition for recording real-time meta annual-ring data of interest as real-time meta annual-ring data to be recorded just after low-resolution annual-ring data at the latest playback time slot prior to the playback time Tsm×Nm is recorded. At step S92, if the control unit 40 determines that Tsm×Nm (playback time of real-time meta annual-ring data) is equal to or more than Tsa×Na (playback time of audio annual-ring data), Tsv×Nv (playback time of video annual-ring data), or Tsl×Nl (playback time of real-time meta annual-ring data), that is, the current timing is not a timing for recording real-time meta annual-ring data of interest, the processing returns to step S92 for repetition. Further, at step S92, if the control unit 40 determines that Tsm×Nm (playback time of real-time meta annual-ring data) is less than Tsa×Na (playback time of audio annual-ring data), Tsv×Nv (playback time of video annual-ring data), and Tsl×Nl (playback time of low-resolution annual-ring data), that is, the current timing is a timing for recording real-time meta annual-ring data of interest, the processing goes to step S93, where the control unit 40 determines whether real-time metadata is supplied from the data conversion unit 39 through the memory controller 37 to the memory 38. At step S93, if the control unit 40 determines that real-time metadata is supplied to the memory 38, the processing goes to step S94. At step S94, the control unit 40 determines whether real-time metadata necessary to playback for the real-time meta annual-ring size Tsm×Nm has been accumulatively stored in the memory 38. If the control unit 40 determines that the real-time metadata for Tsm×Nm has not been stored in the memory 38, the processing returns to step S92 to repeat the steps thereafter. Further, at step S94, if the control unit 40 determines that the real-time metadata for the playback time period Tsm×Nm has been stored in the memory 38, the processing goes to step S95. When the data amount detection unit 62 in the data conversion unit 39 detects an accumulative video signal and audio signal necessary to playback for the playback time period Tsm×Nm, the data amount detection unit 62 sends the detection information to the memory controller 37. Based on the detection information, the memory controller 37 determines whether real-time metadata necessary to playback for the playback time period Tsm×Nm has been accumulatively stored in the memory 38, and sends the determination result to the control unit 40. The control unit 40 performs the determination at step S94 based on the determination result from the memory controller 37. At step S95, the control unit 40 controls the memory controller 37 so that the memory controller 37 reads and extracts, from real-time metadata stored in the memory 38, in a first-in-first-out manner, metadata having the maximum amount of data readable from the memory 38 that is an integral multiple of (n times) the amount of data in a physical recording/playback unit (physical unit area) formed on the optical disk 31, for example, one sector. After that, the processing goes to step S96. Further, real-time meta annual-ring data read from the memory 38 as real-time metadata having the maximum amount of data readable from the memory 38 that is an integral multiple of the amount of data in one sector, is the above-described latest real-time meta annual-ring data prior to the playback time Tsm×Nm. Further, real-time metadata that has not been read out at step S95 remains in the memory 38. At step S96, the control unit 40 allows the memory controller 37 to supply the meta annual-ring data of interest (obtained at step S95) having the amount of data that is an integral multiple of the amount of data in one sector to the signal processing unit 36, and thereby performs recording control so that the real-time meta annual-ring data of interest having the amount of data that is an integral multiple of the amount of data in one sector is recorded in the corresponding number of sectors. Thereby, the meta annual-ring data having the amount of data that is an integral multiple of the amount of data in one sector is recorded in the corresponding number of sectors in such a way that the boundaries of real-time meta annual-ring data coincide with the boundaries of sectors of the optical disk 31. Subsequently, the processing goes to step S97, where the control unit 40 increments the variable Nm by 1 and returns the processing to step S92 to repeat the steps thereafter. On the other hand, at step S93, if the control unit 40 determines that real-time metadata is not supplied to the memory 38, that is, if the supply of real-time metadata from the data conversion unit 39 to the memory controller 37 is stopped, the processing goes to step S98. At step S98, the control unit 40 controls the memory controller 37 to read all real-time metadata remaining in the memory 38 and add padding data to the real-time metadata so that its amount becomes the minimum amount of data that is an integral multiple of the amount of data in one sector. Thus, the real-time metadata read from the memory 38 is formed into real-time meta annual-ring data having the amount of data that is an integral multiple of the amount of data in one sector. Further, the control unit 40 allows the memory controller 37 to supply the real-time meta annual-ring data to the signal processing unit 36, and thereby performs recording control so that the real-time meta annual-ring data having the amount of data that is an integral multiple of the amount of data in one sector is recorded in the corresponding number of sectors. Subsequently, the processing goes to step S99, where the control unit 40 sets the variable Nm to a value corresponding to infinity and ends the real-time metadata recording task. As described above, the real-time metadata includes, for example, LTC, a user bit, UMID, an essence mark, ARIB metadata, or setting/control information of a video camera with which shooting has been performed. These pieces of data are KLV (Key Length Value)-encoded data (hereinafter referred to as KLV data) that is composed of key data 111, length data 112, and value data 113, as shown in FIG. 11. This format is in conformity with SMPTE 335M/RP214. The key data 111 of KLV data 110 is an identifier that indicates a KLV-encoded data item. Identifiers defined in an SMTPE metadata dictionary and corresponding to various data items are used as the identifier. The length data 112 of the KLV data 110 indicates the length of the value data 113 in bytes. The value data 113 of the KLV data 110 is composed of data proper such as text data as in an XML (extensible Markup Language) document or the like. That is, the KLV data 110 is obtained by encoding the data of the data item indicated by the key data 111, whose length is indicated by the length data 112, and which is represented by the value data 113. The real-time metadata includes the above-mentioned various kinds of data which are KLV data having such a data structure. From the viewpoint of contents, the real-time metadata composed of the plurality of data is broadly divided into two parts: an essential part and an optional part. The essential part is composed of real-time metadata that supports all frames, such as LTC, a user bit, UMID, an essence mark, and other KLV data. The optional part is composed of data that is included in the real-time metadata as necessary, such as ARIB metadata and video camera setting/control information. Each data length of the essential part and the optional part is predetermined fixed length. Further, since the real-time performance is required of the real-time metadata to support data transfer according to a synchronization-based communication interface such as SDI, the essential part (and the optional part) is structured with one file in BIM (BInary Format for MPEG-7) so as to be written and read to/from the optical disk 31 at high speed. Data in BIM format is obtained by converting XML data into binary data. It is possible to represent the above-mentioned various kinds of data included in the real-time metadata in XML format. However, the amount of data becomes large in the case of XML; therefore, XML is unsuitable for the real-time metadata that needs to be written and read in reduced time (real time). By using BIM in binary representation having information corresponding to XML representation, it becomes possible to write and read the real-time metadata in real time. Further, by using the real-time metadata in BIM format, it is possible not only to reduce data areas on the optical disk 31 necessary to record the real-time metadata but also to shorten a read/write time and further reduce storage areas in a memory for storing data at the time of writing and reading, thereby making it possible to improve writing/reading speed as a whole. The control unit 40 controls the real-time metadata processing unit 66 so that the real-time metadata processing unit 66 supplies the real-time metadata composed of the above-mentioned KLV data and supplied through the data amount detection unit 62 to the real-time metadata processing unit 66 to the memory controller 37 which records it onto the optical disk 31, as described above. However, for example, if a video signal and an audio signal are inputted from a video camera (nor shown) used for shooting through the signal input/output device 51 to the disk recording/playback apparatus (disk drive) 30, that is, if a video signal and an audio signal obtained by shooting are supplied to the disk recording/playback apparatus 30 without metadata added, metadata such as LTC is not added to the video signal and the audio signal. For example, in the case where the disk recording/playback apparatus 30 is combined with a video camera, a video signal and an audio signal obtained by shooting are supplied to the data conversion unit 39 without processing such as adding real-time metadata or the like. In such a case, the control unit 40 controls the real-time metadata processing unit 66 in the data conversion unit 39 so that the LTC data processing unit 71 included in the real-time metadata processing unit 66 performs LTC data generation processing for generating LTC data. The control unit 101 in the LTC data processing unit 71 performs the LTC data generation processing. Upon being instructed by the real-time metadata processing unit 66 controlled by the control unit 40 to generate LTC data, the control unit 101 generates LTC data in synchronization with the frame of a video signal supplied from the signal input/output device 51 to the data conversion unit 39, and supplies the generated LTC data to the real-time metadata processing unit 66. Referring now to the flowchart of FIG. 12, a description will be made of the LTC data generation processing by the control unit 101 in the LTC data processing unit 71. First, at step S111, the control unit 101 determines whether it has acquired an instruction to start generating LTC data from the real-time metadata processing unit 66, and the processing remains at step S111 until the control unit 101 determines that it has acquired an instruction. If the control unit 101 determines that it has acquired an instruction to start generating LTC data, the control unit 101 advances the processing to step S112, where the control unit 101 determines whether to generate LTC using a real time. In some cases, LTC data is generated using a real time or using a predetermined initial value. The control unit 40 supplies such information accepted through e.g. the operation unit 41, that is, information indicating whether to generate LTC data using a real time, or information indicating whether an initial value has been set in the case of generating LTC data without using a real time, to the real-time metadata processing unit 66 in the data conversion unit 39. The real-time metadata processing unit 66 supplies the information as well as an instruction to start generating LTC data to the control unit 101 in the LTC data processing unit 71. The control unit 101 determines at step S112 whether to generate LTC using a real time, based on the supplied information. If the control unit 101 determines at step S112 to generate LTC using a real time, the control unit 101 advances the processing to step S113, where, as described above, the control unit 101 controls the LTC generation unit 102 and the real-time clock 105 to generate LTC data in accordance with a synchronization signal using a real-time clock. That is, the control unit 101 supplies a synchronization signal to the real-time clock 105 and allows the real-time clock 105 to supply information about the real time to the LTC generation unit 102 in accordance with a synchronization signal. Further, the control unit 101 supplies the synchronization signal to the LTC generation unit 102 for synchronization between the operation of the LTC generation unit 102 and the synchronization signal, and allows the LTC generation unit 102 to generate LTC data, based on the information about the real time supplied from the real-time clock 102. After the completion of step S113, the control unit 101 advances the processing to step S114, where the control unit 101 controls the LTC generation unit 102 so that the LTC generation unit 102 supplies the generated LTC data to the real-time metadata processing unit 66, which supplies it to the memory controller 37. That is, the real-time metadata processing unit 66 supplies the LTC data of real-time metadata supplied from the LTC data processing unit 71 to the memory controller 37. After the supply of the LTC data, the control unit 101 determines at step S115 whether it has acquired an instruction to end LTC data generation supplied from the real-time metadata processing unit 66 as in the case of the control signal and the synchronization signal. That is, the control unit 40 supplies an instruction to end LTC data generation to the real-time metadata processing unit 66 in the data conversion unit 39, based on e.g. an instruction inputted through the operation unit 41 from the user. Upon acquiring the instruction to end LTC data generation, the real-time metadata processing unit 66 supplies the instruction to the control unit 101 in the LTC data processing unit 71. The control unit 101 determines at step S115 whether it has acquired the instruction. At step S115, if the control unit 101 determines that it has not acquired an instruction to end LTC data generation, the control unit 101 returns the processing to step S113 to repeat the steps thereafter. If the control unit 101 determines that it has acquired an instruction to end LTC data generation, the control unit 101 ends the LTC data generation processing. If the control unit 101 determines at step S112 to generate LTC without using a real time, the control unit 101 advances the processing to step S116, where the control unit 101 determines whether the setting of an initial value has been specified, based on the information acquired from the real-time metadata processing unit 66 as described above. If the control unit 101 determines that the setting of an initial value has been specified, the control unit 101 advances the processing to step S117, where the control unit 101 controls the initial-value setting unit 103 to set the initial value of LTC to a specified value. That is, in this case, the control unit 101 supplies information about an initial-value instruction (a specified initial value) to the initial-value setting unit 103 and allows the initial-value setting unit 103 to set the initial value of LTC to the specified value. The initial-value setting unit 103 supplies the set initial value to the LTC generation unit 102. After setting the initial value, the control unit 101 advances the processing to step S119. At step S116, if the control unit 101 determines that the setting of an initial value has not been specified, the control unit 101 advances the processing to step S118, where the control unit 101 controls the initial-value setting unit 103 to set the initial value of LTC to “0”. That is, in this case, the control unit 101 supplies value “0” to the initial-value setting unit 103 and allows the initial-value setting unit 103 to set the initial value of LTC to “0”. After setting the initial value, the control unit 101 advances the processing to step S119. At step S119, the control unit 101 controls the LTC generation unit 102 and the counter 104 so that the LTC generation unit 102 generates LTC data in accordance with the synchronization signal using the counter 104. That is, the counter 104 performs count processing in accordance with the synchronization signal supplied from the control unit 101 and sequentially supplies a calculated count value to the LTC generation unit 102. The LTC generation unit 102 operates in synchronization with the synchronization signal supplied from the control unit 101 and generates LTC data using the initial value supplied from the initial-value setting unit 103 and the count value supplied from the counter 104. After the completion of step S119, at step S120 the control unit 101 controls the LTC generation unit 102 so that the LTC generation unit 102 supplies the generated LTC data to the real-time metadata processing unit 66, which supplies it to the memory controller 37. That is, the real-time metadata processing unit 66 supplies the LTC data of real-time metadata supplied from the LTC data processing unit 71 to the memory controller 37. After the supply of the LTC data, the control unit 101 determines at step S121 whether it has acquired an instruction to end LTC data generation supplied from the real-time metadata processing unit 66 as in the case of step S115. That is, the control unit 40 supplies an instruction to end LTC data generation to the real-time metadata processing unit 66 in the data conversion unit 39, based on e.g. an instruction inputted through the operation unit 41 from the user. Upon acquiring the instruction to end LTC data generation, the real-time metadata processing unit 66 supplies the instruction to the control unit 101 in the LTC data processing unit 71. The control unit 101 determines at step S121 whether it has acquired the instruction. At step S121, if the control unit 101 determines that it has not acquired an instruction to end LTC data generation, the control unit 101 returns the processing to step S119 to repeat the steps thereafter. If the control unit 101 determines that it has acquired an instruction to end LTC data generation, the control unit 101 ends the LTC data generation processing. The LTC data generated as described above and supplied to the memory controller 37 is processed as real-time metadata as described above and recorded onto the optical disk 31 along with audio data and video data. By recording the thus generated LTC data as real-time metadata along with essence data, the disk recording/playback apparatus 30 in FIG. 2 enables the user to more easily perform playback control processing at the time of playing back essence data as described later. Further, the real-time metadata processing unit 66 supplies the LTC data acquired from the LTC data processing unit 71 or the data amount detection unit 62 not only to the memory controller 37 but also to the non-real-time metadata processing unit 67. The non-real-time metadata processing unit 67 supplies the acquired LTC data to the incorporated LTC data processing unit 72. Further, the non-real-time metadata processing unit 67 supplies a control signal, a synchronization signal, or necessary information such as FTC data supplied from the control unit 40 to the LTC data processing unit 72. These pieces of information are supplied in units of frames of video data. Accordingly, the LTC data processing unit 72 performs LTC change point table creation processing to create an LTC change point table based on these pieces of information supplied in units of frames. Referring now to the flowcharts of FIGS. 13 to 15, a description will be made of the LTC change point table creation processing by the LTC data processing unit 72. Further, a description will be made with reference to FIGS. 16 to 20 as necessary. First, at step S141, the acquisition control unit 111 determines whether it has acquired LTC data. If the acquisition control unit 111 determines that it has acquired LTC data, the acquisition control unit 111 supplies the LTC data and FTC data supplied concurrently with the LTC data and corresponding to the LTC data to the determination processing unit 112, and advances the processing to step S142. The determination processing unit 112 which has acquired the LTC data from the acquisition control unit 111 controls the data management unit 113 so that the data management unit 113 checks whether there is LTC data in the data holding unit 114. Based on this control, the data management unit 113 accesses the data holding unit 114 to check whether there is LTC data in the data holding unit 114, and supplies the check result to the determination processing unit 112. At step S142, the determination processing unit 112 determines whether there is LTC data in the data holding unit 114, based on the supplied check result. For example, at step S141 the acquisition control unit 111 has just acquired LTC data corresponding to the first frame of a clip. Therefore, if the determination processing unit 112 determines that there is no LTC data 121 in the data holding unit 114, the determination processing unit 112 advances the processing to step S143, where the determination processing unit 112 supplies the acquired LTC data and FTC data through the data management unit 113 to the data holding unit 114 which holds the LTC data and FTC data. After the determination processing unit 112 allows the data holding unit 114 to hold the LTC data and FTC data, the determination processing unit 112 returns the processing to step S141 to repeat the steps thereafter for LTC data and FTC data of the next frame. At step S142, if the determination processing unit 112 determines that there is LTC data in the data holding unit 114, the determination processing unit 112 advances the processing to step S144, where the determination processing unit 112 controls the data management unit 113 to acquire the LTC data 121 from the data holding unit 114 and compares values between the LTC data (the acquired LTC data) supplied from the acquisition control unit 111 and the LTC data (the held LTC data) acquired from the data holding unit 114. Further, at step S145, the determination processing unit 112 controls the section setting management unit 115 to refer to the section name 123 held in the section setting holding unit 116, that is, the current section setting (status). After the completion of step S145, the determination processing unit 112 advances the processing to step S146, where the determination processing unit 112 determines whether the value of the acquired LTC data is larger than the value of the held LTC data by 1 (consecutive increment), based on the comparison result at step S144. If the determination processing unit 112 determines that it is the consecutive increment, the determination processing unit 112 advances the processing to step S147, where the determination processing unit 112 determines whether the current section is an increment section (a section whose status is “increment”), based on the reference result at step S145. If the determination processing unit 112 determines that the current section is not an increment section, the determination processing unit 112 determines that the status (i.e., the section) has changed, and advances the processing to step S148 in order to put the frame (corresponding to the held LTC data) into an LTC change point. At step S148, the determination processing unit 112 controls the data management unit 113 to acquire the LTC data 121 and the FTC data 122 held in the data holding unit 114 and adds status information (“increment” in this case) to the LTC data and the FTC data. Further, the determination processing unit 112 supplies the LTC data, the FTC data and the status information as elements of the LTC change point table to the registration processing unit 117. The registration processing unit 117 supplies the elements of the LTC change point table as an increment point (a change point whose status is “increment”) to the memory 38 to register them in the LTC change point table. After the completion of step S148, at step S149 the determination processing unit 112 supplies the status determined this time through the section setting management unit 115 to the section setting holding unit 116 which stores it as the section name 123, thus setting the current section to an increment section. After that, the processing goes to step S150. Further, at step S147, if the determination processing unit 112 determines that the current section is an increment section, the determination processing unit 112 omits steps S148 and S149 and advances the processing to step S150. FIG. 16A is a diagram showing an example of the relationship between FTC and LTC in an increment section. The horizontal axis indicates the FTC of a frame, and the vertical axis indicates the LTC of the frame. In FIG. 16A, for example, the LTC value of the frame whose FTC value is “N” (the frame whose frame number is N) is “M”, the LTC value of the next frame (the frame whose FTC value is “N+1”) is “M+1”, and the LTC value of the frame after the next (the frame whose FTC value is “N+2”) is “M+2”. Thus, in the increment section, the LTC value in consecutive frames is incremented by 1 as the FTC value is incremented by 1. For example, in the case where there is no setting of a status (the section setting holding unit 116 does not hold the section name 123) or a set status is not “increment” (the content of the section name 123 held in the section setting holding unit 116 is not “increment”), when a frame group (in which LTC is consecutively incremented) shown in FIG. 16A is inputted to the data conversion unit 39, the determination processing unit 112 determines that the status has changed to “increment” (the section has changed) and creates an element 141 of an LTC change point table 124 shown in FIG. 16B in which the first frame (frame number N) of the frame group is an increment point. As described above, the elements of the LTC change point table includes three items which are a “frame number” which indicates the FTC of the LTC change point, “LTC” which indicates the LTC of the LTC change point, and a “status” which indicates a type of LTC change pattern of frames after the LTC change point. In the case of the element 141 shown in FIG. 16B, the value of item “frame number” is “N”, the value of item “LTC” is “M”, and item “status” is “increment”. After creating the element 141, the determination processing unit 112 supplies the created element to the registration processing unit 117 and allows the registration processing unit 117 to register the element in the LTC change point table 124 stored in the memory 38. In the case where the content of the section name 123 held in the section setting holding unit 116 is “increment”, when a frame group (in which LTC is consecutively incremented) shown in FIG. 16A is inputted to the data conversion unit 39, the determination processing unit 112 determines that the status has not changed (the same section continues) and does not create the element 141 (does not update the status). At step S150, the determination processing unit 112 controls the data management unit 113 so that the data management unit 113 supplies the LTC data and the FTC data acquired this time through the acquisition control unit 111 to the data holding unit 114 to update the LTC data 121 and the FTC data 122 held in the data holding unit 114 using the acquired LTC data and FTC data. After the completion of the update, the determination processing unit 112 advances the processing to step S184 in FIG. 15. At step S146, if the determination processing unit 112 determines that the value of the acquired LTC data is not larger than the value of the held LTC data by 1 (not consecutive increment), the determination processing unit 112 advances the processing to step S161 in FIG. 14. At step S161 in FIG. 14, the determination processing unit 112 determines whether the value of the acquired LTC data is larger than the value of the held LTC data by 2 or more, based on the comparison result at step S144 in FIG. 13. If the determination processing unit 112 determines that the value of the acquired LTC data is larger than the value of the held LTC data by 2 or more, the determination processing unit 112 advances the processing to step S162, where the determination processing unit 112 determines whether the current section is an increase section (a section whose status is “increase”), based on the reference result at step S145 in FIG. 13. If the determination processing unit 112 determines that the current section is not an increase section, the determination processing unit 112 determines that the status (i.e., the section) has changed, and advances the processing to step S163 in order to put the frame (corresponding to the held LTC data) into an LTC change point. At step S163, the determination processing unit 112 controls the data management unit 113 to acquire the LTC data 121 and the FTC data 122 held in the data holding unit 114 and adds status information (“increase” in this case) to the LTC data and the FTC data. Further, the determination processing unit 112 supplies the LTC data, the FTC data and the status information as elements of the LTC change point table to the registration processing unit 117. The registration processing unit 117 supplies the elements of the LTC change point table as an increase point (a change point whose status is “increase”) to the memory 38 to register them in the LTC change point table. After the completion of step S163, at step S164 the determination processing unit 112 supplies the status determined this time through the section setting management unit 115 to the section setting holding unit 116 which stores it as the section name 123, thus setting the current section to an increase section. After that, the processing returns to step S150 in FIG. 13 to repeat the steps thereafter. Further, at step S162 in FIG. 14, if the determination processing unit 112 determines that the current section is an increase section, the determination processing unit 112 omits steps S163 and S164 and returns the processing to step S150 in FIG. 13. FIG. 17A is a diagram showing an example of the relationship between FTC and LTC in an increase section. The horizontal axis indicates the FTC of a frame, and the vertical axis indicates the LTC of the frame. In FIG. 17A, for example, the LTC value of the frame whose FTC value is “N” (the frame whose frame number is N) is “M”, the LTC value of the next frame (the frame whose FTC value is “N+1”) is “M+2”, and the LTC value of the frame after the next (the frame whose FTC value is “N+2”) is “M+5”. Thus, in the increase section, the LTC value in consecutive frames increases by 2 or more as the FTC value increases by 1. For example, in the case where there is no setting of a status (the section setting holding unit 116 does not hold the section name 123) or a set status is not “increase” (the content of the section name 123 held in the section setting holding unit 116 is not “increase”), when a frame group (in which LTC increases by 2 or more) shown in FIG. 17A is inputted to the data conversion unit 39, the determination processing unit 112 determines that the status has changed to “increase” (the section has changed) and creates an element 142 of the LTC change point table 124 shown in FIG. 17B in which the first frame (frame number N) of the frame group is an increase point. In the case of the element 142 shown in FIG. 17B, the value of item “frame number” is “N”, the value of item “LTC” is “M”, and item “status” is “increase”. After creating the element 142, the determination processing unit 112 supplies the created element to the registration processing unit 117 and allows the registration processing unit 117 to register the element in the LTC change point table 124 stored in the memory 38. In the case where the content of the section name 123 held in the section setting holding unit 116 is “increase”, when a frame group (in which LTC increases by 2 or more) shown in FIG. 17A is inputted to the data conversion unit 39, the determination processing unit 112 determines that the status has not changed (the same section continues) and does not create the element 142 (does not update the status). At step S161, if the determination processing unit 112 determines that the value of the acquired LTC data is not larger than the value of the held LTC data by 2 or more, the determination processing unit 112 advances the processing to step S165. At step S165, the determination processing unit 112 determines whether the value of the acquired LTC data is the same as the value of the held LTC data, based on the comparison result at step S144 in FIG. 13. If the determination processing unit 112 determines that the value of the acquired LTC data has not changed and is the same as the value of the held LTC data, the determination processing unit 112 advances the processing to step S166, where the determination processing unit 112 determines whether the current section is a still section (a section whose status is “still”), based on the reference result at step S145 in FIG. 13. If the determination processing unit 112 determines that the current section is not a still section, the determination processing unit 112 determines that the status (i.e., the section) has changed, and advances the processing to step S167 in order to put the frame (corresponding to the held LTC data) into an LTC change point. At step S167, the determination processing unit 112 controls the data management unit 113 to acquire the LTC data 121 and the FTC data 122 held in the data holding unit 114 and adds status information (“still” in this case) to the LTC data and the FTC data. Further, the determination processing unit 112 supplies the LTC data, the FTC data and the status information as elements of the LTC change point table to the registration processing unit 117. The registration processing unit 117 supplies the elements of the LTC change point table as a still point (a change point whose status is “still”) to the memory 38 to register them in the LTC change point table. After the completion of step S167, at step S168 the determination processing unit 112 supplies the status determined this time through the section setting management unit 115 to the section setting holding unit 116 which stores it as the section name 123, thus setting the current section to a still section. After that, the processing returns to step S150 in FIG. 13 to repeat the steps thereafter. Further, at step S166 in FIG. 14, if the determination processing unit 112 determines that the current section is a still section, the determination processing unit 112 omits steps S167 and S168 and returns the processing to step S150 in FIG. 13. FIG. 18A is a diagram showing an example of the relationship between FTC and LTC in a still section. The horizontal axis indicates the FTC of a frame, and the vertical axis indicates the LTC of the frame. In FIG. 18A, for example, the LTC value of the frame whose FTC value is “N” (the frame whose frame number is N) is “M”, the LTC value of the next frame (the frame whose FTC value is “N+1”) is also “M”, and the LTC value of the frame after the next (the frame whose FTC value is “N+2”) is also “M”. Thus, in the still section, the LTC value in consecutive frames does not change as the FTC value increases by 1. For example, in the case where there is no setting of a status (the section setting holding unit 116 does not hold the section name 123) or a set status is not “still” (the content of the section name 123 held in the section setting holding unit 116 is not “still”), when a frame group (in which LTC does not change) shown in FIG. 18A is inputted to the data conversion unit 39, the determination processing unit 112 determines that the status has changed to “still” (the section has changed) and creates an element 144 of the LTC change point table 124 shown in FIG. 18B in which the first frame (frame number N) of the frame group is a still point. In the case of the element 144 shown in FIG. 18B, the value of item “frame number” is “N”, the value of item “LTC” is “M”, and item “status” is “still”. After creating the element 144, the determination processing unit 112 supplies the created element to the registration processing unit 117 and allows the registration processing unit 117 to register the element in the LTC change point table 124 stored in the memory 38. In the case where the content of the section name 123 held in the section setting holding unit 116 is “still”, when a frame group (in which LTC does not change) shown in FIG. 18A is inputted to the data conversion unit 39, the determination processing unit 112 determines that the status has not changed (the same section continues) and does not create the element 144 (does not update the status). At step S165, if the determination processing unit 112 determines that the value of the acquired LTC data is not the same as the value of the held LTC data (i.e., the value of the acquired LTC data has decreased), the determination processing unit 112 advances the processing to step S169. At step S169, the determination processing unit 112 determines whether the current section is a decrease section (a section whose status is “decrease”), based on the reference result at step S145 in FIG. 13. If the determination processing unit 112 determines that the current section is not a decrease section, the determination processing unit 112 determines that the status (i.e., the section) has changed, and advances the processing to step S170 in order to put the frame (corresponding to the held LTC data) into an LTC change point. At step S170, the determination processing unit 112 controls the data management unit 113 to acquire the LTC data 121 and the FTC data 122 held in the data holding unit 114 and adds status information (“decrease” in this case) to the LTC data and the FTC data. Further, the determination processing unit 112 supplies the LTC data, the FTC data and the status information as elements of the LTC change point table to the registration processing unit 117. The registration processing unit 117 supplies the elements of the LTC change point table as a decrease point (a change point whose status is “decrease”) to the memory 38 to register them in the LTC change point table. After the completion of step S170, at step S171 the determination processing unit 112 supplies the status determined this time through the section setting management unit 115 to the section setting holding unit 116 which stores it as the section name 123, thus setting the current section to a still section. After that, the processing returns to step S150 in FIG. 13 to repeat the steps thereafter. Further, at step S169 in FIG. 14, if the determination processing unit 112 determines that the current section is a decrease section, the determination processing unit 112 omits steps S170 and S171 and returns the processing to step S150 in FIG. 13. FIG. 19A is a diagram showing an example of the relationship between FTC and LTC in a decrease section. The horizontal axis indicates the FTC of a frame, and the vertical axis indicates the LTC of the frame. In FIG. 19A, for example, the LTC value of the frame whose FTC value is “N” (the frame whose frame number is N) is “M”, the LTC value of the next frame (the frame whose FTC value is “N+1”) is “M−1”, and the LTC value of the frame after the next (the frame whose FTC value is “N+2”) is “M−3”. Thus, in the decrease section, the LTC value in consecutive frames decreases by 1 or more as the FTC value increases by 1. For example, in the case where there is no setting of a status (the section setting holding unit 116 does not hold the section name 123) or a set status is not “decrease” (the content of the section name 123 held in the section setting holding unit 116 is not “decrease”), when a frame group (in which LTC decreases by 1 or more) shown in FIG. 19A is inputted to the data conversion unit 39, the determination processing unit 112 determines that the status has changed to “decrease” (the section has changed) and creates an element 146 of the LTC change point table 124 shown in FIG. 19B in which the first frame (frame number N) of the frame group is a decrease point. In the case of the element 146 shown in FIG. 19B, the value of item “frame number” is “N”, the value of item “LTC” is “M”, and item “status” is “decrease”. After creating the element 146, the determination processing unit 112 supplies the created element to the registration processing unit 117 and allows the registration processing unit 117 to register the element in the LTC change point table 124 stored in the memory 38. In the case where the content of the section name 123 held in the section setting holding unit 116 is “decrease”, when a frame group (in which LTC decreases) shown in FIG. 19A is inputted to the data conversion unit 39, the determination processing unit 112 determines that the status has not changed (the same section continues) and does not create the element 146 (does not update the status). Further, at step S141 in FIG. 13, if the acquisition control unit 111 determines that it has not acquired LTC data with the original timing for acquiring the LTC data as the input of essence data is stopped for example, the acquisition control unit 111 advances the processing to step S181 in FIG. 15. At step S181 in FIG. 15, the determination processing unit 112 determines that the clip has ended, and the determination processing unit 112 controls the data management unit 113 to acquire the LTC data 121 and the FTC data 122 held in the data holding unit 114 and adds status information (“end” in this case) to the LTC data and the FTC data. Further, the determination processing unit 112 supplies the LTC data, the FTC data and the status information as elements of the LTC change point table to the registration processing unit 117. The registration processing unit 117 supplies the elements of the LTC change point table as an end point (a change point whose status is “end”) to the memory 38 to register them in the LTC change point table. FIG. 20A is a diagram showing an example of the relationship between FTC and LTC at an end point. The horizontal axis indicates the FTC of a frame, and the vertical axis indicates the LTC of the frame. In FIG. 20A, for example, the LTC value of the frame whose FTC value is “N” (the frame whose frame number is N) is “M”, the LTC value of the next frame (the frame whose FTC value is “N+1”) is “M+1”, and the LTC value of the frame after the next (the frame whose FTC value is “N+2”) is “M+2”. That is, the status of this section is “increment”. For example, as shown in FIG. 20B, an element 148 is registered in the LTC change point table 124. In the case of the element 148 shown in FIG. 20B, the value of item “frame number” is “N”, the value of item “LTC” is “M”, and item “status” is “increment”. In this case, if the clip has ended with the frame whose frame number is N+2 and the acquisition control unit 111 has not acquired a frame next to the frame whose frame number is N+2, the determination processing unit 112 determines that the clip has ended, and creates an element 149 of the LTC change point table 124 shown in FIG. 20B in which the last frame (frame number N+2) in the data holding unit 114 is an end point. In the case of the element 149 shown in FIG. 20B, the value of item “frame number” is “N+2”, the value of item “LTC” is “M+2”, and item “status” is “end”. After registering the end point in the LTC change point table as described above, the determination processing unit 112 advances the processing to step S184. Further, after the completion of step S150 through the steps in FIG. 13 and FIG. 14 as described above, the determination processing unit 112 advances the processing to step S182 in FIG. 15, where the determination processing unit 112 controls the registration processing unit 117 so that the registration processing unit 117 checks for free space in the memory 38 and the determination processing unit 112 determines whether it is possible to register two more elements in the LTC change point table 142. If the determination processing unit 112 determines that there is enough free space and it is possible to register two more elements in the LTC change point table 124, the determination processing unit 112 returns the processing to step S141 in FIG. 13 to repeat the steps thereafter for the next frame. At step S182 in FIG. 15, if the determination processing unit 112 determines that there is not enough free space in the memory 38 and only one more element can be added to the LTC change point table 124, the determination processing unit 112 advances the processing to step S183, where the determination processing unit 112 adds status information (“over” in this case) to the LTC data and the FTC data acquired this time through the acquisition control unit 111. Further, the determination processing unit 112 supplies the LTC data, the FTC data and the status information as elements of the LTC change point table to the registration processing unit 117. The registration processing unit 117 supplies the elements of the LTC change point table as an increase point (a change point whose status is “increase”) to the memory 38 to register them in the LTC change point table 124. FIG. 21A is a diagram showing an example of the relationship between FTC and LTC in an over point. The horizontal axis indicates the FTC of a frame, and the vertical axis indicates the LTC of the frame. In FIG. 21A, for example, the LTC value of the first frame whose FTC value is “N” (the frame whose frame number is N) is “M”, the LTC value of the second frame (the frame whose FTC value is “N+1”) is “M+1”, the LTC value of the third frame (the frame whose FTC value is “N+2”) is “M+2”, the LTC value of the fourth frame (the frame whose FTC value is “N+3”) is “M+3”, and the LTC value of the fifth frame (the frame whose FTC value is “N+4”) is “M+4”. That is, the status of this section is “increment”. For example, as shown in FIG. 21B, an element 150 is registered in the LTC change point table 124. In the case of the element 150 shown in FIG. 21B, the value of item “frame number” is “N”, the value of item “LTC” is “M”, and item “status” is “increment”. In this case, if the determination processing unit 112 determines that only one more element can be added to the LTC change point table 124 at the time of acquiring the LTC data and the FTC data of the frame whose frame number is N+2, the determination processing unit 112 creates an element 151 of the LTC change point table 124 shown in FIG. 21B in which the last frame (frame number N+2) acquired this time through the acquisition control unit 111 is an over point. In the case of the element 149 shown in FIG. 21B, the value of item “frame number” is “N+2”, the value of item “LTC” is “M+2”, and item “status” is “over”. After registering the over point in the LTC change point table as described above, the determination processing unit 112 advances the processing to step S184. At step S184, the LTC data processing unit 72 performs end processing and ends the LTC change point table creation processing. Further, the LTC change point table creation processing is performed every time a clip is inputted to the data conversion unit 39. The LTC change point table 124 thus created and stored in the memory 38 is read as non-real-time metadata and recorded on the optical disk 31, at step S11 in FIG. 6. Thus, by creating the LTC change point table incorporating the change point from LTC included in real-time metadata and recording it as non-real-time metadata, the disk recording/playback apparatus 30 in FIG. 2 enables the user to more easily perform playback control processing as described later. According to the recording processing of FIG. 6, the audio data recording task of FIG. 7, the video data recording task of FIG. 8, the low-resolution data recording task of FIG. 9, the real-time metadata recording task of FIG. 10, the LTC data generation processing of FIG. 12, and the LTC change point table creation processing of FIGS. 13 to 15 as described above, the audio annual-ring data, the video annual-ring data, the low-resolution annual-ring data, the real-time meta annual-ring data, and the non-real-time metadata are recorded on the optical disk 31, as shown in FIG. 22. As described above, audio annual-ring data, video annual-ring data, low-resolution annual-ring data, and real-time meta annual-ring data at similar playback time slots are recorded in forwarder positions on the optical disk 31 in the order of the audio annual-ring data, the video annual-ring data, the low-resolution annual-ring data, and the real-time meta annual-ring data. With reference to, for example, audio annual-ring data with the highest priority, after audio annual-ring data at a certain playback time slot is recorded, video annual-ring data, low-resolution annual-ring data, and real-time meta annual-ring data at a similar playback time slots are recorded following the audio annual-ring data. Thus, as shown in FIG. 22, audio annual-ring data, video annual-ring data, low-resolution annual-ring data, and real-time meta annual-ring data are recorded on the optical disk 31 from its inner to its outer circumference in the order of audio annual-ring data 161, video annual-ring data 162, low-resolution annual-ring data 163, and real-time meta annual-ring data 164, repeatedly. Further, non-real-time metadata 165 of which real-time performance is not required is recorded in an area other than areas for the above-mentioned annual-ring data. Each relationship between the audio annual-ring size Tsa, the video annual-ring size Tsv, the low-resolution annual-ring size Tsl, and the real-time meta annual-ring size Tsm may be any relationship. As described above, the audio annual-ring size Tsa, the video annual-ring size Tsv, the low-resolution annual-ring size Tsl, and the real-time meta annual-ring size Tsm can be set, for example, to the same time period, or to different time period. Further, as a matter of course, each of the low-resolution annual-ring size Tsl and the real-time meta annual-ring size Tsm may be two times each of the audio annual-ring size Tsa and the video annual-ring size Tsv. Furthermore, the audio annual-ring size Tsa, the video annual-ring size Tsv, the low-resolution annual-ring size Tsl, and the real-time meta annual-ring size Tsm can be set for matching, for example, uses and purposes of use of the optical disk 31. For example, each of the low-resolution annual-ring size Tsl and the real-time meta annual-ring size Tsm can be set to be greater than each of the audio annual-ring size Tsa and the video annual-ring size Tsv. Further, the non-real-time metadata 165 may be recorded in any position on the optical disk 31. For example, as shown in FIG. 23A, the non-real-time metadata 165 may be recorded between one annual-ring data and another. In the case of FIG. 23A, after annual-ring data 170 composed of audio annual-ring data 171, video annual-ring data 172, low-resolution annual-ring data 173, and real-time meta annual-ring data 174 are recorded a plurality of times, non-real-time metadata 181 is recorded, and subsequently another annual-ring data is recorded. As described with reference to the flowchart of FIG. 6, non-real-time metadata is recorded after the audio data recording task, the video data recording task, the low-resolution data recording task, and the real-time metadata recording task are completed. Thus, with this timing, the non-real-time metadata 181 is recorded subsequently to the last annual-ring data 170 that has already been recorded, and the annual-ring data to be recorded at the next initiated recording processing is recorded subsequently to the last non-real-time metadata 181 that has been recorded. The real-time meta annual-ring data 174 includes LTC data 175 corresponding to the audio annual-ring data 171 and the video annual-ring data 172 included in the same annual-ring data. Thus, the LTC data 175 is recorded close to the audio annual-ring data 171 and the video annual-ring data 172 that the LTC data 175 corresponds to. Therefore, in the case of reading the LTC data 175 at the time of playback of the audio annual-ring data 171 and the video annual-ring data 172 included in the annual-ring data 170, it is possible to reduce seek time and enhance the speed for reading the LTC data 175. Further, the non-real-time metadata 181 includes an LTC change point table 182 corresponding to LTC data included in the first annual-ring data or annual-ring data subsequent to the preceding non-real-time metadata to the preceding annual-ring data. Therefore, the LTC change point table 182 is recorded somewhat closer (compared to the case in FIG. 23B described later) to the audio annual-ring data 171 and the video annual-ring data 172 that the LTC change point table 182 corresponds to. Metadata included in the non-real-time metadata 181 is basically metadata of which real-time performance is not required. However, for example, in the case where the user instructs the disk recording/playback apparatus 30 to play back a certain frame using the LTC change point table 182, recording the audio annual-ring data 171 and the video annual-ring data 172 in close to the LTC change point table 182 makes it possible to reduce seek time and enhance the speed for reading the audio annual-ring data 171 and the video annual-ring data 172 for suitable operation. Further, non-real-time metadata may be, for example, collectively recorded in areas other than areas where annual-ring data is stored, as shown in FIG. 23B. In the case of FIG. 23B, non-real-time metadata 201-1, non-real-time metadata 201-2, and non-real-time metadata 201-3 are recorded in areas other than areas where annual-ring data 190-1 composed of audio annual-ring data 191-1, video annual-ring data 192-1, low-resolution annual-ring data 193-1, and real-time meta annual-ring data 194-1 and annual-ring data 190-2 composed of audio annual-ring data 191-2, video annual-ring data 192-2, low-resolution annual-ring data 193-2, and real-time meta annual-ring data 194-2 are stored. In this case, as described with reference to the flowchart of FIG. 6, non-real-time metadata is recorded in areas other than areas for annual-ring data after the audio data recording task, the video data recording task, the low-resolution data recording task, and the real-time metadata recording task are completed. Thus, an LTC change point table 202-1, an LTC change point table 202-2, and an LTC change point table 202-3 respectively included in the non-real-time metadata 201-1, the non-real-time metadata 201-2, and the non-real-time metadata 201-3 are recorded close to each other. Accordingly, in the case of retrieving a certain frame using a plurality of conversion tables, it is possible to reduce seek time and retrieve a target frame at high speed. Further, in the case of playing back audio data and video data, since non-real-time metadata unnecessary for playback does not exist between them, it is possible to reduce reading time and enhance the speed of the playback processing. Since non-real-time metadata is composed of metadata of which real-time performance is not required, it is unnecessary to consider the seek time; therefore, non-real-time metadata may be placed in any physical position in storage areas on the optical disk 31. For example, a piece of non-real-time metadata may be recorded in a plurality of positions in a distributed manner. As described above, LTC is recorded as real-time metadata, along with essence data composed of audio data and video data, and also an LTC change point table composed of LTC change points is recorded as non-real-time metadata. Therefore, in the case of editing the above-described data recorded on the optical disk 31, the user can easily perform playback control processing based on LTC, such as retrieving and play backing a target frame based on LTC. Data thus recorded on the optical disk 31 is managed in units of files of directory structures shown in FIGS. 24 and 25, for example, by a file system such as UDF (Universal Disk Format) Any file system including UDF may be used as the file system for managing files on the optical disk 31, as long as it is a file system that the disk recording/playback apparatus 30 in FIG. 2 can support, such as ISO 9660 (International Organization for Standardization 9660). In the case where a magnetic disk such as a hard disk is used in place of the optical disk 31, FAT (File Allocation Tables), NTFS (New Technology File System), HFS (Hierarchical File System), UFS (Unix (registered trademark) File System) or the like may be used as the file system. Alternatively, a dedicated file system may be used. A root directory (ROOT) 251 in FIG. 24 has a PROAV directory 252 including subdirectories in which information about essence data such as video data, audio data and the like, edit lists representing results of editing the essence data, and the like are disposed. The PROAV directory 252 includes: a disk metadata file (DISCMETA.XML) 253 as a file including information such for example as a title and comments for all the essence data recorded on the optical disk 31 and a path to video data corresponding to a representative picture as a frame representative of all the video data recorded on the optical disk 31; and an index file (INDEX.XML) 254 and an index file (INDEX.BUP) 255 including for example managing information for managing all clips and edit lists recorded on the optical disk 31. Further, the index file 255 is a replica of the index file 254. The two files are provided to improve reliability. The PROAV directory 252 includes a disk information file (DISCINFO.XML) 256 and a disk information file (DISCINFO.BUP) 257, which are metadata for the entire data recorded on the optical disk 31 and a file including information such as a playback history. Further, the disk information file 257 is a replica of the disk information file 256. The two files are provided to improve reliability. In addition to the files described above, the PROAV directory 252 further includes a clip root directory (CLPR) 258 having clip data disposed in subdirectories and an edit list root directory (EDTR) 259 having edit list data disposed in subdirectories. In the clip root directory 258, the clip data recorded on the optical disk 31 is managed in different, separate directories one for each clip. In the case of FIG. 24, for example, three pieces of clip data are managed in three separate directories, that is, a clip directory (C0001) 261, a clip directory (C0002) 262, and a clip directory (C0003) 263. Specifically, data of a first clip recorded on the optical disk 31 is managed as files in a subdirectory of the clip directory 261; data of a second clip recorded on the optical disk 31 is managed as files in a subdirectory of the clip directory 262; and data of a third clip recorded on the optical disk 31 is managed as files in a subdirectory of the clip directory 263. In the edit list root directory 259, the edit lists recorded on the optical disk 31 are managed in different, separate directories one for each edit process. In the case of FIG. 24, for example, four edit lists are managed in four separate directories, that is, an edit list directory (E0001) 264, an edit list directory (E0002) 265, an edit list directory (E0003) 266, and an edit list directory (E0004) 267. Specifically, the edit list representing a result of first editing of the clips recorded on the optical disk 31 is managed as files in a subdirectory of the edit list directory 264; the edit list representing a result of second editing is managed as files in a subdirectory of the edit list directory 265; the edit list representing a result of third editing is managed as files in a subdirectory of the edit list directory 266; and the edit list representing a result of fourth editing is managed as files in a subdirectory of the edit list directory 267. In the subdirectory of the clip directory 261 provided in the above-described clip root directory 258, the data of the first clip recorded on the optical disk 31 is provided and managed as files as shown in FIG. 25. In the case of FIG. 25, the clip directory 261 includes: a clip information file (C0001C01.SMI) 271 for managing this clip; a video data file (C0001V01.MXF) 272 including video data of the clip; eight audio data files (C0001A01.MXF to C0001A08.MXF) 273 to 280 including audio data of channels of the clip; a low-resolution data file (C0001S01.MXF) 161 including substream data of the clip; a non-real-time metadata file (C0001M01.XML) 282 corresponding to the essence data of the clip and including non-real-time metadata of which real-time performance is not required; a real-time metadata file (C0001R01.BIM) 283 corresponding to the essence data of the clip and including real-time metadata of which real-time performance is required; and a picture pointer file (C0011I01.PPF) 284 for describing the frame structure of the video data file 272 (for example, information about a compression form of each picture in MPEG or the like, and information about an offset address from the start of the file and the like). In the case of FIG. 23, video data, low-resolution data, and real-time metadata, of which real-time performance is required at the time of playback, are each managed as one file so as not to increase reading time. While the real-time performance is required also of audio data at the time of playback, eight channels are provided to support multiple audio channels such as 7.1 channels or the like, and are managed as different files, respectively. That is, audio data is managed as eight files in the above description; however, the present invention is not limited to this, and a number of files corresponding to audio data may be 7 or less, or 9 or more. Similarly, video data, low-resolution data, and real-time metadata may be each managed as two or more files in some cases. In FIG. 25, non-real-time metadata of which real-time performance is not required is managed as a file different from that of real-time metadata of which real-time performance is required. This is to prevent reading of metadata that is not required during normal playback of video data and the like. It is thereby possible to reduce the processing time of playback processing and a load necessary in the processing. While the non-real-time metadata file 282 is described in XML format for versatility, the real-time metadata file 283 is a file in BIM (BInary format for MPEG-7 data) format obtained by compiling a file in XML format in order to reduce the processing time of playback processing and a load necessary in the processing. The example of structure of the files in the clip directory 261 shown in FIG. 25 is applicable in all the clip directories corresponding to clips recorded on the optical disk 31. Specifically, the example of structure of the files shown in FIG. 25 is applicable in the other clip directories 262 and 263 shown in FIG. 24. Therefore, a description thereof will be omitted. While the files included in a clip directory corresponding to one clip have been described above, the structure of the files is not limited to the above example, and any structure may be employed. FIG. 26 is an illustration showing an example of a specific description in an LTC change point table included in a non-real-time metadata file described in XML. The numbers added at the beginnings of lines are for convenience in description and are not part of the XML description. The description [<Ltc Change Table tcFps=“30”>] on the 1st line in FIG. 26 is a start tag indicating the start of the description in the LTC change point table. The description [tcFps=“30”] indicates that the time code is described as 30 frames per second in the LTC change point table. On the 2nd to 12th lines, elements indicating LTC change points are described. On the 2nd to 12th lines, the description [“frameCount=” “] indicates a frame number, that is, an FTC value; the description [value=“ ”] indicates an LTC value of the frame; and the description [status=“ ”] indicates a status of the frame. For example, in the case of the description [<LtcChange frameCount=“0” value=“55300201” status=“increment”/>] on the 2nd line, the change point is the frame whose frame number is “0”, the LTC is “55300201”, and the status of the section starting from this frame is “increment”. The structure of the descriptions on the 3rd to 12th lines is basically the same as that of the 2nd line except that values are different. Therefore, description thereof will be omitted. The description [</LtcChangeTable>] on the 13th line is an end tag indicating the end of the description in the LTC change point table. For example, when the user specifies a frame to be displayed using LTC, the disk recording/playback apparatus 30 in FIG. 2, as described later, reads an LTC change point table described as shown in FIG. 26 from non-real-time metadata, and retrieves and displays the specified frame based on this description. Thereby, the disk recording/playback apparatus 30 can retrieve a target frame more easily than it retrieves a target LTC (frame) from an LTC group described in real-time metadata associated with frames. The disk recording/playback apparatus 30 shown in FIG. 2 may be, for example as shown in FIG. 27, a disk recording unit 301 in a camcorder 300 having an imaging unit 302 other than the foregoing. In this case, the imaging unit 302 in place of the signal input/output device 51 is connected to the disk recording unit 301, and essence data including video data imaged by the camera of the imaging unit 302 and audio data picked up by the microphone of the imaging unit 302 is inputted to the disk recording unit 301. The structure of the disk recording unit 301 is the same as that of the disk recording/playback apparatus 30, so that the disk recording unit 301, operating in the same manner as in the disk recording/playback apparatus 30, records essence data and metadata added to the essence data which are supplied from the imaging unit 302 onto the optical disk 31. Next, a description will be made of an example of the specific manner in which the above-described LTC change point table is used. FIG. 28 is an illustration showing an example of an editing system which edits essence data recorded on the optical disk 31 and records the edit result onto another optical disk 31. In FIG. 28, an editing system 310 is composed of two disk recording/playback apparatuses 321 and 323 which are connected to each other through a network 322 and an editing control apparatus 324 which controls the editing of essence data. The disk recording/playback apparatus 321 has a drive 321A supporting the optical disk 31. The disk recording/playback apparatus 321, controlled by the editing control apparatus 324 connected through the network 322, plays back essence data etc. recorded on the optical disk 31 mounted on the drive 321A and supplies the played back essence data etc. to the disk recording/playback apparatus 323 through the network 322. Further, the disk recording/playback apparatus 321 has a monitor 321B for displaying images and displays the image corresponding to video data played back from the optical disk 31 mounted on the drive 321A. The network 322 is a network represented by the Internet, Ethernet (registered trademark), or the like. The disk recording/playback apparatus 321, the disk recording/playback apparatus 323, and the editing control apparatus 324 are connected to the network 322, and various kinds of data are transferred among these apparatuses through the network 322. The disk recording/playback apparatus 323 has a drive 323A and a monitor 323B as in the case of the disk recording/playback apparatus 321. The disk recording/playback apparatus 323, controlled by the editing control apparatus 324 connected through the network 322, records the essence data etc. supplied through the network 323 onto the optical disk 31 mounted on the drive 323A and displays the image corresponding to the recorded video data onto the monitor 323B. The editing control apparatus 324 controls the disk recording/playback apparatuses 321 and 323 through the network 322 so that the disk recording/playback apparatus 321 supplies the essence data etc. played back at the disk recording/playback apparatus 321 to the disk recording/playback apparatus 323 and the disk recording/playback apparatus 323 records the essence data etc. onto the optical disk 31. Further, the editing control apparatus 324 is provided with an LTC inputting key 324A which is a ten key that the user operates at the time of specifying LTC, and a display unit 324B which displays the inputted LTC to be checked. The structure of the disk recording/playback apparatuses 321 and 323 is basically the same as that of the disk recording/playback apparatus 30 shown in FIG. 2, so that the disk recording/playback apparatuses 321 and 323 operate in the same manner as in the disk recording/playback apparatus 30. However, each of the disk recording/playback apparatuses 321 and 323 has a communication unit in place of the signal input/output device 51 and communicates with another apparatus through the network so as to exchange various kinds of data such as essence data. FIG. 29 is a block diagram showing an example of the internal structure of the editing control apparatus 324 in FIG. 28. In FIG. 29, a CPU (Central Processing Unit) 331 in the editing control apparatus 324 executes various kind of processing in accordance with a program stored in a ROM (Read Only Memory) 332. Data and programs that are necessary for the CPU 331 to execute various kind of processing are stored in a RAM (Random Access Memory) 333 if necessary. A playback control unit 334 controls the playback processing by the disk recording/playback apparatus 321 and the disk recording/playback apparatus 323 through a communication unit 344. For example, the playback control unit 334 controls the disk recording/playback apparatus 323 so that the disk recording/playback apparatus 323 plays back a clip of essence data etc. from the optical disk 31 mounted on the drive 323A and displays a frame image corresponding to LTC specified by the user onto the monitor 323B. An editing control unit 335 controls the disk recording/playback apparatus 321 and the disk recording/playback apparatus 323 through the communication unit 344 to control the editing processing of essence data. For example, the editing control unit 335 controls the disk recording/playback apparatus 321 through the network 322 so that the disk recording/playback apparatus 321 performs playback (normal playback, fast-forward playback, fast-rewind playback, pause, stop, etc.) of a clip, displays the video corresponding to the played back clip onto the monitor 321B, and supplies the clip data to the disk recording/playback apparatus 323 through the network 322. Further, the editing control unit 335 controls the disk recording/playback apparatus 323 through the network 322 so that the disk recording/playback apparatus 323 acquires clip data supplied thereto and records it onto the optical disk 31 mounted on the drive 323A. The CPU 331, the ROM 332, the RAM 333, the playback control unit 334, and the editing control unit 335 are interconnected through a bus 336. Further, an input/output interface 340 is connected to the bus 336. An input unit 341 composed of an LTC inputting ten key, various kinds of instruction inputting buttons, etc. is connected to the input/output interface 340, and the input unit 341 outputs a signal inputted to the input unit 341 to the CPU 331. Further, an output unit 342 including the display unit 324B etc. is also connected to the input/output interface 340. Further, a storage unit 343 including a magnetic drive such as a hard disk, an EEPROM (Electronically Erasable and Programmable Read Only Memory), etc., and the communication unit 344 communicating data with the disk recording/playback apparatus 321 and the disk recording/playback apparatus 323 through the network 322 are also connected to the input/output interface 340. A removable medium 346 which is a recording medium such as a magnetic disk, an optical disk, a magneto-optical disk, or a semiconductor memory is mounted on a drive 345 as necessary. The drive 345 controls the reading of a program and data stored in the removable medium 346 mounted on the drive 345. FIG. 30 is a block diagram showing an example of the detailed structure of the playback control unit 334 in FIG. 29. In FIG. 30, the playback control unit 334 includes a control unit 351 which controls the whole of the playback control unit 334, an input acceptance processing unit 352 which accepts a user input inputted through the input unit 341, an information acquisition unit 353 which acquires non-real-time metadata (NRT) such as LTC and FTC acquired through the communication unit 344, a holding unit 354 which holds non-real-time metadata acquired by the information acquisition unit 353, a cue-up processing unit 355 which controls cue-up processing for specifying a frame image to be displayed onto the monitor using LTC, and a command processing unit 356 which outputs various kinds of command information supplied from the control unit 351. The control unit 351 includes a ROM and a RAM (not shown) and controls the operation of each unit in the playback control unit 334 by executing various kinds of programs. The input acceptance processing unit 352 controls the acceptance of a user input inputted through the input unit 341 and supplies the accepted user input to the control unit 351. Upon acquiring non-real-time metadata (NRT) supplied through the communication unit 344 for example, the information acquisition unit 353, controlled by the control unit 351, supplies the acquired non-real-time metadata to the holding unit 354 which holds it. The holding unit 354 is composed of a recording medium such as a hard disk or a semiconductor memory and holds non-real-time metadata supplied from the information acquisition unit 353. That is, the holding unit 354 holds an LTC change point table 361 included in non-real-time metadata. The cue-up processing unit 355 performs cue-up processing, out of processing for playing back a clip, in which the user specifies the frame number of a frame image to be displayed on the monitor using LTC. For example, upon receiving LTC specified by the user from the control unit 351, the cue-up processing unit 355 accesses the holding unit 354, refers to the LTC change point table 361 held in the holding unit 354, identifies a frame corresponding to the specified LTC, and supplies the FTC information (frame number) of the frame to the control unit 351. The command processing unit 356 supplies command information etc. supplied from the control unit 351 to the disk recording/playback apparatus 323 etc. through the communication unit 344. Next, a description will be made of editing processing in the editing system 310 in FIG. 28. The user, by operating the input unit 341 of the editing control apparatus 324 in the editing system 310 in FIG. 28, allows the editing system to play back clip data recorded on the optical disk 31 mounted on the drive 321A of the disk recording/playback apparatus 321 and record the played back clip data onto the optical disk 31 mounted on the drive 323A of the disk recording/playback apparatus 323. The editing control unit 335 in the editing control apparatus 324 controls the disk recording/playback apparatus 321 based on the user input so that the disk recording/playback apparatus 321 plays back a clip, supplies the clip data to the disk recording/playback apparatus 323 through the network 322, and displays the image corresponding to the video data of the clip onto the monitor 321B. Further, the editing control unit 335 in the editing control apparatus 324 controls the disk recording/playback apparatus 323 based on the user input so that the disk recording/playback apparatus 323 records the clip data (essence data and metadata) supplied to the disk recording/playback apparatus 323. At this time, the user, by operating the input unit 341 of the editing control apparatus 324, e.g. referring to the image displayed on the monitor 321B to instruct the editing control apparatus on normal playback, fast-forward playback, fast-rewind playback, pause, stop, or the like as necessary and input a playback control instruction for the clip. The editing control unit 335 in the editing control apparatus 324 controls the disk recording/playback apparatus 321 based on the user input to control the playback processing of the clip. That is, clip data including such a playback operation (clip data in which a playback operation such as normal playback, fast-forward playback, fast-rewind playback, pause, stop, or the like performed at the disk recording/playback apparatus 321 is reflected) is recorded on the optical disk 31 mounted on the drive 323A of the disk recording/playback apparatus 323. Therefore, when normal playback is performed on the clip data thus recorded on the optical disk 31 mounted on the drive 323A of the disk recording/playback apparatus 323, images are displayed on the monitor 323B in the following manner. For example, a fast-forwarded image is displayed as to a portion where the fast-forward playback is performed at the disk recording/playback apparatus 321, a rewound image is displayed as to a portion where the fast-rewind playback is performed at the disk recording/playback apparatus 321, and a paused image is displayed as to a portion where the pause is performed at the disk recording/playback apparatus 321. For example, when the user instructs the disk recording/playback apparatus 321 to perform fast-forward playback, the disk recording/playback apparatus 321 performs fast-forward playback by thinning out frames. In such a case, at the disk recording/playback apparatus 323, only the frames that remain after subjected to thinning out are recorded as to a portion where the fast-forward playback is performed. Accordingly, real-time metadata of the clip is recorded, a part of the real-time metadata being thinned out. Therefore, in a frame of this portion, while FTC is continuously incremented by 1 (since new FTC is assigned when real-time metadata is recorded onto the optical disk 31), LTC increases discontinuously (by 2 or more). That is, in the clip thus recorded, the increase/decrease pattern of LTC changes in accordance with playback processing performed by the disk recording/playback apparatus 321. The disk recording/playback apparatus 323, in the same way as in the disk recording/playback apparatus 30 in FIG. 2, receives clip data, creates an LTC change point table based on LTC data of real-time metadata, and records it as non-real-time metadata onto the optical disk 31. Further, the user operates the editing control apparatus 324 to control the disk recording/playback apparatus 323 so that the disk recording/playback apparatus 323 plays back the clip thus recorded and displays the video onto the monitor 303B. At this time, the user can also select a frame to be displayed on the monitor 323B using LTC by operating the LTC inputting ten key 324A of the editing control apparatus 324. Next, a description will be made of the operation of the playback control unit 334 in the editing control apparatus 324. Upon acquiring an LTC change point table 361 from the outside, the information acquisition unit 353 in the playback control unit 334, controlled by the control unit 351, supplies the acquired LTC change point table 361 to the holding unit 354 which holds it. The input acceptance processing unit 352, upon accepting a user input of a cue-up instruction from the outside, supplies the user input (cue-up instruction) through the control unit 351 to the cue-up processing unit 355. The cue-up processing unit 355, upon acquiring the cue-up instruction, refers to the LTC change point table 361 held in the holding unit 354 in order to identify the frame number (FTC) of a frame corresponding to LTC (which specifies a frame to be displayed) included in the instruction. Based on the LTC change point table 361, the cue-up processing unit 355 identifies the frame number of a frame corresponding to the LTC (a frame to be displayed, that is, a frame to be cued up), and supplies this information to the control unit 351. Based on the information (information as to the FTC of a frame to be cued up), the control unit 351 supplies command information including a command for displaying the frame (cueing up the frame) through the command processing unit 356 to the disk recording/playback apparatus 323. The thus supplied command information is supplied to the disk recording/playback apparatus 323 through the network 322. Based on the command information, the disk recording/playback apparatus 323 performs cue-up processing and displays the frame image of the specified frame onto the monitor 323B. FIG. 31 is an illustration showing an example of a frame image displayed on the monitor 323B. In FIG. 31, the frame image 371 displayed on the monitor 323B shows the LTC of the frame such as “01:15:32:08” besides the video data. Next, a description will be made of the playback control processing performed by the playback control unit 334, with reference to the flowchart of FIG. 32. If the playback control processing is performed by being controlled by the CPU 331 when for example, the editing control apparatus 324 is turned on, first at step S201, the input acceptance processing unit 352 starts accepting user inputs, and the processing goes to step S202. At step S202, the control unit 351 controls the input acceptance processing unit 352 to determine whether the input acceptance processing unit 352 has accepted specification of a clip to be played back. If the control unit 351 determines that the input acceptance processing unit 352 has accepted specification of a clip, the control unit 351 controls the command processing unit 356 to request non-real-time metadata of the specified clip from the disk recording/playback apparatus 323. Based on the request, the disk recording/playback apparatus 323 reads the specified non-real-time metadata from the disk 31 mounted on the drive 323A and supplies it to the editing control apparatus 324 through the network 322. Upon acquiring the non-real-time metadata, the communication unit 344 in the editing control apparatus 324 supplies it to the information acquisition unit 353 in the playback control unit 334 through the bus 336. At step S203, the information acquisition unit 353 acquires the supplied non-real-time metadata (the non-real-time metadata of the specified clip) and, controlled by the control unit 351, supplies it to the holding unit 354. The holding unit 354 holds the supplied non-real-time metadata in the storage area. After the holding unit 354 holds the non-real-time metadata, the processing goes to step S204. At step S202, if the control unit 351 determines that the input acceptance processing unit 352 has not accepted specification of a clip, the control unit 351 omits step S203 and advances the processing to step S204. At step S204, the control unit 351 controls the input acceptance processing unit 352 to determine whether the input acceptance processing unit 352 has accepted a playback control instruction. If the control unit 351 determines that the input acceptance processing unit 352 has accepted a playback control instruction (e.g., normal playback, fast-forward playback, fast-rewind playback, pause, stop, or the like), the control unit 351 advances the processing to step S205, where the control unit 351 creates command information for controlling the playback of the specified clip based on the playback control instruction and supplies it through the command processing unit 356 to the disk recording/playback apparatus 323 to control the playback. After the completion of step S205, the control unit 351 advances the processing to step S206. At step S204, if the control unit 351 determines that the input acceptance processing unit 352 has not accepted a playback control instruction, the control unit 351 omits step S205 and advances the processing to step S206. At step S206, the control unit 351 controls the input acceptance processing unit 352 to determine whether the input acceptance processing unit 352 has accepted a display frame specification input performed by the user using LTC. If the control unit 351 determines that the input acceptance processing unit 352 has accepted a display frame specification input, the control unit 351 advances the processing to step S207, where the control unit 351 performs cue-up control processing described later in which the control unit 351 controls the cue-up processing unit 355 so that the cue-up processing unit 355 identifies the frame number of a frame to be displayed, based on the specified LTC. The cue-up processing unit 355 refers to the LTC change point table 361 held in the holding unit 354, identifies the frame number of a frame to be displayed based on the specified LTC, and supplies this information to the control unit 351. The control unit 351 creates command information for displaying the frame corresponding to the frame number and supplies the command information through the command processing unit 356 to the disk recording/playback apparatus 323 which displays the image of the specified frame onto the monitor 323B. After the completion of step S207, the control unit 351 advances the processing to step S208. At step S206, if the control unit 351 determines that the input acceptance processing unit 352 has not accepted a display frame specification input, the control unit 351 omits step S207 and advances the processing to step S208. At step S208, the control unit 351 determines whether to end the playback control processing. If the control unit 351 determines not to end the playback control processing, the control unit 351 returns the processing to step S202 to repeat the steps thereafter. At step S208, if the control unit 351 determines to end the playback control processing, the control unit 351 performs end processing at step S209 and ends the playback control processing. By performing the playback control as described, the playback control unit 334 enables the user to more easily perform the playback control processing. Next, a description will be made of cue-up control processing for controlling cue-up processing in which the user specifies a frame to be displayed using LTC, with reference to the flowcharts of FIGS. 33 to 35. Further, a description will be made with reference to FIGS. 36 to 40 as necessary. This processing corresponds to step S207. When the cue-up control processing starts, at step S231 in FIG. 33 the cue-up processing unit 355, controlled by the control unit 351, refers to the LTC change point table 361 held in the holding unit 354 and sets the current status section based on the currently displayed frame. That is, the cue-up processing unit 355 finds which status section the FTC (or LTC) (supplied from the control unit 351) of a frame that is currently displayed on the disk recording/playback apparatus 323 is positioned at in the LTC change point table 361, and sets the current status section to the status section of the position. After the cue-up processing unit 355 sets the current status section, the processing goes to step S232, where the cue-up processing unit 355 acquires from the control unit 351, the LTC of a frame to be cued up, that is, a target LTC and advances the processing to step S233. At step S233, the cue-up processing unit 355 refers to the LTC change point table 361 and determines based on the target LTC acquired at step S232 whether the status section of the target LTC is the same as the current status section. If the cue-up processing unit 355 determines that the status section of the target LTC is the same as the current status section, the cue-up processing unit 355 advances the processing to step S234. At step S234, the cue-up processing unit 355 determines based on the LTC change point table 361 whether the status section of the target LTC (i.e., the current status section) is an increment section. If the cue-up processing unit 355 determines that the status section of the target LTC is an increment section, the cue-up processing unit 355 advances the processing to step S235. At step S235, the cue-up processing unit 355 performs cue-up command processing so that the disk recording/playback apparatus 323 displays the frame of the target LTC. Specifically, the cue-up processing unit 355 supplies cue-up command information through the control unit 351 and the command processing unit 356 to the disk recording/playback apparatus 323 which displays the frame of the target LTC. That is, if both the current status section and the status section of the target LTC are the same increment section, the cue-up processing unit 355 calculates the FTC of the frame corresponding to the target LTC based on the LTC change point table 361 and supplies the FTC to the control unit 351. The control unit 351 creates cue-up command information using the FTC of the frame to be cued up and supplies it to the command processing unit 356. The command processing unit 356 supplies the acquired cue-up command information through the communication unit 344 to the disk recording/playback apparatus 323 which displays the frame to be cued up that is specified by the FTC. FIG. 36 is a diagram showing an example of the relationship between LTC and FTC. The horizontal axis indicates FTC, and the vertical axis indicates LTC. Frame numbers “H” to “H+3” in frames correspond to LTC values “101” to “104” respectively, and therefore this status section is an increment section. For example, in the case of cueing up frame a of LTC “101” (frame of frame number “H”) to frame b of LTC “103” (frame of frame number “H+2”) in this increment section, the cue-up processing unit 355 executes step S235 and calculates the FTC of frame b, namely, frame number “H+2”. Thereby, the frame image of frame b is displayed onto the monitor 323B. After the completion of step S355, the cue-up processing unit 355 ends the cue-up control processing. At step S234, if the cue-up processing unit 355 determines that the status section of the target LTC (i.e., the current status section) is not an increment section, the cue-up processing unit 355 ends the cue-up control processing not to cue up a frame since there is no guarantee that a frame corresponding to the target LTC exists. In FIG. 36, frame numbers “J” to “J+3” in frames correspond to LTC values “101”, “103”, “105”, and “107” respectively, which increase by twos. Therefore, this status section is an increase section. For example, in the case of cueing up frame c of LTC value “101” (frame of frame number “J”) to frame d of LTC value “103” (frame of frame number “J+1”) in this increase section, it is possible to cue up it since frame d (frame of frame number “J+1”) exists in reality. However, for example, in the case where “106” is specified as an LTC value of a frame to be cued up, that is, in the case of being instructed to cue up frame c to frame e of LTC value “106”, the cue-up processing unit 355 cannot cue up it since frame e does not exist in reality. Thus, in the case where a frame to be cued up exist in an increase section, there is a possibility that a load of processing increases since the cue-up processing unit 355 needs to directly check the existence of each frame. Therefore, in such a case, the cue-up processing unit 355 does not execute step S235 and ends the cue-up control processing. Further, in FIG. 36, frame numbers “K” to “K+3” in frames correspond to the same LTC value “106”, which does not change. Therefore, this status section is a still section. For example, in this still section, all frames have the same LTC value “106”, and the LTC value does not change in e.g., frame f (frame of frame number “K”) and frame g (frame of frame number “K+2”); therefore, it is not possible to identify these frames by LTC. Thus, in the case where a frame to be cued up exist in a still section, it is unknown which frame has been specified. Therefore, in such a case, the cue-up processing unit 355 does not execute step S235 and ends the cue-up control processing. Furthermore, in FIG. 36, frame numbers “L” to “L+3” in frames correspond to LTC values “106”, “105”, “103”, and “101” respectively, which decrease by 1 or more. Therefore, this status section is a decrease section. For example, in the case of performing cue-up processing in this decrease section, there is a possibility that a load of processing increases since the cue-up processing unit 355 needs to directly check the existence of each frame, in the same way as in the increase section. Therefore, in such a case, the cue-up processing unit 355 does not execute step S235 and ends the cue-up control processing. Thus, in the case of being instructed to cue up a frame in a status section other than an increment section, the cue-up processing unit 355 ends the cue-up control processing without cueing up a frame. At step S233, if the cue-up processing unit 355 determines that the status section of the target LTC is not the same as the current status section, the cue-up processing unit 355 advances the processing to step S241 in FIG. 34. At step S241 in FIG. 34, the cue-up processing unit 355 determines whether the value of the target LTC is larger than the value of the LTC (the current LTC) of the currently displayed frame. If the cue-up processing unit 355 determines that the value of the target LTC is larger than the value of the current LTC, that is, if the cue-up processing unit 355 determines that the frame to be cued up is after the current frame in terms of time, the cue-up processing unit 355 advances the processing to step S242. Basically, if the value of the target LTC is larger than the value of the current LTC, the cue-up processing unit 355 retrieves a frame to be cued up from frames after the current frame (frames having larger FTC). If the value of the target LTC is smaller than the value of the current LTC, the cue-up processing unit 355 retrieves a frame to be cued up from frames before the current frame (frames having smaller FTC). At step S242, the cue-up processing unit 355 refers to the LTC change point table 361 and determines whether the status section subsequent to the current status section is a decrease section. If the cue-up processing unit 355 determines that the next status section is not a decrease section, the cue-up processing unit 355 advances the processing to step S243, where the cue-up processing unit 355 determines based on the LTC change point table 361 whether the frame of the target LTC is included in the status section subsequent to the current status section. If the cue-up processing unit 355 determines that the frame of the target LTC is not included in the status section subsequent to the current status section, the cue-up processing unit 355 advances the processing to step S244, where the cue-up processing unit 355 determines based on the LTC change point table 361 whether the next status (i.e., the status of the next change point in the LTC change point table) is “end”. If the cue-up processing unit 355 determines that the next change point in the LTC change point table is not an end point, that is, the next status is not “end”, the cue-up processing unit 355 advances the processing to step S245. At step S245, the cue-up processing unit 355 updates the setting of the current status section to the next status section and returns the processing to step S242 to repeat the steps thereafter. That is, the cue-up processing unit 355 retrieves a frame to be cued up for each status section in the same direction as time travels in data. At step S244, if the cue-up processing unit 355 determines that the next status is “end”, the cue-up processing unit 355 advances the processing to step S246, where the cue-up processing unit 355 performs the cue-up command processing so that the disk recording/playback apparatus 323 displays a frame that is registered in the LTC change point table 361 as an end point. That is, the cue-up processing unit 355 supplies the FTC of the endpoint frame to be cued up to the control unit 351. The control unit 351 creates cue-up command information using the FTC of the frame to be cued up and supplies it to the command processing unit 356. The command processing unit 356 supplies the acquired cue-up command information through the communication unit 344 to the disk recording/playback apparatus 323 which displays the frame to be cued up that is specified by the FTC. FIG. 37 is a diagram showing an example of the relationship between LTC and FTC. The horizontal axis indicates FTC, and the vertical axis indicates LTC. Frame numbers “H” to “H+4” in frames correspond to LTC values “101” to “105” respectively, and therefore this status section is an increment section. Further, this clip ends at the frame having frame number “H+4”, and the frame having frame number “H+4” is an end point. For example, in the case of being instructed to cue up frame a of LTC “102” (frame of frame number “H+1”) to frame b of LTC “106”, frame b is a frame after the end of the clip, judged from the LTC; therefore, frame b does not exist in reality. In practice, there is a possibility of existence before frame a. However, in order to check it, the cue-up processing unit 355 needs to directly check for each frame, thereby causing a possibility that a load of processing increases. Therefore, the cue-up processing unit 355 executes step S246 and calculates the FTC of the end point frame, namely, frame number “H+4”. Thereby, the frame image of frame number “H+4” is displayed onto the monitor 323B. After the completion of step S246, the cue-up processing unit 355 ends the cue-up control processing. At step S243, if the cue-up processing unit 355 determines that the frame of the target LTC is included in the next status section, the cue-up processing unit 355 advances the processing to step S247, where the cue-up processing unit 355 determines whether the next status section is an increment section. If the cue-up processing unit 355 determines that the next status section is an increment section, the cue-up processing unit 355 advances the processing to step S248, where the cue-up processing unit 355 performs the cue-up command processing so that the disk recording/playback apparatus 323 displays the frame of the target LTC. That is, if the next status section is an increment section, in the status section, the cue-up processing unit 355 calculates the FTC of the frame corresponding to the target LTC based on the LTC change point table 361 and supplies the FTC of the frame to be cued up to the control unit 351. The control unit 351 creates cue-up command information using the FTC of the frame to be cued up and supplies it to the command processing unit 356. The command processing unit 356 supplies the acquired cue-up command information through the communication unit 344 to the disk recording/playback apparatus 323 which displays the frame to be cued up that is specified by the FTC. FIG. 38 is a diagram showing an example of the relationship between LTC and FTC. The horizontal axis indicates FTC, and the vertical axis indicates LTC. Frame numbers “H” to “H+3” in frames correspond to the same LTC value “101”, and therefore this status section is a still section. Further, frame numbers “H+3” to “H+6” in frames correspond to LTC values “101” to “104” respectively, and therefore this status section is an increment section. For example, in the case of being instructed to cue up frame a (frame of frame number “H”) in this still section to frame b of LTC “103” (frame of frame number “H+5”), the cue-up processing unit 355 retrieves frame b for each status section, thereby making it possible to calculate the FTC. Therefore, the cue-up processing unit 355 executes step S248 and calculates the FTC of frame b, namely, frame number “H+5”. Thereby, the frame image of frame b is displayed onto the monitor 323B. After the completion of step S248, the cue-up processing unit 355 ends the cue-up control processing. At step S247, if the cue-up processing unit 355 determines that the status section subsequent to the current status section is not an increment section, the cue-up processing unit 355 advances the processing to step S249 since there is no guarantee that a frame corresponding to the target LTC exists. At step S249, the cue-up processing unit 355 performs the cue-up command processing so that the disk recording/playback apparatus 323 displays the first frame of the next status section in which the frame of the target LTC exists. That is, if the status section of the target LTC is an increase section, a still section or the like that exists after the current status section, the cue-up processing unit 355 calculates the FTC of the first frame of the status section based on the LTC change point table 361 and supplies the FTC of the frame to be cued up to the control unit 351. The control unit 351 creates cue-up command information using the FTC of the frame to be cued up and supplies it to the command processing unit 356. The command processing unit 356 supplies the acquired cue-up command information through the communication unit 344 to the disk recording/playback apparatus 323 which displays the frame to be cued up that is specified by the FTC. In FIG. 38, frame numbers “J” to “J+3” in frames correspond to LTC values “101” to “104” respectively, and therefore this status section is an increment section. Further, frame numbers “J+3” to “J+5” in frames correspond to LTC values “104”, “106”, and “108” respectively, which increase by twos. Therefore, this status section is an increase section. For example, in the case of being instructed to cue up frame c (frame of frame number “J”) in this increment section to frame d of LTC “106” (frame of frame number “J+4”), the cue-up processing unit 355 cannot check the existence of frame d as described above since frame d exists in the increase section. Therefore, in such a case, the cue-up processing unit 355 executes step S249 and performs control to cue up the first frame (frame of frame number “J+3”) of the status section in which frame d exists. After the completion of step S249, the cue-up processing unit 355 ends the cue-up control processing. At step S242, if the cue-up processing unit 355 determines that the status section subsequent to the current status section is a decrease section, the cue-up processing unit 355 advances the processing to step S250, where the cue-up processing unit 355 performs the cue-up command processing so that the disk recording/playback apparatus 323 displays the first frame of the decrease section in which the frame of the target LTC exists. That is, if the status section of the target LTC is a decrease section or the like that exists after the current status section, the cue-up processing unit 355 calculates the FTC of the first frame of the decrease section based on the LTC change point table 361 and supplies the FTC of the frame to be cued up to the control unit 351. The control unit 351 creates cue-up command information using the FTC of the frame to be cued up and supplies it to the command processing unit 356. The command processing unit 356 supplies the acquired cue-up command information through the communication unit 344 to the disk recording/playback apparatus 323 which displays the frame to be cued up that is specified by the FTC. FIG. 39 is a diagram showing an example of the relationship between LTC and FTC. The horizontal axis indicates FTC, and the vertical axis indicates LTC. Frame numbers “H” to “H+2” in frames correspond to LTC values “102” to “104” respectively, and therefore this status section is an increment section (increment 1). Further, frame numbers “H+2” to “H+4” in frames correspond to LTC values “104”, “103”, and “101” respectively, and therefore this status section is a decrease section. Furthermore, frame numbers “H+4” and “H+5” in frames correspond to LTC values “101” and “102” respectively, and therefore this status section is an increment section (increment 2). For example, in the case of being instructed to cue up frame a of LTC “101” (frame of frame number “H”) to frame b of LTC “102” (frame of frame number “H+5”), the cue-up processing unit 355 retrieves frame b for each status section. However, in the case where a decrease section exists in the course of retrieval, it is unknown whether a frame of a specified LTC can be identified since there are cases where a plurality of frames having the same LTC exist, such as frame numbers “H” and “H+4”. Therefore, in such a case, the cue-up processing unit 355 executes step S250 and performs control to cue up the first frame (frame of frame number “H+2”) of the this decrease section. After the completion of step S250, the cue-up processing unit 355 ends the cue-up control processing. At step S241, if the cue-up processing unit 355 determines that the value of the target LTC is not larger than the value of the current LTC, that is, if the cue-up processing unit 355 determines that the frame to be cued up is before the current frame in terms of time, the cue-up processing unit 355 advances the processing to step S261 in FIG. 35. At step S261 in FIG. 35, the cue-up processing unit 355 refers to the LTC change point table 361 and determines whether the status section just prior to the current status section is a decrease section. If the immediately preceding status section is not a decrease section, the cue-up processing unit 355 advances the processing to step S262, where the cue-up processing unit 355 determines based on the LTC change point table 361 whether the frame of the target LTC is included in the status section just prior to the current status section. If the cue-up processing unit 355 determines that the frame of the target LTC is not included in the status section just prior to the current status section, the cue-up processing unit 355 advances the processing to step S263, where the cue-up processing unit 355 determines based on the LTC change point table 361 whether the frame number (FTC) of the first frame of the status section just prior to the current status section is “0”. If the cue-up processing unit 355 determines that the frame number (FTC) of the first frame of the immediately preceding status section is not “0”, the cue-up processing unit 355 advances the processing to step S264. At step S264, the cue-up processing unit 355 updates the setting of the current status section to the immediately preceding status section and returns the processing to step S261 to repeat the steps thereafter. That is, the cue-up processing unit 355 retrieves a frame to be cued up for each status section in the direction opposite to the time traveling direction in data. At step S263, if the cue-up processing unit 355 determines that the frame number (FTC) of the first frame of the immediately preceding status section is “0”, the cue-up processing unit 355 advances the processing to step S265, the cue-up processing unit 355 performs the cue-up command processing so that the disk recording/playback apparatus 323 displays the frame having frame number “0”. That is, the cue-up processing unit 355 supplies the FTC (i.e., “0”) of the first frame of the clip to be cued up to the control unit 351. The control unit 351 creates cue-up command information using the FTC of the frame to be cued up and supplies it to the command processing unit 356. The command processing unit 356 supplies the acquired cue-up command information through the communication unit 344 to the disk recording/playback apparatus 323 which displays the frame to be cued up that is specified by the FTC. FIG. 40 is a diagram showing an example of the relationship between LTC and FTC. The horizontal axis indicates FTC, and the vertical axis indicates LTC. Frame numbers “0” to “4” in frames correspond to LTC values “103” to “107” respectively, and therefore this status section is an increment section. Further, this clip starts at the frame having frame number “0”. For example, in the case of being instructed to cue up frame a of LTC “107” (frame of frame number “H+4”) to frame b of LTC “101”, frame b is a frame before the start of the clip, judged from the LTC; therefore, frame b does not exist in reality. In practice, there is a possibility of existence after frame a. However, in order to check it, the cue-up processing unit 355 needs to directly check for each frame, thereby causing a possibility that a load of processing increases. Therefore, the cue-up processing unit 355 executes step S265 and calculates the FTC of the first frame of the clip, namely, frame number “0”. Thereby, the frame image of frame number “0” is displayed onto the monitor 323B. After the completion of step S265, the cue-up processing unit 355 ends the cue-up control processing. At step S262, if the cue-up processing unit 355 determines that the frame of the target LTC is included in the status section just prior to the current status section, the cue-up processing unit 355 advances the processing to step S266, where the cue-up processing unit 355 determines whether the immediately preceding status section is an increment section. If the cue-up processing unit 355 determines that the immediately preceding status section is an increment section, the cue-up processing unit 355 advances the processing to step S267, where the cue-up processing unit 355 performs the cue-up command processing so that the disk recording/playback apparatus 323 displays the frame of the target LTC. That is, if the immediately preceding status section is an increment section, in the status section, the cue-up processing unit 355 calculates the FTC of the frame corresponding to the target LTC based on the LTC change point table 361 and supplies the FTC of the frame to be cued up to the control unit 351. The control unit 351 creates cue-up command information using the FTC of the frame to be cued up and supplies it to the command processing unit 356. The command processing unit 356 supplies the acquired cue-up command information through the communication unit 344 to the disk recording/playback apparatus 323 which displays the frame to be cued up that is specified by the FTC. For example, in FIG. 38, in the case of being instructed to cue up frame d of LTC “106” (frame of frame number “J+4”) to frame c of LTC “101” (frame of frame number “J”), the cue-up processing unit 355 retrieves frame b for each status section, thereby making it possible to calculate the FTC. Therefore, the cue-up processing unit 355 executes step S267 and calculates the FTC of frame c, namely, frame number “J”. Thereby, the frame image of frame c is displayed onto the monitor 323B. After the completion of step S267, the cue-up processing unit 355 ends the cue-up control processing. At step S266, if the cue-up processing unit 355 determines that the status section just prior to the current status section is not an increment section, the cue-up processing unit 355 advances the processing to step S268 since there is no guarantee that a frame corresponding to the target LTC exists. At step S268, the cue-up processing unit 355 performs the cue-up command processing so that the disk recording/playback apparatus 323 displays the first frame of the current status section. That is, if the status section of the target LTC is an increase section, a still section or the like that exists before the current status section, the cue-up processing unit 355 calculates the FTC of the first frame of the status section subsequent to the status section of the target LTC based on the LTC change point table 361 and supplies the FTC of the frame to be cued up to the control unit 351. The control unit 351 creates cue-up command information using the FTC of the frame to be cued up and supplies it to the command processing unit 356. The command processing unit 356 supplies the acquired cue-up command information through the communication unit 344 to the disk recording/playback apparatus 323 which displays the frame to be cued up that is specified by the FTC. For example, in FIG. 38, in the case of being instructed to cue up frame b of LTC “103” (frame of frame number “H+5”) to frame a of LTC “101” (frame of frame number “H”), the cue-up processing unit 355 cannot identify the FTC of frame a as described above since frame a exists in a still section. Therefore, in such a case, the cue-up processing unit 355 executes step S268 and performs control to cue up the first frame (frame of frame number “H+3”) of the current status section. After the completion of step S268, the cue-up processing unit 355 ends the cue-up control processing. At step S261, if the immediately preceding status section is a decrease section, the cue-up processing unit 355 advances the processing to step S269, where the cue-up processing unit 355 performs the cue-up command processing so that the disk recording/playback apparatus 323 displays the first frame of the increment section that is, in the cue-up direction, prior to and the closest to the decrease section in which the frame of the target LTC exists. That is, if the status section of the target LTC is a decrease section or the like that exists before the current status section, the cue-up processing unit 355 calculates the FTC of the first frame of the increment section that is before the decrease section in the cue-up direction and the closest to the decrease section based on the LTC change point table 361 and supplies the FTC of the frame to be cued up to the control unit 351. The control unit 351 creates cue-up command information using the FTC of the frame to be cued up and supplies it to the command processing unit 356. The command processing unit 356 supplies the acquired cue-up command information through the communication unit 344 to the disk recording/playback apparatus 323 which displays the frame to be cued up that is specified by the FTC. In FIG. 39, frame numbers “J” to “J+3” in frames correspond to LTC values “101” to “104” respectively, and therefore this status section is an increment section (increment 1). Further, frame numbers “J+3” and “J+4” in frames correspond to LTC values “104” and “101” respectively, and therefore this status section is a decrease section. Furthermore, frame numbers “J+4” to “J+6” in frames correspond to LTC values “101”, “103”, and “105” respectively, and therefore this status section is an increase section. Furthermore, frame numbers “J+6” and “J+7” in frames correspond to LTC values “105” and “106” respectively, and therefore this status section is an increment section (increment 2). For example, in the case of being instructed to cue up frame c of LTC “104” (frame of frame number “J+7”) to frame d of LTC “101” (frame of frame number “J”), the cue-up processing unit 355 retrieves frame d for each status section. However, in the case where a decrease section exists in the course of retrieval, it is unknown whether a frame of a specified LTC can be identified since there are cases where a plurality of frames having the same LTC exist, such as frame numbers “J” and “J+4”. Therefore, in such a case, the cue-up processing unit 355 executes step S269 and performs control to cue up the first frame (frame of frame number “J+6”) of the increment section (increment 2) that is prior to and the closest to this decrease section. After the completion of step S269, the cue-up processing unit 355 ends the cue-up control processing. The cue-up processing unit 355 performs the cue-up control processing by referring to the LTC change point table 361, as described above. Thus, by specifying the LTC of a frame to be cued up, the user can easily display the specified frame or a frame close to the specified frame. In this manner, the editing system 310 in FIG. 28 enables the user to more easily perform the playback control processing. As described above, in the case where the frame of a target LTC exists in a section other than an increment section, the cue-up processing unit 355 does not cue up the frame. However, the editing control apparatus 324 may perform more advanced retrieval using real-time metadata LTC to identify a specified frame as long as the editing control apparatus 324 has enough capability. The LTC values and FTC values used in the above description are one example, and LTC values and FTC values are not limited to the above example. Further, the order in which status sections are arranged in the above description may be any other order. Furthermore, status types are not limited to the foregoing, and any status type and any number of status types can be used. As described above, there are cases where a frame to be actually cued up differs from a specified frame to be cued up depending on the status of the specified frame. However, a frame to be actually cued up may be a frame other than the foregoing. The above description has been made on the case of performing the cue-up processing using an LTC change point table incorporating a change point where an increase/decrease pattern of LTC changes. However, a table used in the cue-up processing may be any other table besides an LTC change point table as long as LTC is associated with FTC. The description has been made on the example of the editing system 310 composed of the two disk recording/playback apparatuses 321 and 323 and the editing control apparatus 324 which are interconnected through the network 322 in FIG. 28. However, the structure of the editing system may be varied. For example, the number of disk recording/playback apparatuses or editing control apparatuses may be one or more than one. Further, the disk recording/playback apparatus 321 or 323 may have two drives, and the playback and recording of a clip is performed between these drives. Furthermore, the editing system 310 may include another apparatus such as the camcorder 300. Moreover, the editing system 310 may be a playback control system composed of a disk recording/playback apparatus with a drive equipped with the optical disk 31 on which a clip edited beforehand is recorded and an editing control apparatus. Further, the disk recording/playback apparatus 321 or 323 and the editing control apparatus 324 may be configured as one apparatus, and a part of the function of the apparatuses may further be configured as a separate device. The present invention can also be applied to an information processing apparatus having a function other than the above-described functions. Therefore, the disk recording/playback apparatuses 30, 321 and 323, the camcorder 300, and the editing control apparatus 324 may have a function besides the above-described functions. The above-described consecutive processing can be carried out not only by hardware but also by software as described above. In the case of using software to carry out the consecutive processing, a program forming the software is installed from a recording medium or the like onto a computer incorporated in special hardware, or e.g. a general-purpose personal computer that can execute various functions by installing various programs thereon. For example, as shown in FIG. 29, the recording medium is not only formed by the removable medium 346 distributed to the user to provide the program separately from a computer, the removable medium 346 including a packaged medium such as a magnetic disk (including a flexible disk), an optical disk (including a CD-ROM (Compact Disc-Read Only Memory) and a DVD (Digital Versatile Disc)), a magneto-optical disk (including an MD(Mini-Disc) (registered trademark)), a semiconductor memory or the like which has the program recorded thereon, but also formed by the ROM 332, the hard disk including the storage unit 343, or the like which has the program stored thereon and is provided to the user in a state of being preincorporated in the computer. It is to be noted that in the present specification, the steps describing the program recorded on the recording medium include not only processing carried out in time series in the described order but also processing carried out in parallel or individually and not necessarily in time series. Further, in the present specification, a system refers to an apparatus as a whole formed by a plurality of apparatus. FIG. 1A 12-1: 12-1 CLIP FIG. 1B FIG. 2 32: SPINDLE MOTOR 33: PICKUP UNIT 34: RF AMPLIFIER 35: SERVO CONTROL UNIT 36: SIGNAL PROCESSING UNIT 37: MEMORY CONTROLLER 38: MEMORY 39: DATA CONVERSION UNIT 40: CONTROL UNIT 41: OPERATION UNIT 51: SIGNAL INPUT/OUTPUT DEVICE FIG. 3 61: DEMULTIPLEXER 62: DATA AMOUNT DETECTION UNIT 63: VIDEO SIGNAL CONVERSION UNIT 64: AUDIO SIGNAL CONVERSION UNIT 65: LOW-RESOLUTION DATA GENERATION UNIT 66: REAL-TIME METADATA PROCESSING UNIT 67: NON-REAL-TIME METADATA PROCESSING UNIT 71: LTC DATA PROCESSING UNIT 72: LTC DATA PROCESSING UNIT 81: VIDEO DATA CONVERSION UNIT 82: AUDIO DATA CONVERSION UNIT 83: LOW-RESOLUTION DATA PROCESSING UNIT 84: REAL-TIME METADATA PROCESSING UNIT 85: NON-REAL-TIME METADATA PROCESSING UNIT 51 : FROM SIGNAL INPUT/OUTPUT DEVICE 51 51 : TO SIGNAL INPUT/OUTPUT DEVICE 51 37 : TO MEMORY CONTROLLER 37 37 : FROM MEMORY CONTROLLER 37 FIG. 4 71: LTC DATA PROCESSING UNIT 101: CONTROL UNIT 102: LTC GENERATION UNIT 103: INITIAL-VALUE SETTING UNIT 104: COUNTER 105: REAL-TIME CLOCK : CONTROL SIGNAL AND SYNC SIGNAL LTC : LTC DATA FIG. 5 LTC FTC : LTC DATA AND FTC DATA 111: ACQUISITION CONTROL UNIT 112: DETERMINATION PROCESSING UNIT 113: DATA MANAGEMENT UNIT 114: DATA HOLDING UNIT 115: SECTION SETTING MANAGEMENT UNIT 116: SECTION SETTING HOLDING UNIT 117: REGISTRATION PROCESSING UNIT 121: LTC DATA 122: FTC DATA 123: SECTION NAME 38: MEMORY 124: LTC CHANGE POINT TABLE FIG. 6 : RECORDING PROCESSING START S1: SET AUDIO ANNUAL-RING SIZE Tsa, VIDEO ANNUAL-RING SIZE Tsv, LOW-RESOLUTION ANNUAL-RING SIZE Tsl, AND REAL-TIME META ANNUAL-RING SIZE Tsm S2: START AUDIO SIGNAL CONVERSION PROCESSING, VIDEO SIGNAL CONVERSION PROCESSING, REAL-TIME METADATA PROCESSING, LOW-RESOLUTION DATA GENERATION PROCESSING, AND NON-REAL-TIME METADATA PROCESSING, AND ALSO START AUDIO DATA STORAGE PROCESSING, VIDEO DATA STORAGE PROCESSING, REAL-TIME METADATA STORAGE PROCESSING, LOW-RESOLUTION DATA STORAGE PROCESSING, AND NON-REAL-TIME METADATA STORAGE PROCESSING S3: START AUDIO DATA RECORDING TASK S4: START VIDEO DATA RECORDING TASK S5: START LOW-RESOLUTION DATA RECORDING TASK S6: START REAL-TIME METADATA RECORDING TASK S7: RECORDING END INSTRUCTION SUPPLIED ? S8: ALL RECORDING TASKS ENDED ? S9: END AUDIO SIGNAL CONVERSION PROCESSING, VIDEO SIGNAL CONVERSION PROCESSING, REAL-TIME METADATA PROCESSING, AND LOW-RESOLUTION DATA GENERATION PROCESSING, AND ALSO END AUDIO DATA STORAGE PROCESSING, VIDEO DATA STORAGE PROCESSING, REAL-TIME METADATA STORAGE PROCESSING, AND LOW-RESOLUTION DATA STORAGE PROCESSING S10: ALL RECORDING TASKS ENDED ? S11: READ NON-REAL-TIME METADATA STORED IN MEMORY, PERFORM PADDING SO THAT AMOUNT OF NON-REAL-TIME METADATA BECOMES INTEGRAL MULTIPLE OF AMOUNT OF DATA IN ONE SECTOR AND SUPPLY IT TO SIGNAL PROCESSING UNIT, AND THEREBY PERFORM RECORDING CONTROL SO THAT NON-REAL-TIME METADATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR IS RECORDED IN CORRESPONDING NUMBER OF SECTORS S12: END NON-REAL-TIME METADATA PROCESSING AND NON-REAL-TIME METADATA STORAGE PROCESSING : RECORDING PROCESSING END FIG. 7 : AUDIO DATA RECORDING TASK START S33: IS AUDIO DATA SUPPLIED ? S34: HAS AUDIO DATA OF AUDIO SIGNAL FOR Tsa×Na BEEN STORED IN MEMORY ? S35: READ AND EXTRACT AUDIO DATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR, FROM AUDIO DATA STORED IN MEMORY S36: SUPPLY AUDIO DATA TO SIGNAL PROCESSING UNIT, AND THEREBY PERFORM RECORDING CONTROL SO THAT AUDIO DATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR IS RECORDED IN CORRESPONDING NUMBER OF SECTORS S38: READ AUDIO DATA REMAINING IN MEMORY, PERFORM PADDING SO THAT AMOUNT OF AUDIO DATA BECOMES INTEGRAL MULTIPLE OF AMOUNT OF DATA IN ONE SECTOR AND SUPPLY IT TO SIGNAL PROCESSING UNIT, AND THEREBY PERFORM RECORDING CONTROL SO THAT AUDIO DATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR IS RECORDED IN CORRESPONDING NUMBER OF SECTORS : AUDIO DATA RECORDING TASK END FIG. 8 : VIDEO DATA RECORDING TASK START S53: IS VIDEO DATA SUPPLIED ? S54: HAS VIDEO DATA OF VIDEO SIGNAL FOR Tsv×Nv BEEN STORED IN MEMORY ? S55: READ AND EXTRACT VIDEO DATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR, FROM VIDEO DATA STORED IN MEMORY S56: SUPPLY VIDEO DATA TO SIGNAL PROCESSING UNIT, AND THEREBY PERFORM RECORDING CONTROL SO THAT VIDEO DATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR IS RECORDED IN CORRESPONDING NUMBER OF SECTORS S58: READ VIDEO DATA REMAINING IN MEMORY, PERFORM PADDING SO THAT AMOUNT OF VIDEO DATA BECOMES INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR AND SUPPLY IT TO SIGNAL PROCESSING UNIT, AND THEREBY PERFORM RECORDING CONTROL SO THAT VIDEO DATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR IS RECORDED IN CORRESPONDING NUMBER OF SECTORS : VIDEO DATA RECORDING TASK END FIG. 9 : LOW-RESOLUTION DATA RECORDING TASK START S73: IS LOW-RESOLUTION DATA SUPPLIED ? S74: HAS LOW-RESOLUTION DATA FOR PLAYBACK TIME PERIOD Tsl×Nl BEEN STORED IN MEMORY ? S75: READ AND EXTRACT LOW-RESOLUTION DATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR, FROM LOW-RESOLUTION DATA STORED IN MEMORY S76: SUPPLY LOW-RESOLUTION DATA TO SIGNAL PROCESSING UNIT, AND THEREBY PERFORM RECORDING CONTROL SO THAT LOW-RESOLUTION DATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR IS RECORDED IN CORRESPONDING NUMBER OF SECTORS S78: READ LOW-RESOLUTION DATA REMAINING IN MEMORY, PERFORM PADDING SO THAT AMOUNT OF LOW-RESOLUTION DATA BECOMES INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR AND SUPPLY IT TO SIGNAL PROCESSING UNIT, AND THEREBY PERFORM RECORDING CONTROL SO THAT LOW-RESOLUTION DATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR IS RECORDED IN CORRESPONDING NUMBER OF SECTORS : LOW-RESOLUTION DATA RECORDING TASK END FIG. 10 : REAL-TIME METADATA RECORDING TASK START S93: IS REAL-TIME METADATA SUPPLIED ? S94: HAS REAL-TIME METADATA FOR PLAYBACK TIME PERIOD Tsm×Nm BEEN STORED IN MEMORY ? S95: READ AND EXTRACT REAL-TIME METADATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR, FROM REAL-TIME METADATA STORED IN MEMORY S96: SUPPLY REAL-TIME METADATA TO SIGNAL PROCESSING UNIT, AND THEREBY PERFORM RECORDING CONTROL SO THAT REAL-TIME METADATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR IS RECORDED IN CORRESPONDING NUMBER OF SECTORS S98: READ REAL-TIME METADATA REMAINING IN MEMORY, PERFORM PADDING SO THAT AMOUNT OF REAL-TIME METADATA BECOMES INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR AND SUPPLY IT TO SIGNAL PROCESSING UNIT, AND THEREBY PERFORM RECORDING CONTROL SO THAT REAL-TIME METADATA WHOSE AMOUNT IS INTEGRAL MULTIPLE OF DATA AMOUNT IN ONE SECTOR IS RECORDED IN CORRESPONDING NUMBER OF SECTORS : REAL-TIME METADATA RECORDING TASK END FIG. 11 FIG. 12 LTC : LTC DATA GENERATION PROCESSING START S111: INSTRUCTION TO START GENERATING LTC DATA ACQUIRED ? S112: GENERATE LTC USING REAL TIME ? S113: GENERATE LTC DATA IN ACCORDANCE WITH SYNC SIGNAL USING REAL-TIME CLOCK S114: SUPPLY GENERATED LTC DATA TO MEMORY CONTROLLER S115: INSTRUCTION TO END LTC DATA GENERATION ACQUIRED ? S116: SETTING OF INITIAL VALUE SPECIFIED ? S117: SET INITIAL VALUE TO SPECIFIED VALUE S118: SET INITIAL VALUE TO “0” S119: GENERATE LTC DATA IN ACCORDANCE WITH SYNC SIGNAL USING COUNTER S120: SUPPLY GENERATED LTC DATA TO MEMORY CONTROLLER S121: INSTRUCTION TO END LTC DATA GENERATION ACQUIRED ? : END FIG. 13 LTC : LTC CHANGE POINT TABLE CREATION PROCESSING START S141: LTC DATA ACQUIRED ? S142: IS THERE LTC DATA STORED ? S143: HOLD ACQUIRED LTC DATA AND FTC DATA S144: COMPARE ACQUIRED LTC DATA AND HELD LTC DATA S145: REFER TO CURRENT SECTION SETTING S146: CONSECUTIVE INCREMENT ? S147: INCREMENT SECTION ? S148: REGISTER HELD LTC DATA AND FTC DATA IN LTC CHANGE POINT TABLE AS INCREMENT POINT S149: SET TO INCREMENT SECTION S150: UPDATE HELD LTC DATA AND FTC DATA FIG. 14 S161: INCREASE BY 2 OR MORE ? S162: INCREASE SECTION ? S163: REGISTER HELD LTC DATA AND FTC DATA IN LTC CHANGE POINT TABLE AS INCREASE POINT S164: SET TO INCREASE SECTION S165: NO CHANGE ? S166: STILL SECTION ? S167: REGISTER HELD LTC DATA AND FTC DATA IN LTC CHANGE POINT TABLE AS STILL POINT S168: SET TO STILL SECTION S169: DECREASE SECTION ? S170: REGISTER HELD LTC DATA AND FTC DATA IN LTC CHANGE POINT TABLE AS DECREASE POINT S171: SET TO DECREASE SECTION FIG. 15 S181: REGISTER HELD LTC DATA AND FTC DATA IN LTC CHANGE POINT TABLE AS END POINT S182: IS IT POSSIBLE TO REGISTER TWO OR MORE ELEMENTS IN LTC TABLE ? S183: REGISTER ACQUIRED LTC DATA AND FTC DATA IN LTC CHANGE POINT TABLE AS OVER POINT S184: PERFORM END PROCESSING : END FIG. 16A FIG. 16B : FRAME NUMBER : STATUS : INCREMENT FIG. 17A FIG. 17B : FRAME NUMBER : STATUS : INCREASE FIG. 18A FIG. 18B : FRAME NUMBER : STATUS : STILL FIG. 19B : FRAME NUMBER : STATUS : DECREASE FIG. 20A : CLIP END FIG. 17B : FRAME NUMBER : STATUS : INCREMENT : END FIG. 21A : NO FREE SPACE IN MEMORY FIG. 21B : FRAME NUMBER : STATUS : INCREMENT : OVER FIG. 22 FIG. 23A 171: AUDIO ANNUAL-RING DATA 172: VIDEO ANNUAL-RING DATA 173: LOW-RESOLUTION ANNUAL-RING DATA 174: REAL-TIME META ANNUAL-RING DATA 175: LTC DATA 181: NON-REAL-TIME METADATA 182: LTC CHANGE POINT TABLE FIG. 23B 191-1: AUDIO ANNUAL-RING DATA 192-1: VIDEO ANNUAL-RING DATA 193-1: LOW-RESOLUTION ANNUAL-RING DATA 194-1: REAL-TIME META ANNUAL-RING DATA 195-1: LTC DATA 201-1: NON-REAL-TIME METADATA 202-1: LTC CHANGE POINT TABLE FIG. 24 FIG. 25 FIG. 26 FIG. 27 32: SPINDLE MOTOR 33: PICKUP UNIT 34: RF AMPLIFIER 35: SERVO CONTROL UNIT 36: SIGNAL PROCESSING UNIT 37: MEMORY CONTROLLER 38: MEMORY 39: DATA CONVERSION UNIT 40: CONTROL UNIT 41: OPERATION UNIT 302: IMAGING UNIT FIG. 28 322: NETWORK FIG. 29 334: PLAYBACK CONTROL UNIT 335: EDITING CONTROL UNIT 340: INPUT/OUTPUT INTERFACE 341: INPUT UNIT 342: OUTPUT UNIT 343: STORAGE UNIT 344: COMMUNICATION UNIT 345: DRIVE 346: REMOVABLE MEDIUM FIG. 30 351: CONTROL UNIT 352: INPUT ACCEPTANCE PROCESSING UNIT 353: INFORMATION ACQUISITION UNIT 354: HOLDING UNIT 355: CUE-UP PROCESSING UNIT 356: COMMAND PROCESSING UNIT 361: LTC CHANGE POINT TABLE : COMMAND : USER INPUT FIG. 31 FIG. 32 : PLAYBACK CONTROL PROCESSING START S201: START ACCEPTING USER INPUTS S202: SPECIFICATION OF CLIP ACCEPTED ? S203: ACQUIRE NON-REAL-TIME METADATA OF SPECIFIED CLIP S204: PLAYBACK CONTROL INSTRUCTION ACCEPTED ? S205: CONTROL PLAYBACK BASED ON INSTRUCTION S206: DISPLAY FRAME SPECIFICATION INPUT ACCEPTED ? S207: DISPLAY SPECIFIED FRAME S208: END ? S209: PERFORM END PROCESSING : END FIG. 33 : CUE-UP CONTROL PROCESSING START S231: SET CURRENT STATUS SECTION BASED ON CURRENT FRAME S232: ACQUIRE TARGET LTC S233: IS STATUS SECTION OF TARGET LTC SAME AS CURRENT STATUS SECTION ? S234: INCREMENT SECTION? S235: PERFORM CUE-UP COMMAND PROCESSING SO THAT FRAME OF TARGET LTC IS DISPLAYED : END FIG. 34 S241: CURRENT LTC<TARGET LTC ? S242: DECREASE SECTION ? S243: IS TARGET LTC INCLUDED IN NEXT STATUS SECTION ? S244: IS NEXT STATUS “END” ? S245: UPDATE CURRENT STATUS SECTION S246: PERFORM CUE-UP COMMAND PROCESSING SO THAT FRAME OF END POINT IS DISPLAYED S247: INCREMENT SECTION ? S248: PERFORM CUE-UP COMMAND PROCESSING SO THAT FRAME OF TARGET LTC IS DISPLAYED S249: PERFORM CUE-UP COMMAND PROCESSING SO THAT FIRST FRAME OF NEXT STATUS SECTION IS DISPLAYED S250: PERFORM CUE-UP COMMAND PROCESSING SO THAT FIRST FRAME OF DECREASE SECTION IS DISPLAYED FIG. 35 S261: DECREASE SECTION ? S262: IS TARGET LTC INCLUDED IN IMMEDIATELY PRECEDING STATUS SECTION ? S263: IS FRAME NUMBER OF FIRST FRAME OF IMMEDIATELY PRECEDING STATUS SECTION “0” ? S264: UPDATE CURRENT STATUS SECTION S265: PERFORM CUE-UP COMMAND PROCESSING SO THAT FRAME HAVING FRAME NUMBER 0 IS DISPLAYED S266: INCREMENT SECTION ? S267: PERFORM CUE-UP COMMAND PROCESSING SO THAT FRAME OF TARGET LTC IS DISPLAYED S268: PERFORM CUE-UP COMMAND PROCESSING SO THAT FIRST FRAME OF CURRENT STATUS SECTION IS DISPLAYED S269: PERFORM CUE-UP COMMAND PROCESSING SO THAT FIRST FRAME OF INCREMENT SECTION THAT IS PRIOR TO AND CLOSEST TO DECREASE SECTION FIG. 36 : INCREMENT : INCREASE : STILL : DECREASE FIG. 37 : CLIP END : INCREMENT : END FIG. 38 : STILL : INCREMENT : INCREASE FIG. 39 : INCREMENT 1 : DECREASE : INCREMENT 2 : INCREASE FIG. 40 : CLIP START : INCREMENT

<SOH> BACKGROUND ART <EOH>In recent years, there has become widespread a method by which when video data and audio data acquired by shooting or the like are recorded onto a recording medium, additional information as editing information is added to the video data and the audio data (e.g., see patent document 1). For example, in the case where video data and audio data are recorded onto videotape by a VCR or the like, as shown in FIG. 1A , the audio data and the video data (skewed black rectangular portions in FIG. 1A ) are in turn recorded in an essence data recording area 11 which is a predetermined recording area on videotape 10 , and also LTC (Linear Time Code), associated with the video data, which is a time code of each frame of the video data is recorded in an additional-information recording area 13 which is a predetermined recording area. In the case of FIG. 1A , three clips (clips 12 - 1 to 12 - 3 ) including the video data and the audio data are recorded in the essence data recording area 11 on the videotape 10 , and LTC, associated with the clips, is recorded in the additional-information recording area 13 . The values of the first LTCs 14 - 1 to 14 - 3 of LTCs associated with the clips 12 - 1 to 12 - 3 are “00:10:20:00”, “12:34:56:10”, and “00:00:30:15”, respectively. LTCs are continuous in each clip. However, there are cases where LTCs are discontinuous over clips, or there are cases where LTCs having the same value exist in a plurality of clips. In recent years, a method of non-linear editing (NLE) to perform editing with a personal computer or the like has been employed as a method for editing video data and audio data. In the non-linear editing, as shown in FIG. 1B , video data and audio data are recorded, as files in units of clips for example, on a hard disk (HDD) 20 or the like in a personal computer used as a data editing apparatus. In the case of FIG. 1B , essence data which is data to be edited including video data and audio data is recorded on the hard disk 20 , as files 21 - 1 and 21 - 2 . In this case, it is possible to specify essence data in units of frames for example, and each frame has a frame number assigned thereto in each file. This frame number is managed as FTC (File Time Code), and a user who edits essence data can directly specify a necessary part in a necessary file using the FTC. The FTC (frame number) is relative position information in which, the number of the first frame of each file being “0”, FTC is assigned to each frame in order from the first frame. Therefore, there are cases where FTC (frame number) of the same value exists in a plurality of files. [Patent document 1] Japanese Patent Application Laid-Open No. 2001-29241 (pages 14 and 15, FIG. 8 )

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1A is an illustration of assistance in explaining conventional LTC. FIG. 1B is an illustration of assistance in explaining conventional FTC. FIG. 2 is a block diagram showing an example of the structure of a disk recording/playback apparatus (disk drive) according to an embodiment of the invention. FIG. 3 is a block diagram showing an example of the detailed structure of a data conversion unit in FIG. 2 . FIG. 4 is a block diagram showing an example of the detailed structure of an LTC data processing unit incorporated in a real-time metadata processing unit of FIG. 3 . FIG. 5 is a block diagram showing an example of the detailed structure of an LTC data processing unit incorporated in a non-real-time metadata processing unit of FIG. 3 . FIG. 6 is a flowchart of assistance in explaining recording processing by a control unit of FIG. 2 . FIG. 7 is a flowchart of assistance in explaining audio data recording task initiated at step S 3 in FIG. 6 . FIG. 8 is a flowchart of assistance in explaining video data recording task initiated at step S 4 in FIG. 6 . FIG. 9 is a flowchart of assistance in explaining low-resolution data recording task initiated at step S 5 in FIG. 6 . FIG. 10 is a flowchart of assistance in explaining real-time metadata recording task initiated at step S 6 in FIG. 6 . FIG. 11 is a schematic diagram of assistance in explaining the data structure of KLV-encoded data. FIG. 12 is a flowchart of assistance in explaining LTC data generation processing. FIG. 13 is a flowchart of assistance in explaining LTC change point table creation processing. FIG. 14 is a flowchart of assistance in explaining LTC change point table creation processing, subsequent to FIG. 13 . FIG. 15 is a flowchart of assistance in explaining LTC change point table creation processing, subsequent to FIG. 14 . FIG. 16A is a diagram of assistance in explaining an example of a state of LTC change. FIG. 16B is a diagram of assistance in explaining an example of an element of an LTC change point table. FIG. 17A is a diagram of assistance in explaining another example of a state of LTC change. FIG. 17B is a diagram of assistance in explaining another example of an element of an LTC change point table. FIG. 18A is a diagram of assistance in explaining another example of a state of LTC change. FIG. 18B is a diagram of assistance in explaining another example of an element of an LTC change point table. FIG. 19A is a diagram of assistance in explaining another example of a state of LTC change. FIG. 19B is a diagram of assistance in explaining another example of an element of an LTC change point table. FIG. 20A is a diagram of assistance in explaining another example of a state of LTC change. FIG. 20B is a diagram of assistance in explaining another example of an element of an LTC change point table. FIG. 21A is a diagram of assistance in explaining another example of a state of LTC change. FIG. 21B is a diagram of assistance in explaining another example of an element of an LTC change point table. FIG. 22 is a schematic diagram showing an example of the structure of data recorded on an optical disk in FIG. 2 . FIG. 23A is a schematic diagram of assistance in explaining an example of the structure of data recorded on an optical disk in FIG. 2 . FIG. 23B is a schematic diagram of assistance in explaining another example of the structure of data recorded on an optical disk in FIG. 2 . FIG. 24 is an illustration showing an example of a directory structure in an optical disk of FIG. 2 . FIG. 25 is an illustration showing an example of a more detailed directory structure shown in FIG. 24 . FIG. 26 is an illustration showing an example of an XML description of a non-real-time metadata file. FIG. 27 is a block diagram showing an example of the structure of a camcorder according to an embodiment of the invention. FIG. 28 is an illustration showing an example of the structure of an editing system according to an embodiment of the invention. FIG. 29 is a block diagram showing an example of the internal structure of an editing control apparatus in FIG. 28 . FIG. 30 is a block diagram showing an example of the detailed structure of a playback control unit in FIG. 29 . FIG. 31 is an illustration of assistance in explaining an example of a display by a monitor in FIG. 28 . FIG. 32 is a flowchart of assistance in explaining playback control processing. FIG. 33 is a flowchart of assistance in explaining cue-up control processing. FIG. 34 is a flowchart of assistance in explaining cue-up control processing, subsequent to FIG. 33 . FIG. 35 is a flowchart of assistance in explaining cue-up control processing, subsequent to FIG. 34 . FIG. 36 is a diagram of assistance in explaining an example of a state of cue-up processing. FIG. 37 is a diagram of assistance in explaining another example of a state of cue-up processing. FIG. 38 is a diagram of assistance in explaining another example of a state of cue-up processing. FIG. 39 is a diagram of assistance in explaining another example of a state of cue-up processing. FIG. 40 is a diagram of assistance in explaining another example of a state of cue-up processing. detailed-description description="Detailed Description" end="lead"?

20060208

20110201

20070111

63859.0

H04N700

ZHAO, DAQUAN

PLAYBACK APPARATUS, PLAYBACK METHOD, AND PROGRAM FOR THE SAME

UNDISCOUNTED

ACCEPTED

H04N

ACCEPTED

A Conduit Threading Device And Method

A conduit threading device is provided for passing a pull-cord (24) through a conduit (17) by imposing suction at one end of a conduit to draw a shuttle (16) having a zone of maximum diameter that is commensurate with the internal diameter of the conduit and that is introduced at the other end of the conduit, through the conduit. The conduit threading device includes a positive displacement pump (1), typically a hand operated piston and cylinder pump, having a suction inlet (14) generally at the end of a flexible suction 10 pipe (13) configured for releasable attachment, by way of one of a selection of adapters, to an end of a conduit. Interposed between the pump and suction inlet is a separate collection chamber (9) for waste solids and liquids drawn into the suction inlet during use. The pull-cord is preferably a light weight polypropylene string, or the like.

1-10. (canceled) 11: A conduit threading system for passing a pull-cord through a conduit by imposing suction at one end of the conduit, said conduit threading system comprising: a pull-cord; a shuttle having a zone of maximum diameter corresponding to the internal diameter of the conduit and adapted to be received within the conduit, said shuttle being removably attachable to an end of said pull-cord; a positive displacement pump having a suction inlet; a collection chamber attached to said suction inlet of said positive displacement pump; and a suction pipe releasably attachable to said collection chamber and the conduit. 12: The conduit threading system as set forth in claim 11, wherein said positive displacement pump is a manually operable pump having a vertically movable piston and cylinder assembly. 13: The conduit threading system as set forth in claim 12, wherein said positive displacement pump further comprising two lateral extensions adapted for an operator to stand upon in order to operate said pump by way of a transverse handle carried at the operatively upper end of said piston rod. 14: The conduit threading system as set forth in claim 12, wherein said positive displacement pump has a volumetric displacement of from 1 to 4 litres (about 2 to about 8 pints). 15: The conduit threading system as set forth in claim 11, wherein said collection chamber further comprising a suction outlet and a suction inlet, said suction outlet of said collection chamber being releasably attachable to said suction inlet of said pump, said suction inlet of said collection chamber being removably attachable to said suction pipe, said suction inlet and suction outlet of said collection chamber both terminate at a position elevated from the bottom of said collection chamber. 16: The conduit threading system as set forth in claim 15, wherein said suction outlet of said collection chamber further comprising a filter means for preventing debris becoming entrapped with air drawn into said pump. 17: The conduit threading system as set forth in claim 11 further comprising a plurality of adapters releasably attachable to the free end of said suction pipe, each of said adapters having a different outer diameter. 18: The conduit threading system as set forth in claim 17 further comprising a storage unit removably attachable to the upper section of said collection chamber, said storage unit being adapted to receive said adapters. 19: The conduit threading system as set forth in claim 11, wherein said shuttle having a generally bell-shaped resiliently flexible diaphragm, and an axially extending attachment member, said diaphragm having a leading end and a trailing end, said trailing end of said attachment member having a maximum diameter corresponding to the internal diameter of the conduit, said attachment member having an eye located at its trailing end and a generally spherical guide element located at its leading end, said eye being removably attachable to said pull-cord through an attachment means. 20: The conduit threading system as set forth in claim 19, wherein said attachment member further comprising a groove adapted to receive an edge of said leading end of said diaphragm, said groove being located adjacent said guide element. 21: The conduit threading system as set forth in claim 11, wherein said pull-cord being stored in a roll form for unwinding by withdrawing said pull-cord generally axially from the center of the roll with said pull-cord having a weight of about one half to two grams per meter, and where said pull-cord is selected from the group consisting of a nylon string, a polypropylene string. 22: A conduit threading system comprising: a pull-cord; an attachment means removably attachable to said pull-cord; a shuttle having a generally bell-shaped resiliently flexible diaphragm, and an axially extending attachment member, said diaphragm having a leading end and a trailing end, said trailing end of said attachment member having a maximum diameter corresponding to the internal diameter of the conduit, said attachment member having an eye located at its trailing end and a generally spherical guide element located at its leading end, said eye being removably attachable to said attachment means; a positive displacement pump having a suction inlet; a collection chamber having a suction outlet and a suction inlet, said suction outlet of said collection chamber being attached to said suction inlet of said positive displacement pump, said suction inlet and suction outlet of said collection chamber both terminate at a position elevated from the bottom of said collection chamber; a suction pipe releasably attachable to said suction inlet of said collection chamber; and an adapter removably attachable to the free end of said suction pipe, the free end of said adapter being receivable in said conduit. 23: The conduit threading system as set forth in claim 22, wherein said positive displacement pump is a manually operable pump having a vertically movable piston and cylinder assembly. 24: The conduit threading system as set forth in claim 23, wherein said positive displacement pump further comprising two lateral extensions adapted for an operator to stand upon in order to operate said pump by way of a transverse handle carried at the operatively upper end of said piston rod. 25: The conduit threading system as set forth in claim 22, wherein said suction outlet of said collection chamber further comprising a filter means for preventing debris becoming entrapped with air drawn into said pump. 26: The conduit threading system as set forth in claim 22, wherein said attachment member further comprising a groove adapted to receive an edge of said leading end of said diaphragm, said groove being located adjacent said guide element. 27: The conduit threading system as set forth in claim 22, wherein said pull-cord being stored in a roll form for unwinding by withdrawing said pull-cord generally axially from the center of the roll with said pull-cord having a weight of about one half to two grams per meter, and where said pull-cord is selected from the group consisting of a nylon or polypropylene string. 28: The conduit threading system as set forth in claim 22 further comprising a storage unit removably attachable to the upper section of said collection chamber, said storage unit being adapted to receive said adapter. 29: The conduit threading system as set forth in claim 22, wherein said adapter having a connection end and a spigot, said connection end being releasably attachable with a socket located at the free end of said suction pipe, said spigot being located opposite of said connection end and being tapered. 30: A method of passing a pull-cord through a conduit, said method comprising the steps of: a step of providing an apparatus, said apparatus comprising a pull-cord; a shuttle having a zone of maximum diameter corresponding to the internal diameter of the conduit and adapted to be received within the conduit, said shuttle being removably attachable to an end of said pull-cord; a positive displacement pump having a suction inlet; a collection chamber releasably attachable said suction inlet of said positive displacement pump; a suction pipe attached to said collection chamber; and an adapter removably attachable to the free end of said suction pipe; introducing the free end of said adapter into the conduit; attaching said shuttle to a free end of said pull-cord; introducing said shuttle into the conduit opposite said adapter with the end opposite of said pull-cord attachment being introduced first; attaching the free end of said suction pipe to said collection chamber; attaching said suction inlet of said positive displacement pump to said collection chamber; and operating said positive displacement pump until said shuttle reaches said adapter.

FIELD OF THE INVENTION This invention relates to a conduit threading device and method of using same for introducing an electrical wire or communications cable, or both, into a conduit through which they are to pass utilizing a pull-cord that is introduced into the conduit in preparation therefor. In particular, but not exclusively, the invention relates to a conduit threading device for assisting in threading a pull-cord through a conduit whilst simultaneously, or in advance, serving to safely clear the conduit of any water, debris or the like that may have accumulated in the conduit, typically during the building operations. It is to be understood that the term pull-cord as used in this specification is intended to refer to any cord or line that is commonly introduced into a conduit firstly and then used in pulling electrical wires, communications cables, or a more robust pull-cord for the latter purpose through the conduit. BACKGROUND TO THE INVENTION The threading of pull-cords through conduits in buildings for the purpose of pulling electrical wires and communications cables through the conduits is time consuming and often difficult due to the fact that the conduits may be lengthy and have multiple bends. The most common method for threading electrical wires or pull-cords through conduits makes use of a long spring steel wire, often referred to in the trade as a fishwire or fishtape, that is manually pushed through a conduit from one end to the other. An electrical wire or communications cable or a plurality thereof may then be secured to the free end of the fishtape that is then pulled back through the conduit in order to pull the electrical wire or communications cable through the conduit. This method is often time consuming and difficult to carry out as the fishwire generally has to be forced around a series of bends of the conduit, sometimes with great resistance, and sometimes without success. The one fishwire may then have to be retrieved from the opposite end of the conduit with a second fish wire. A wide variety of different devices has been proposed in the prior art that utilise, in most cases, an elevated pressure, typically that of compressed air at high pressure in canisters, but in other cases an elevated or sub-atmospheric pressure created using an electrical blower, most typically, a vacuum cleaner. Thus, for example, British patent GB 1910 10705 describes the introduction of a pull-cord that has a reel on which the cord is wound and a source of compressed air to blow a dart with an expendable flange through the conduit with one end of the cord attached to its head. This arrangement has the disadvantage that high pressure can build up behind the dart especially if the movement of the dart along the conduit takes place irregularly according to obstructions typically in the form of foreign matter encountered and also bends in the conduit that have to be negotiated; and the general effect can be that dirt, water and other debris can be expelled from the open end of the conduit with some force and velocity thereby creating a safety hazard to property and persons who may be in the vicinity of the open end of the conduit. Also, the unwinding of a cord from a reel is considered by applicant to be inappropriate to the effective implementation of such a method. Still further, the operator is generally not able to observe the arrival of the pull-cord at its destination, resulting in an undesirable lack of control especially on noisy building sites where communication is often a problem. A similar high pressure system is proposed in U.S. Pat. No. 4,043,537 to Russo which accordingly has the disadvantages associated with high pressure that are indicated above. On the other hand, U.S. Pat. No. 5,246,207 to Horii et al; U.S. Pat. No. 5,374,034 to Flores et al; and U.S. Pat. No. 5,730,424 to Flores Snr all propose systems in which there is no plug or dart to carry an end of the cord or line that is simply blown through the conduit utilising elevated fluid pressure that once more has the disadvantages indicated above. U.S. Pat. No. 3,793,732 to Hamrick discloses a similar arrangement that utilises either the elevated pressure or suction developed by a vacuum cleaner to achieve the same objective. Whilst the positive or negative pressure developed by a vacuum cleaner is unlikely to be sufficiently high to create a danger, the air pressure differential generated is also considered by applicant to be insufficiently high to be effective for the purpose at hand. Once more a reel of cord is employed with attendant disadvantages. OBJECT OF THE INVENTION It is an object of this invention to provide a simple, yet highly effective conduit threading device for passing pull-cords through conduits that overcomes, at least to some extent, the difficulties outlined above. SUMMARY OF THE INVENTION In accordance with one aspect of this invention there is provided a conduit threading device for passing a pull-cord through a conduit by imposing a negative pressure on a leading end of a shuttle having a zone of maximum diameter that is commensurate with the internal diameter of the conduit and attachment means for the attachment of a pull-cord to the shuttle so that suction applied to a target end of a conduit operatively draws the shuttle and attached pull-cord through the conduit, the conduit threading device being characterised in that it includes a positive displacement pump having a suction inlet configured for releasable attachment to an end of a conduit or conduit fitting and in that there is interposed between the pump and suction inlet a separate collection chamber for solids and liquids drawn into the suction inlet during use. Further features of this aspect of the invention provide for the positive displacement pump to be a manually operable pump preferably having a vertically movable piston assembly with the pump having a volumetric displacement from 1 to 4 litres (about 2 to about 8½ pints), typically about 2½ to 3 litres (about 5¼ to about 6½ pints) in the case of 20 millimetre (about ¾ inche) and 25 millimetre (about 1 inche) diameter conduits; for a suction outlet from the collection chamber to communicate with a suction inlet to the pump; or both a suction inlet to, and suction outlet from, the collection chamber to both terminate at a position elevated from the bottom of the collection chamber; for the suction outlet from the collection chamber to the pump to have filter means associated with it to prevent dirt becoming entrapped with air drawn into the pump; for the suction inlet to be a free end of a flexible pipe connected at its other end to the collection chamber; and for the conduit threading device to include a selection of different tapered adapters that are preferably transparent for selective cooperation with the suction inlet according to the size and orientation of an open end of a conduit or conduit fitting in relation to which the device is to be used. Still further features of the invention provide for the device to include a shuttle having an operatively leading and trailing section and wherein the trailing section has said zone of maximum diameter that is commensurate with the internal diameter of the conduit; for the shuttle to comprise a generally bell-shaped, somewhat resiliently flexible substantially non-expansible body; for the shuttle to have a rigid or semi-rigid attachment member running longitudinally through its centre with the attachment means at its operatively trailing end; for the body of the shuttle to resemble a diaphragm manufactured from silicon rubber or other suitable resiliently flexible material; for the attachment member to have an integral generally part-spherical or ellipsoidal guide element at its leading end; and for the pull-cord to comprise a nylon, polypropylene or other suitably strong and light weight string, preferably stored in a coreless roll form for unwinding by withdrawing the string generally axially from the centre of the roll with the string preferably having a weight of about one half to two grams per metre, typically about one gram per metre. In accordance with a second aspect of the invention there is provided a method of threading a pull-cord through a conduit comprising applying suction to one end of the conduit utilising a conduit threading device as defined above with a shuttle installed at the opposite end of said conduit and having an end of a pull-cord attached thereto. The pump is conveniently a standard dual action operatively vertically orientated hand pump having both suction and pressure outlets. In such an instance the hand pump generally has a base that an operator can anchor with the feet whilst the piston is raised and lowered in order to create a suction at the suction inlet and simultaneously to create an outflow at the pressure outlet. It is to be noted that the invention also envisages use of the pressure outlet under appropriate circumstances simply for blowing debris from a conduit in the event that it is considered to be necessary and safe, preparatory to installing a pull-cord in the conduit utilising the suction inlet. It has been found that standard manual pumps of a type commercially available for the purpose of inflating inflatable items such as inflatable furniture, dinghies, boats and rafts operate highly effectively when combined with a suitable collection chamber and other components of the device provided by the invention. In order that the above and other features of the invention may be more fully understood one embodiment thereof will now be described with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS In the drawings:— FIG. 1 is a view of one embodiment of pump and collection chamber assembly from one side thereof; FIG. 2 is a view of the pump and collection chamber assembly from the other side thereof; FIG. 3 is an isometric view illustrating the application of the device of this embodiment of the invention; FIG. 4 is a sectional detail of one embodiment of shuttle in situ in a length of conduit; FIG. 5 is a sectional elevation of one form of adapter for applying suction to a conduit under particular circumstances; FIG. 6 is a perspective illustration thereof; FIG. 7 is a perspective illustration of one alternative form of adapter for application in other circumstances; and, FIG. 8 is an illustration showing the different circumstances in which different adapters are appropriate. DETAILED DESCRIPTION WITH REFERENCE TO THE DRAWINGS In the embodiment of the invention illustrated in the drawings, a conduit threading device comprises a manually operable positive displacement pump (1) that extends upwardly from a base (2) that has two lateral extensions (3) (see FIG. 3) adapted for an operator to stand upon in order to operate the pump by way of a transverse handle (4) carried at the operatively upper end of a piston rod (5). The pump is a conventional piston and cylinder type of pump and, in this embodiment of the invention, is a commercially available pump sold for the purpose of inflating and deflating large inflatable items such as inflatable furniture, dinghies, so-called rubber ducks, boats and the like. The pump has a vacuum inlet connection (6) as shown in FIG. 1 and, on the opposite side, a pressure outlet connection (7), as shown in FIG. 2. The pump, in this case, typically has a displacement capacity of about two to four litres (about 4¼ to about 8½ pints), and, most typically, from two and a half to three litres (about 5¼ to about 6½ pints). This volume represents the volume of about 6 metres (about 20 feet) of 25 millimetre (about 1 inch) diameter conduit and about 12 metres (about 40 feet) of 20 millimetre (about ¾ inch) outside diameter conduit. Fixed to the pump by means of a pair of vertically spaced horizontally extending bracket assemblies (8) is a similarly dimensioned collection chamber (9) that is positioned laterally offset from the pump, but extending parallel to it. The suction inlet (6) to the pump is connected to the interior of the collection chamber by means of a suction pipe (10). The entrance to the suction pipe is positioned at an elevated position in the collection chamber and has a filter (11) for preventing transfer of any dirt or liquid droplets in the collection chamber to the pump. Also in the central region of the collection chamber is a suction inlet (12) to which is removably fitted one end of a flexible suction pipe (13). The other end of the suction pipe has a socket (14) for the selective attachment of adapters to it according to requirements. The arrangement is such that dirt, liquids, and other debris generally indicated by numeral (15) collect in the bottom of the collection chamber for periodic disposal, from time to time. As a separate component of the conduit threading device there is provided a shuttle (16) (see FIG. 4) for introduction into one end of a conduit (17), the shuttle being adapted in use to be drawn by suction to the opposite end of the conduit. The shuttle (16) is, in this embodiment of the invention, composed of two parts, the first of which is a generally bell-shaped resiliently flexible diaphragm (18) manufactured from silicon rubber or other suitable material that exhibits suitable low friction properties relative to the material from which conduits are made. The maximum diameter of the diaphragm is approximately the same as the internal diameter of a conduit with which it is to be used, and preferably slightly larger. Accordingly, a complete conduit threading device may comprise two or more different sizes of shuttle so as to enable a pull-cord to be installed in a number of different sizes of conduits. The other component of the shuttle is an axially extending injection moulded attachment member (19) that has an eye (20) at its trailing end and a generally spherical or ellipsoidal guide element (21) at its leading end. A locating groove (22) for receiving the edge of the leading end of the diaphragm is provided immediately adjacent the trailing end of the guide element. Any suitable attachment means such as a split ring (23) can be attached to the eye of the attachment member so that a free end of a pull-cord (24) can be attached thereto. Of course, one entire shuttle assembly will be provided for each different size of conduit with which the conduit threading device is to be used. The pull-cord is preferably a rather lightweight element and most conveniently is a plastics string, such as a polypropylene string, that is generally supplied in coreless rolls (25) thereof from which the string is designed to be withdrawn with substantially no resistance from the centre of the roll by a sort of unravelling process in well-known manner. Indeed, in order to avoid any difficulties that may be created by rewinding pull-cords as in prior art situations, it is proposed that, in view of the extremely low cost of such a polypropylene string, the string be regarded as disposable or, at least, not reusable for this particular purpose. By continuously withdrawing string of this nature from its original roll form, substantially no resistance will be experienced in withdrawing string as required. Finally, and referring now to FIGS. 5 to 8 of the drawings, the adapters to be selectively used on the suction end of the socket (14) of the suction pipe (13) may be of basically two different types, namely those (26) embodying a right angle (see FIGS. 5, 6 and 8), and those (27) that are straight (see FIG. 7). Each of a right angled adapter and a straight adapter are provided for each cross-sectional size of conduit with which the device is to be used and all of the adapters and, for that matter shuttles, are conveniently stored in a storage unit indicated by numeral (28) carried at the operatively upper end of the collection chamber. Each adapter has a connection end (29) for releasable cooperation with the socket (14) of the suction pipe and a spigot (30) at the other end that is preferably tapered to ensure a tight fit in an open end (31) on a conduit. Clearly, the right angled adapters are for use in coupling the suction pipe to conduits that extend in a plane parallel to that of a supporting wall, as indicated by numeral (31a), and the straight adapters are for use in coupling the suction pipe to conduits (31b) that extend at right angles to the relevant wall. Preferably the adapters are all made of injection moulded plastics material and are transparent so that the arrival of the shuttle, that is typically coloured a bright colour such as bright orange, can be observed through the wall of the adapter by the operator. It will be clear to those skilled in the art that, in use, an appropriate adapter is attached to the socket (14) of the suction pipe (13) and the adapter is engaged in the appropriate end of the relevant conduit. The shuttle has attached to the split ring (23) the free end of a polypropylene string (24) of the type described above and the shuttle is located in the opposite end of the conduit. Application of a suction to the conduit by operating the pump will cause the shuttle to move into the conduit and, depending on the length of the conduit, a number of strokes of the pump may be required to draw the shuttle through to the end of the conduit in which the adapter is engaged. The arrival of the shuttle at that end will be observed through the wall of the relevant adapter. During this procedure, the string will be drawn freely off the roll thereof as indicated above and become threaded through the conduit. It has been found that the device described above operates extremely effectively in practice and that little or no maintenance is required, apart from periodic removal of accumulated debris from the collection chamber. As indicated above, it is also possible, according to circumstances, and in the event that appreciable debris and possibly water are present in a conduit, that it is desirable to blow the debris and water out. This can be achieved simply by disengaging the suction pipe (13) from the collection chamber and engaging it with the pressure outlet connection (7) from the pump. The suction pipe can then be connected to a conduit by means of an appropriate adapter and air can be pumped under pressure through the conduit in order to clear it or, simply for the purpose of identifying the other end of a conduit. Following this operation, the shuttle can be drawn through the conduit and the suction in the manner described above. It will be understood that numerous variations may be made to the embodiment of the invention described above without departing from the scope hereof. Indeed there are many aspects of the invention that can be varied and, in particular, the design of the shuttle can be varied widely; the nature of the positive displacement pump can be varied widely; and the configuration of the collection chamber can be varied according to requirements.

<SOH> BACKGROUND TO THE INVENTION <EOH>The threading of pull-cords through conduits in buildings for the purpose of pulling electrical wires and communications cables through the conduits is time consuming and often difficult due to the fact that the conduits may be lengthy and have multiple bends. The most common method for threading electrical wires or pull-cords through conduits makes use of a long spring steel wire, often referred to in the trade as a fishwire or fishtape, that is manually pushed through a conduit from one end to the other. An electrical wire or communications cable or a plurality thereof may then be secured to the free end of the fishtape that is then pulled back through the conduit in order to pull the electrical wire or communications cable through the conduit. This method is often time consuming and difficult to carry out as the fishwire generally has to be forced around a series of bends of the conduit, sometimes with great resistance, and sometimes without success. The one fishwire may then have to be retrieved from the opposite end of the conduit with a second fish wire. A wide variety of different devices has been proposed in the prior art that utilise, in most cases, an elevated pressure, typically that of compressed air at high pressure in canisters, but in other cases an elevated or sub-atmospheric pressure created using an electrical blower, most typically, a vacuum cleaner. Thus, for example, British patent GB 1910 10705 describes the introduction of a pull-cord that has a reel on which the cord is wound and a source of compressed air to blow a dart with an expendable flange through the conduit with one end of the cord attached to its head. This arrangement has the disadvantage that high pressure can build up behind the dart especially if the movement of the dart along the conduit takes place irregularly according to obstructions typically in the form of foreign matter encountered and also bends in the conduit that have to be negotiated; and the general effect can be that dirt, water and other debris can be expelled from the open end of the conduit with some force and velocity thereby creating a safety hazard to property and persons who may be in the vicinity of the open end of the conduit. Also, the unwinding of a cord from a reel is considered by applicant to be inappropriate to the effective implementation of such a method. Still further, the operator is generally not able to observe the arrival of the pull-cord at its destination, resulting in an undesirable lack of control especially on noisy building sites where communication is often a problem. A similar high pressure system is proposed in U.S. Pat. No. 4,043,537 to Russo which accordingly has the disadvantages associated with high pressure that are indicated above. On the other hand, U.S. Pat. No. 5,246,207 to Horii et al; U.S. Pat. No. 5,374,034 to Flores et al; and U.S. Pat. No. 5,730,424 to Flores Snr all propose systems in which there is no plug or dart to carry an end of the cord or line that is simply blown through the conduit utilising elevated fluid pressure that once more has the disadvantages indicated above. U.S. Pat. No. 3,793,732 to Hamrick discloses a similar arrangement that utilises either the elevated pressure or suction developed by a vacuum cleaner to achieve the same objective. Whilst the positive or negative pressure developed by a vacuum cleaner is unlikely to be sufficiently high to create a danger, the air pressure differential generated is also considered by applicant to be insufficiently high to be effective for the purpose at hand. Once more a reel of cord is employed with attendant disadvantages.

<SOH> SUMMARY OF THE INVENTION <EOH>In accordance with one aspect of this invention there is provided a conduit threading device for passing a pull-cord through a conduit by imposing a negative pressure on a leading end of a shuttle having a zone of maximum diameter that is commensurate with the internal diameter of the conduit and attachment means for the attachment of a pull-cord to the shuttle so that suction applied to a target end of a conduit operatively draws the shuttle and attached pull-cord through the conduit, the conduit threading device being characterised in that it includes a positive displacement pump having a suction inlet configured for releasable attachment to an end of a conduit or conduit fitting and in that there is interposed between the pump and suction inlet a separate collection chamber for solids and liquids drawn into the suction inlet during use. Further features of this aspect of the invention provide for the positive displacement pump to be a manually operable pump preferably having a vertically movable piston assembly with the pump having a volumetric displacement from 1 to 4 litres (about 2 to about 8½ pints), typically about 2½ to 3 litres (about 5¼ to about 6½ pints) in the case of 20 millimetre (about ¾ inche) and 25 millimetre (about 1 inche) diameter conduits; for a suction outlet from the collection chamber to communicate with a suction inlet to the pump; or both a suction inlet to, and suction outlet from, the collection chamber to both terminate at a position elevated from the bottom of the collection chamber; for the suction outlet from the collection chamber to the pump to have filter means associated with it to prevent dirt becoming entrapped with air drawn into the pump; for the suction inlet to be a free end of a flexible pipe connected at its other end to the collection chamber; and for the conduit threading device to include a selection of different tapered adapters that are preferably transparent for selective cooperation with the suction inlet according to the size and orientation of an open end of a conduit or conduit fitting in relation to which the device is to be used. Still further features of the invention provide for the device to include a shuttle having an operatively leading and trailing section and wherein the trailing section has said zone of maximum diameter that is commensurate with the internal diameter of the conduit; for the shuttle to comprise a generally bell-shaped, somewhat resiliently flexible substantially non-expansible body; for the shuttle to have a rigid or semi-rigid attachment member running longitudinally through its centre with the attachment means at its operatively trailing end; for the body of the shuttle to resemble a diaphragm manufactured from silicon rubber or other suitable resiliently flexible material; for the attachment member to have an integral generally part-spherical or ellipsoidal guide element at its leading end; and for the pull-cord to comprise a nylon, polypropylene or other suitably strong and light weight string, preferably stored in a coreless roll form for unwinding by withdrawing the string generally axially from the centre of the roll with the string preferably having a weight of about one half to two grams per metre, typically about one gram per metre. In accordance with a second aspect of the invention there is provided a method of threading a pull-cord through a conduit comprising applying suction to one end of the conduit utilising a conduit threading device as defined above with a shuttle installed at the opposite end of said conduit and having an end of a pull-cord attached thereto. The pump is conveniently a standard dual action operatively vertically orientated hand pump having both suction and pressure outlets. In such an instance the hand pump generally has a base that an operator can anchor with the feet whilst the piston is raised and lowered in order to create a suction at the suction inlet and simultaneously to create an outflow at the pressure outlet. It is to be noted that the invention also envisages use of the pressure outlet under appropriate circumstances simply for blowing debris from a conduit in the event that it is considered to be necessary and safe, preparatory to installing a pull-cord in the conduit utilising the suction inlet. It has been found that standard manual pumps of a type commercially available for the purpose of inflating inflatable items such as inflatable furniture, dinghies, boats and rafts operate highly effectively when combined with a suitable collection chamber and other components of the device provided by the invention. In order that the above and other features of the invention may be more fully understood one embodiment thereof will now be described with reference to the accompanying drawings.

20060208

20071225

20070215

63405.0

E21C2916

WILSON, LEE D

CONDUIT THREADING DEVICE AND METHOD

SMALL

ACCEPTED

E21C

ACCEPTED

Filling Level Sensor

In the case of a filling level sensor (1) for detecting a fuel filling level in a fuel tank (2), a lever arm (7) which secures a float (6) has a guide part (14). The guide part (14) interacts with an installation opening (3) in the fuel tank (2) and deflects the lever arm (7) in a designated direction. This avoids the filling level sensor (1) being damaged during installation in the fuel tank (2).

1. A filling level sensor for detecting a fuel filling level in a fuel tank of a motor vehicle, which tank has an installation opening through which the level sensor is inserted into the tank, the sensor having a lever arm (7) which secures a float (6), follows the fuel filling level and has a support (5) provided for installation in the fuel tank, and with a plastic clip (9) mounting the lever arm (7) on the support (5), wherein the plastic clip (9) has a guide part (14) which protrudes laterally over the support (5) and has a contour having a guide curve (15) on its side facing away from the support (5) to contact the boundary of the installation opening to pivot the lever arm. 2. The filling level sensor as claimed in claim 1, characterized in that the guide part curve (15) is defined by a curved edge (16) pointing away from the support (5). 3. The filling level sensor as claimed in claim 1 or 2, characterized in that the support (5) has an edge (17) with a smooth contour on its side facing away from the guide part (14) of the lever arm (7). 4. The filling level sensor as defined in claim 1 or 2, wherein the guide part (14) has a latching connection on the lever arm (7). 5. The filling level sensor as defined in claim 1 or 2, wherein the guide part (14) is manufactured integrally with the lever arm (7). 6. The filling level sensor as defined in claim 1 or 2, wherein the lever arm (7) has a plastic clip (9) mounted on the support (5) and a lever wire (10) which is connected to the plastic clip (9) and secures the float (6), and in that the guide part (14) is arranged on the plastic clip (9). 7. The filling level sensor as defined in claim 1, wherein the support (5) or a component connected fixedly to the support (5) is essentially the width of an installation opening (3) in the fuel tank (2). 8. The filling level sensor as defined in claim 7, wherein the support (5) is dependent from an installation flange (4) designed for the closure of an installation opening (3) in the fuel tank (2).

BACKGROUND OF THE INVENTION The invention relates to a filling level sensor for detecting a fuel filling level in a fuel tank of a motor vehicle, with a lever arm which secures a float, follows the fuel filling level and has a support provided for installation in the fuel tank, and with a mounting of the lever arm on the support. Filling level sensors of this type generally have a potentiometer arranged on the support or a magnetically passive position sensor for detecting the deflection of the lever arm, and are known from practice. In the case of fuel tanks nowadays which are generally very shallow and long, the lever arm is likewise very long. For installation, the filling level sensor is introduced with the float in front into the fuel tank through an installation opening which is kept very small. The support is subsequently fastened in the fuel tank. It is necessary in this case for the filling level sensor to be threaded through the installation opening into the fuel tank in a sufficiently careful manner, since the lever arm in particular can be damaged. Furthermore, when the filling level sensor is introduced into the fuel tank, the lever arm has to be pivoted in order to prevent the float from bumping against a wall of the fuel tank. The invention is based on the problem of developing a filling level sensor of the type mentioned at the beginning in such a manner that it permits particularly simple installation in the fuel tank. BRIEF DESCRIPTION OF THE INVENTION This problem is solved according to the invention in that the lever arm has a guide part which protrudes laterally over the support and has a contour having a guide curve on its side facing away from the support. This design makes it possible for the lever arm to be deflected by the guide part when the guide curve is pressed against the edge of the installation opening. The contour of the guide curve makes it possible to define the angle through which the lever arm is deflected as a function of the position of the filling level sensor according to the invention in relation to the fuel tank. The lever arm does not therefore need to be deflected by hand when the filling level sensor according to the invention is introduced into the fuel tank. The filling level sensor according to the invention therefore permits particularly simple installation in the fuel tank. The contour of the guide curve can be defined in a simple manner as a function of the shape and length of the lever arm and of the fuel tank. In the case of fuel tanks and lever arms of the same shape, the guide part turns out to be structurally particularly simple, according to an advantageous development of the invention, if it has a curved edge pointing away from the support. Particularly reliable guidance of the lever arm can be achieved if the filling level sensor slides on one side with an edge of the support and on the other side with the guide curve of the guide part along the edge of the installation opening. By this means, the filling level sensor according to the invention can be introduced straight into the fuel tank. In this case, the lever arm is automatically pivoted into the designated position. According to another advantageous development of the invention, such an automatic pivoting of the lever arm can be achieved in a simple manner if the support has an edge with a smooth contour on its side facing away from the guide part of the lever arm. According to another advantageous development of the invention, existing filling level sensors can be retrofitted in a simple manner if the guide part has a latching connection on the lever arm. The filling level sensor according to the invention can be manufactured particularly cost-effectively if the guide part is manufactured integrally with the lever arm. The lever arm generally has a lever wire fastened to a plastic clip, the lever wire holding the float. The plastic clip has latching elements for connection to the lever wire. In the case of the known filling level sensors, the latching elements are frequently exposed to the risk of damage if they arrive against the edge of the installation opening during installation of the filling level sensor in the fuel tank. However, the risk of individual components of the filling level sensor according to the invention being damaged is further reduced if the lever arm has a plastic clip mounted on the support and a lever wire which is connected to the plastic clip and secures the float, and if the guide part is arranged on the plastic clip. The installation of the filling level sensor according to the invention in the fuel tank is further simplified if the support or a component connected fixedly to the support is essentially the width of an installation opening in the fuel tank. The filling level sensor according to the invention is therefore guided by the support or the component connected to the support and the edge of the installation opening when it is introduced into the fuel tank. Since, however, the guide part protrudes over the support, the lever arm is deflected when the filling level sensor is introduced into the fuel tank. The installation of the filling level sensor according to the invention is further simplified if the support is arranged on an installation flange designed for the closure of an installation opening of the fuel tank. BRIEF DESCRIPTION OF THE DRAWINGS The invention permits numerous embodiments. To further clarify its basic principle, one of these is illustrated in the drawing and is described below. In the drawing FIG. 1 shows a filling level sensor according to the invention during introduction into a fuel tank, FIG. 2 shows the filling level sensor according to the invention from FIG. 1 in the state in which it is virtually completely introduced into the fuel tank, FIG. 3 shows, on a greatly enlarged scale, a perspective illustration of a plastic clip of the filling level sensor according to the invention from FIG. 1. FIG. 1 shows a filling level sensor 1 during installation in a fuel tank 2. The fuel tank 2 has an installation opening 3. The filling level sensor 1 has a support 5 fastened to an installation flange 4. In the fitted state, the installation flange 4 closes the installation opening 3 of the fuel tank 2, so that the filling level sensor 1 is situated within the fuel tank 2. The filling level sensor 1 has a lever arm 7 which supports a float 6 and is coupled to the support 5 via a mounting 8. The lever arm 7 has a plastic clip 9 to which a lever wire 10, which is connected to the float 6, is fastened via a latching connection 11. The position of the lever arm 7 is detected by a potentiometer 12. In this case, the lever arm 7 may secure, for example, a contact bridge (not illustrated) which interacts with slideways 13 arranged on the support 5. As an alternative, the position of the lever arm 7 may also be detected via a magnetically passive position sensor, with the lever arm 7 holding a magnet and a resistance network with spring tongues which can be deflected by the magnet being arranged on the support 5. The plastic clip 9 has a guide part 14 which protrudes over the support 5 and has a guide curve 15. The guide curve 15 is arranged on an edge 16 pointing away from the support 5. On the side facing away from the guide part 14, the support 5 has an edge 17 with a smooth contour. For installation of the filling level sensor 1 in the fuel tank 2, first of all the float 6 is introduced through the installation opening 3 into the fuel tank 2. When the support 5 is subsequently introduced into the installation opening 3, the guide part 14 arrives against the boundary of the installation opening 3 and pivots the lever arm 7 in accordance with the contour of the guide curve 15. The position of the lever arm 7, at which the boundary of the installation opening 3 deflects the lever arm 7, is illustrated in FIG. 1. As the filling level sensor 1 is introduced further, the guide part 14 passes out of the region of the installation opening 3, as illustrated in FIG. 2. This avoids the movement of the lever arm 7 being obstructed and therefore avoids the guide part 14 detecting the fuel filling level in the fuel tank 2. FIG. 3 shows, on an enlarged scale in a perspective illustration, the plastic clip 9 of the filling level sensor 1 from FIG. 1 with the guide part 14. It can be seen in this case that the guide part 14 is manufactured integrally with the plastic clip 9. The plastic clip 9 has a bearing hole 18 in the mounting 8, through which an angled end of the lever wire 10 illustrated in FIG. 1 is guided and forms the bearing spindle. The latching connection 11 for securing the lever wire 10 is likewise manufactured integrally with the plastic clip 9. In an embodiment (not illustrated), the guide part 14 may also have latching hooks and be latched to the plastic clip 9.

<SOH> BACKGROUND OF THE INVENTION <EOH>The invention relates to a filling level sensor for detecting a fuel filling level in a fuel tank of a motor vehicle, with a lever arm which secures a float, follows the fuel filling level and has a support provided for installation in the fuel tank, and with a mounting of the lever arm on the support. Filling level sensors of this type generally have a potentiometer arranged on the support or a magnetically passive position sensor for detecting the deflection of the lever arm, and are known from practice. In the case of fuel tanks nowadays which are generally very shallow and long, the lever arm is likewise very long. For installation, the filling level sensor is introduced with the float in front into the fuel tank through an installation opening which is kept very small. The support is subsequently fastened in the fuel tank. It is necessary in this case for the filling level sensor to be threaded through the installation opening into the fuel tank in a sufficiently careful manner, since the lever arm in particular can be damaged. Furthermore, when the filling level sensor is introduced into the fuel tank, the lever arm has to be pivoted in order to prevent the float from bumping against a wall of the fuel tank. The invention is based on the problem of developing a filling level sensor of the type mentioned at the beginning in such a manner that it permits particularly simple installation in the fuel tank.

<SOH> BRIEF DESCRIPTION OF THE INVENTION <EOH>This problem is solved according to the invention in that the lever arm has a guide part which protrudes laterally over the support and has a contour having a guide curve on its side facing away from the support. This design makes it possible for the lever arm to be deflected by the guide part when the guide curve is pressed against the edge of the installation opening. The contour of the guide curve makes it possible to define the angle through which the lever arm is deflected as a function of the position of the filling level sensor according to the invention in relation to the fuel tank. The lever arm does not therefore need to be deflected by hand when the filling level sensor according to the invention is introduced into the fuel tank. The filling level sensor according to the invention therefore permits particularly simple installation in the fuel tank. The contour of the guide curve can be defined in a simple manner as a function of the shape and length of the lever arm and of the fuel tank. In the case of fuel tanks and lever arms of the same shape, the guide part turns out to be structurally particularly simple, according to an advantageous development of the invention, if it has a curved edge pointing away from the support. Particularly reliable guidance of the lever arm can be achieved if the filling level sensor slides on one side with an edge of the support and on the other side with the guide curve of the guide part along the edge of the installation opening. By this means, the filling level sensor according to the invention can be introduced straight into the fuel tank. In this case, the lever arm is automatically pivoted into the designated position. According to another advantageous development of the invention, such an automatic pivoting of the lever arm can be achieved in a simple manner if the support has an edge with a smooth contour on its side facing away from the guide part of the lever arm. According to another advantageous development of the invention, existing filling level sensors can be retrofitted in a simple manner if the guide part has a latching connection on the lever arm. The filling level sensor according to the invention can be manufactured particularly cost-effectively if the guide part is manufactured integrally with the lever arm. The lever arm generally has a lever wire fastened to a plastic clip, the lever wire holding the float. The plastic clip has latching elements for connection to the lever wire. In the case of the known filling level sensors, the latching elements are frequently exposed to the risk of damage if they arrive against the edge of the installation opening during installation of the filling level sensor in the fuel tank. However, the risk of individual components of the filling level sensor according to the invention being damaged is further reduced if the lever arm has a plastic clip mounted on the support and a lever wire which is connected to the plastic clip and secures the float, and if the guide part is arranged on the plastic clip. The installation of the filling level sensor according to the invention in the fuel tank is further simplified if the support or a component connected fixedly to the support is essentially the width of an installation opening in the fuel tank. The filling level sensor according to the invention is therefore guided by the support or the component connected to the support and the edge of the installation opening when it is introduced into the fuel tank. Since, however, the guide part protrudes over the support, the lever arm is deflected when the filling level sensor is introduced into the fuel tank. The installation of the filling level sensor according to the invention is further simplified if the support is arranged on an installation flange designed for the closure of an installation opening of the fuel tank.

20070529

20100525

20071108

94816.0

B65B5706

SHABMAN, MARK A

FILLING LEVEL SENSOR

UNDISCOUNTED

ACCEPTED

B65B

ACCEPTED

Vehicle body transfer apparatus

A vehicle transfer apparatus (1), which transfers a vehicle body (M) in an up-and-down direction, is composed of a pair of stanchions (2), a lift-unit (3), a tire supporter (6) (7), a lift-unit driver (4), and a tire supporter driver (53) In this apparatus (1), a lift-unit (3) is provided to respective stanchions (2), which are disposed on both sides of the vehicle body (M), and is allowed to slide in an up-and-down direction along the stanchion (2) in compliance with the operation by the lift-unit driver (4). In this apparatus (1), the tire supporter (6), which supports the tire (T) in the condition that the lower part of the tire (T) is exposed under the tire supporter (6) is provided to each lift-unit (3), is adapted to control a linear motion between a tire support position and a passing position by the tire supporter driver (4).

1. A vehicle transfer apparatus, which transfers a vehicle body between a conveyance line disposed in a lower-side of the vehicle conveyance line and a conveyance line disposed in an upper-side of the vehicle conveyance line, the vehicle transfer apparatus comprising: a stanchion disposed on both sides of the vehicle body; a lift-unit, which is provided to each stanchion in the condition that a slide in an up-and-down direction along the stanchion of the lift-unit is allowed; a tire supporter which is provided to each lift-unit and supports a tire of the vehicle body in the condition that the lower part of the tire is exposed under the tire supporter. a lift-unit driver which moves respective lift-units in an up-and-down direction a tire supporter driver which controls a linear motion of the tire supporter and changes the position of the tire supporter between a tire support position and a passing position. 2. A vehicle transfer apparatus according to claim 1, wherein the tire supporter comprising: a pair of chucking arms; and an arm driver which controls an open-and-shut motion of chucking arms and changes the position of the pair of chucking arms between a tire holding position and a tire release position. 3. A vehicle transfer apparatus according to claim 2, wherein a part of the chucking arm that has contact with the tire is a rotatable roller.

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a vehicle transfer apparatus, which performs a transfer of a vehicle body between an upper-side conveyance line and a lower-side conveyance line that are installed in a vehicle assembly line. 2. Description of Relevant Art Conventionally, a vehicle assembly line includes a hanger-type conveyance line and a support-type conveyance line. The hanger-type conveyance line suspends a vehicle body using a conveyance hanger in order to install various parts, such as an engine, a transmission, an exhaust nozzle, and tires etc., which are normally installed from a bottom-side of the vehicle body. The support-type conveyance line holds the vehicle body using a slat conveyor from a bottom-side of the vehicle body in order to install exterior parts etc., which are normally installed from an upper-side of the vehicle body. In this kind of the assembly line, a vehicle body transfer apparatus, which transfers a vehicle body from the hanger-type conveyance line to the support-type conveyance line, is provided. As an example of this kind of the vehicle body transfer apparatus, the vehicle body transfer apparatus disclosed in Japanese unexamined Patent Publication No. H11-268823 has been discovered. The apparatus disclosed in this Japanese unexamined Patent Publication is composed of guide-stanchions positioned on both sides of a vehicle body to be transferred, a lift-unit which moves in an up-and-down direction along the guide-stanchion, and a support-base which moves in a horizontal direction from the lift-unit and changes the total length thereof in order to support the vehicle body. In this vehicle body transfer apparatus, a vehicle body is once passed to a support tool disposed on the support-base from the conveyance hanger at the upper-side of the vehicle body transfer apparatus. Then, the vehicle body is moved downwardly together with the lift-unit and is passed to a slat conveyor positioned in a lower-side of the vehicle body transfer apparatus. In this apparatus, normally, the vehicle body is transferred while supporting a flange of a side-sill of the vehicle body using the support tool, when performing the transfer of the vehicle body. This is because each jack-up point of the vehicle body is already being supported by the conveyance hanger in order to convey the vehicle body. In this conventional vehicle body transfer apparatus, since the flange of the side-sill of the vehicle body is held by the support tool, the impact, which is caused when the vehicle body is passed to the support tool from the conveyance hanger or when the lift-unit is stopped at the predetermined position, may cause the deformation on the flange of the side-sill. Therefore, the vehicle body transfer apparatus, by which a vehicle body is surely transferred between the upper-side conveyance line and the lower-side conveyance line without causing the deformation on the vehicle body, has been required. SUMMARY OF THE INVENTION The present invention relates to a vehicle transfer apparatus, which transfers a vehicle body between a conveyance line disposed in a lower-side of a vehicle conveyance line and a conveyance line disposed in an upper-side of the vehicle conveyance line. The vehicle transfer apparatus is composed of a pair of stanchions, a lift-unit, a tire supporter, a lift-unit driver, and a tire supporter driver. In this apparatus, a lift-unit is provided to respective stanchions, which are disposed on both sides of the vehicle body, and is allowed to slide in an up-and-down direction along the stanchion in compliance with the operation by the lift-unit driver. In this apparatus, additionally, the tire supporter, which supports the tire in the condition that the lower part of the tire is exposed under the tire supporter, is provided to each lift-unit, and this tire supporter is adapted to move between a tire support position and a passing position by a linear motion under the control of tire supporter driver. According to this vehicle transfer apparatus, when vehicle body is transferred to the conveyance line disposed in a lower-side from the conveyance line disposed in a upper-side of the vehicle conveyance line, the vehicle body, whose jack-up points are being held by conveyance hangers, respectively, is raised by the tire supporter of the lift-unit in the condition that each tire of the vehicle body is held by the tire supporter. Next, after disengaging each conveyance hanger from the vehicle body, the lift-unit, which is placing the vehicle body thereon, is moved downwardly till the tire of the vehicle body comes in contact with the conveyance line disposed in a lower-side. Then, after moving the tire supporter to the passing position in compliance with the actuation of the tire supporter driver, the vehicle body is conveyed by the conveyance line disposed in a lower-side. That is, in the present invention, the vehicle body is transferred while holding the tires of the vehicle body, when vehicle body is transferred to the conveyance line disposed in the lower-side from the conveyance line disposed in the upper-side of the vehicle conveyance line using the vehicle transfer apparatus. Therefore, since the impact to be caused during the transfer of the vehicle is mitigated by tire, the occurrence of the deformation of the vehicle body due to the impact can be prevented. In the present invention, additionally, when the vehicle body is passed to the conveyance line disposed in the lower side from the vehicle transfer apparatus, since each tire T is supported by the tire supporter in the condition that the lower part of the tire is exposed under the tire supporter, the tire T firstly comes in contact with the surface of the conveyance line disposed in the lower-side. Therefore, since the impact to be caused when the vehicle body is passed to the conveyance line disposed in the lower-side from the vehicle transfer apparatus is mitigated by tire, the occurrence of the deformation of the vehicle body due to the impact can be prevented. In the present invention, preferably but it is not necessary, the tire supporter includes a pair of chucking arms and an arm driver, which controls the position of the pair of chucking arms between a tire holding position and a tire release position. According to the vehicle transfer apparatus, when the vehicle body is passed from the vehicle transfer apparatus to the conveyance line disposed in a lower-side, the vehicle body is transferred while holding the tire by chucking arms placed at the tire holding position. Then, chucking arms are removed from the tire by changing the position of chucking arms to the tire release position after the tire comes in contact with the surface of the conveyance line disposed in the lower-side and the load due to the vehicle body is not received by chucking arms. Thereby, the vehicle body can be passed to the conveyance line disposed in the lower-side. That is, the hold and release of each tire of the vehicle body is controlled by changing the position of chucking arms between the tire holding position and the tire release position, when the vehicle body is passed from the vehicle transfer apparatus to the conveyance line disposed in the lower-side. Thus, chucking arms are easily removed from the tire. In the present invention, additionally, it is preferable that a part of the chucking arm that has contact with the tire is a rotatable roller. In this case, since the rotatable roller is provided, chucking arms can be removed from the tire even if the load due to the vehicle body is being applied to the chucking arms. This is because a frictional restriction between the tire and the chucking arm prevents the removing of the chucking arm from the tire, if the chucking arm is un-rotatable, in comparison with the case where the chucking arm is being rotatable. That is, when the vehicle body is passed to the conveyance line disposed in the lower-side from the vehicle conveyance line, the chucking arm can be removed from the tire due to the rotation of the roller even if the load caused by the vehicle body is applied to the chucking arm. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a perspective view showing a gantry transfer apparatus according to the present invention's embodiment. FIG. 2 is an enlarged perspective view showing the lift-unit of FIG. 1 in detail FIG. 3A is an enlarged perspective view showing the front tire supporter of FIG. 2 in detail. FIG. 3B is an enlarged perspective view showing the rear tire supporter of FIG. 2 in detail. FIG. 4 is a front view of the release unit to be used for releasing the hanger arm. FIG. 5 is an enlarged perspective view showing a conveyance hanger. FIG. 6A is a side view showing the state where a vehicle body is conveyed to the gantry transfer apparatus. FIG. 6B is a side view showing the state where a vehicle body is raised by a lift-unit. FIG. 7 is a side view showing the state where a vehicle body is placed on the slat conveyor by the lift-unit. FIG. 8A is a front view showing the state where each chucking arm comes away from a tire. FIG. 8B is a front view showing the state where each chucking arm comes near to a tire. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The preferred embodiment of the present invention will be explained with reference to accompanying drawings. Referring to FIG. 1, a gantry transfer apparatus (vehicle transfer apparatus) 1 transfers a vehicle body M to a support-type conveyance line SL disposed in a lower-side of a vehicle conveyance (assembly) line from a hanger-type conveyance line HL disposed in an upper-side of the vehicle conveyance (assembly) line. Here, the hanger-type conveyance line HL is a line, in which a vehicle body M is held by a conveyance hanger H suspended from an overhead conveyor OH and is conveyed in the condition that the vehicle body M is suspended from the overhead conveyor OH. The support-type conveyance line SL is a line, in which a vehicle body M is conveyed while holding the tires T of the vehicle body M on the slat conveyor. The hanger-type conveyance line HL and the support-type conveyance line SL are arranged coaxially, that is, the hanger-type conveyance line HL and the support-type conveyance line SL are disposed in a line along a conveyance direction when each line is viewing from the top. In each conveyance line, each vehicle body is conveyed while directing the front-side of the vehicle body M to a conveyance direction. In the following explanation, the term “up-and-down direction” and “left-and-right direction” mean an up-and-down direction and a left-and-right direction with respect to the vehicle body M, respectively. That is, the term “right-side”, “left-side”, “fore-side”, and “rear-side” are defined based on a transfer direction of the vehicle body M. The gantry transfer apparatus 1 includes essentially a pair of stanchion 2, lift-units 3, and a servomotor (a lift-unit driving unit) 4. Here, the lift-unit 3 is provided to each stanchion 2 and is moved in an up-and-down direction along the stanchion 2 by the servomotor 4. The stanchion 2 is a column-like shaped frame, and is disposed on both sides of a vehicle body M so that the vehicle body M conveyed from the hanger-type conveyance line HL is positioned between adjacent stanchions 2. Rails 21, which guide the movement in an up-and-down direction of the lift-unit 3, are provided on the fore-side and rear-side of the stanchion 2, respectively. Respective rails 21 are provided along an axial direction of the stanchion 2. In FIG. 1, the rail 21 provided in the rear-side of the stanchion 2 is under cover of the stanchion 2, and is therefore not shown in this figure. A rack 22 for placing the servomotor 4 etc., is provided at the top of respective stanchions 2. A connection beam 23, which is an approximately U-like shaped beam in sectional viewing, is laid across racks 22 in the condition that a groove of the connection beam 23 is directed upwardly. The rack 22 of the stanchion 2 positioned in a left-side with respect to the vehicle body M (shown in a right-side in FIG. 1) is provided with the servomotor 4 and a driving gear 41, which is connected to a rotation shaft of the servomotor 4. The rack 22 of the stanchion 2 positioned in a right-side with respect to the vehicle body M is provided with a driven gear 42, which rotates in response to the drive of the driving gear 41. In the present embodiment, the stanchion 2 positioned in a left-side with respect to the vehicle body M and the stanchion 2 positioned in a right-side with respect to the vehicle body M are indicated as “left-side stanchion” and “right-side stanchion”, respectively, as appropriate. One end of chains 43 and 44 is respectively fixed to the driving gear 41. The other end of the chain 43 is fixed to the lift-unit 3 of the left-side stanchion 2, and the other end of the chain 44 is fixed to the lift-unit 3 of the right-side stanchion 2. As can be seen from FIG. 1, the chain 44 lubricated with oil is passed through the groove of the connection beam 23, which is an approximately U-like shaped beam in sectional viewing. Thus, the oil of the chain 44 is not dripped down and does not adhere (contaminate) to the vehicle body M to be conveyed along the overhead conveyor OH. As shown in FIG. 2, the lift-unit 3 is mainly composed of a lifter body 31, a slider unit 5, a front tire supporter 6, and a rear tire supporter 7. Here, the front tire supporter 6 and the rear tire supporter 7 serve as a tire supporter. The lifter body 31 is formed of a hollow casing having base-parts 31a and 31a, which are arranged so as to cover the fore-and-rear sides of the stanchion 2. Guide rollers 31b, each pair of which sandwiches the rail 21 and allows the lifter body 31 to move in an up-and-down direction, is disposed inside of respective base-parts 31a. The slider unit 5 is mainly composed of a guide 51, a slider 52, and a cylinder 53. The slider 52 is held by the guide 51 and is allowed to slide along the guide 51 under the control of the cylinder 53. That is, in the present embodiment, the slider 52 is held by the guide 51 in the condition that the slider 52 is allowed to slide in a left-and-right direction under the control of the cylinder 53. The guide 51 is mainly composed of a pair of guide frames 51a and guide rails 51b. The guide frame 51a is provided with a guide rail 51b, which has an alphabet “H” shape in sectional viewing. In this embodiment, a total of two guide frames 51a are fixed to the bottom of the lifter body 31 along a left-and-right direction, and the position where the guide frame 51a is fixed are the fore-side end and the rear-side end of the lifter body 31. The slider 52 is mainly composed of a pair of support arm 52a and a support plate 52b, which is fixed to the end of respective support arms 52a. A pair of hook-shaped fittings 52c, which are adapted to engage with fore-side and rear-side ends of the guide rail 51b, is provided on each support arm 52a. In this embodiment, both right-side and left-side of each support arm 52a are provided with a pair of hook-shaped fittings 52c with a predetermined distance therebetween. Here, one of hook-shaped fittings 52c positioned in the rear-side of the support arm 52a is under cover of the support arm 52a in FIG. 2. The slider 52 is suspended from guide rails 51b using fittings 52c and is allowed to slide in a left-and-right direction in the state where the slider 52 is hung down from the guide rail 51b. The cylinder 53 is disposed only on a fore-side of the lifter body 31, and is fixed using a supporting bracket 53a, which is provided across the base-part 31a of the lifter body 31 and the guide frame 51a. A cylinder rod 53b of the cylinder 53 connects with a bracket 53c at the end thereof, and the cylinder 53 is fixed in place to the support plate 52b through the bracket 53c. The front tire supporter 6 for holding the front tire T of the vehicle body M is provided at the fore-side end of the support plate 52b. The front tire supporter 6 is adapted to move in a left-and-right direction together with the slide of the slider 52. That is, in this embodiment, the front tire supporter 6 is allowed to move between the tire support position and the passing position. To be more specific, the front tire supporter 6, as shown in FIG. 3A, includes a cylinder support plate 61, a chuck cylinder 62, a pair of arm support plates 63 and 63, a pair of guide rods 64 and 64, and a pair of chucking arms 65 and 65. Here, the term “tire support position” means that the front tire supporter 6 is positioning at the position where the front tire T of the vehicle M transferred within the gantry transfer apparatus 1 can be supported, from the bottom of the tire T, by the front tire supporter 6. That is, the term “tire support position” means that the position where the front tire supporter 6 is located at a vehicle body side in a left-and-right direction. Additionally, the term “passing position” means that the front tire supporter 6 is positioning at the position where the front tire T of the vehicle body M cannot be supported by the front tire supporter 6. That is, the term “passing position” means that a position where the front tire supporter 6 is located at an opposite side in a left-and-right direction with respect to the vehicle body M so that the front tire supporter 6 departs from the vehicle body M. The cylinder support plate 61, which is an approximately U-like shaped plate in sectional viewing, is obtained by bending upwardly both fore-and-rear ends of a flat-shaped plate in order to strengthen the stiffness of the cylinder support plate 61. The cylinder support plate 61 is fixed to the fore-side end of the support plate 52b at a base region thereof. The opposing end with respect to the base region of the cylinder support plate 61 is provided with the chuck cylinder 62 and rod supporters 61a. Here, the chuck cylinder 62 is fixed to the top of the cylinder support plate 61 using a bracket (not shown), and the rod supporter 61a, which is used for receiving column-shaped guide-rods therein, is fixed to the bottom of the cylinder support plate 61. The chuck cylinder 62 moves mutually chucking arms 65 and 65 along a fore-and-rear direction, and changes the position of the chucking arms 65 between the tire holding position and the tire release position. A body-side bracket 62b is provided at a fore-side end of the cylinder body 62a and a rod-side bracket 62d is provided at a rear-side end of a cylinder rod 62c. Here, the term “tire holding position” means the position where the distance between chucking arms 65 is smaller than the diameter of the tire T, and the term “tire release position” means the position where the distance between chucking arms 65 is larger than the diameter in a fore-and-rear direction of the tire T. The arm support plate 63 placed in a fore-side is pivotably supported by the body-side bracket 62b using a bracket 63a, and the arm support plate 63 placed in a rear-side is also pivotably supported by the rod-side bracket 62d using a bracket 63b. Each arm support plate 63 is provided with guides 63c, each of which slidably supports the guide-rod 64 therein so as to allow the slide along the guide-rod 64. Also, each arm support plate 63 is provided with a support part 63d, which rotatably supports the chucking arm 65 therein. That is, the chucking arm 65 serves as a roller, which is rotatably connected to the support part 63d. In this embodiment, respective chucking arms 65 are a column-like shaped member, and are arranged so that a predetermined interval is provided therebetween. Thereby, since a pair of chucking arms 65 provides a two-points support for a tire T, the tire T is supported by a pair of chucking arms 65 from a bottom-side thereof in the condition that a part of the lower part of the tire T is positioned under the chucking arms 65. The chucking arm 65 positioned in a rear-side is allowed to move in a fore-and-rear direction. To be more precise, when the chucking arm 65 positioned in a rear-side is pushed to the rear-side by the chuck cylinder 62, the position of chucking arms 65 is changed from the tire holding position to the tire release position. On the contrary, when the chucking arm 65 positioned in a rear-side is pulled to the fore-direction by the chuck cylinder 62, the position of chucking arms 65 is changed from the tire release position to the tire holding position. As shown in FIG. 3B, the rear tire supporter 7 has the same construction as the front tire supporter 6, and is mainly composed of a cylinder support plate 71, a chuck cylinder 72, a pair of arm support plates 73, a pair of guide-rods 74, and a pair of chucking arms 75, each has the same construction as corresponding component of the front tire supporter 6. The rear tire supporter 7 further includes rod supporters 72a, a body-side bracket 72b, a rod-side bracket 72d, a bracket 73a, a bracket 73b, guides 73c, support parts 73d, each has the same construction as corresponding component of the front tire supporter 6. In the rear tire supporter 7, differing from the front tire supporter 6, the chuck cylinder 72 is installed so that a cylinder rod 72c is positioned in a fore-side. Thereby, the chucking arm 75 placed in a fore-side is allowed to move along a fore-and-rear direction. The cylinder support plate 71 of the rear tire supporter 7 is adapted to move in a fore-and-rear direction by a supporter slide mechanism 8, which is disposed at the rear-side end of the support plate 52b. The supporter slide mechanism 8 is mainly composed of an L-shaped bracket 81, a slider base 82, a servo motor 83, a pair of guide rods 84, and a slider body 85. The L-shaped bracket 81 is an L-like shaped plate formed by bending a flat shaped plate into an L-like shape in sectional viewing. Both fore-and-rear ends of the L-shaped bracket 81 are bent upwardly so as to strengthen the stiffness of the L-shaped bracket 81. In the present embodiment, as shown in FIG. 3B, the L-shaped bracket 81 is fixed to the rear-side of the support plate 52b, such that one end of the L-shaped bracket 81 is directed to an inside (vehicle body) direction and the other end of the L-shaped bracket 81 is directed to a downward direction. In this occasion, the L-shaped bracket 81 is fixed so that a predetermined space is provided between the surface of the bend-part on one end of the L-shaped bracket 81 and the top surface of the support plate 52b. The slider base 82, which is an approximately U-like shaped plate in sectional viewing, and is obtained by bending into the same direction both fore-and-rear ends of a flat-shaped plate. Here, the bend-end disposed in a fore-side serves as a fore-side wall 82a and the bend-end disposed in a rear-side serves as a rear-side wall 82c, and the remainder of the plate serves as a bottom wall 82b. As can be seen from FIG. 3B, the bottom of the bend end of the L-shaped bracket 81 is fixed to the slider base 82 so that the space enclosed by the fore-side wall 82a and the rear-side wall 82c is directed to a downward direction. A body-part of the servo motor 83 is fixed to the rear-side wall 82c of the slider base 82 at approximate center of the rear-side wall 82c. A threaded rod 83a, which is obtained by forming a thread on a rotation shaft of the servo motor 83, is rotatably supported by the fore-side wall 82a and the rear-side wall 82c. A pair of guide rods 84, each of which connects fore-side wall and rear-side wall, are disposed on left-and-right sides of the threaded rod 83a. The slider body 85 is provided with a center through hole 85a and through holes 85b and 85b, each of which penetrates the slider body 85 along a fore-and-rear direction. The center through hole 85a is positioned at middle in a longitudinal direction of the slider body 85 and is provided with an internal thread therein. The through hole 85b is positioned on both sides in a left-and-right direction of the center through hole 85a. In this embodiment, the threaded rod 83a is screwed into the center through hole 85a, and guide rod 84 is slidably inserted into each through hole 85b. The bottom of the slider body 85 is fixed to the cylinder support plate 71, which serves as the base of the rear tire supporter 7. According to these constructions, when the threaded rod 83a is rotated in compliance with the actuation of the servo motor 83, the slider body 85 is moved in a fore-and-rear direction together with rear tire supporter 7. As shown in FIG. 4, the gantry transfer apparatus 1 is provided with a release unit 9 which releases a vehicle body M from the engagement with the hanger arm h1 of the conveyance hanger H. The release unit 9 is provided at an upper left position and an upper right position of the gantry transfer apparatus 1. Here, in FIG. 4, the release unit 9 provided at the upper left position is omitted. In the following explanations, since each release unit 9 has the same construction, the explanation is mainly made with respect to the release unit 9 provided at the upper right position of the gantry transfer apparatus 1, and the explanation about the other of the release unit 9 will be omitted. The release unit 9 is mainly composed of a frame 91, a first cylinder 92, a second cylinder 93, and an engagement part 94. The frame 91 is fixed to the bottom of the connection beam 23 of the gantry transfer apparatus 1, and is connected to a body part 92a of the first cylinder 92 at the bottom thereof, while allowing a pivotal movement in a left-and-right direction of the body part 92a. A body part 93a of the second cylinder 93 is fixed to the inner-side of the stanchion 2 of the gantry transfer apparatus 1, the end of a cylinder rod 93b is pivotably connected to the body part 92a of the first cylinder 92. The engagement part 94 is provided at the end of a cylinder rod 92b of the first cylinder 92, and elongates to an inward direction from the cylinder rod 92b so as to hook the arm connection beam h2, which is positioned at lower-side, of the hanger arm h1 by the engagement part 94. In the release unit 9 having these constructions, in usual state, overall length of the cylinder rod 92b of the first cylinder 92 is being extended and overall length of the cylinder rod 93b of the second cylinder 93 is being shortened. When disengaging the hold by hanger arm h1, firstly, the first cylinder 92 is turned to an inward direction (toward a vehicle body M) by extending the overall length of the cylinder rod 93b of the second cylinder 93. Then, the arm connection beam h2 is hooked by the engagement part 94 and is moved to an obliquely upward direction by shortening the overall length of the cylinder rod 92b of the first cylinder 92. Thereby, the disengagement of the hanger arms h1 can be achieved. As shown in FIG. 5, the conveyance hanger H is mainly composed of connecting rods h4, a hanger base h5, arm struts h6, hanger arms h1, and arm connection beams h2. In this conveyance hanger H, the connecting rod h4 connects a moving body h3, which is movable along an overhead conveyor OH, with the hanger base h5. Each corner (a total of four corners) of the hanger base h5 is provided with the arm strut h6, which elongates to a sideward direction and which pivotably supports the hanger arm h1 at end thereof. Thereby, a pair of hanger arms h1, which are connected each other by arm connection beams h2, are provided to each side of the hanger base h5. A connection beam h7, which elongates to an inward direction, is provided at the bottom of each hanger arm h1, and a support h8 which supports a jack-up point m2 provided at the side-sill of the vehicle body M, is provided at the end of the connection beam h7. In other words, each hanger arm h is provided with the connection beam h7 which elongates toward the vehicle body M from the bottom thereof, and the inside end (vehicle body side end) of the connection beam h7 is provided with the support h8 for supporting the jack-up point m2 of the vehicle body M. Next a vehicle transfer method using the gantry transfer apparatus 1 will be explained. As shown in FIG. 6A, the conveyance hanger H holding the vehicle body M therein is conveyed into the gantry transfer apparatus 1. In this occasion, the lift-unit 3 of the gantry transfer apparatus 1 is on standby at the lower-side position in the condition where each chucking arm 65 is closed. In this occasion, each chucking arm 65 is positioned at the tire holding position. As shown in FIG. 6B, when the conveyance hanger H is stopped at the predetermined position by a stopper (not shown), the lift-unit 3 moves to an upward direction, and each pair of chucking arms 65 contacts with the corresponding tire T of the vehicle body M. This upward movement of the lift-unit 3 is continued till the vehicle body M, which is supported by the support h8 of the conveyance hanger H at the jack-up point m2, is disengaged from the support h8. Next, each hanger arm h1 of the conveyance hanger H is swung to a sideward direction by the actuation of the release unit 9, and is disengaged from the vehicle body M. Then, the vehicle body M is moved to a downward direction together with the lift-unit 3 (see FIG. 7). In this occasion, this downward movement is continued till the lift-unit 3 reaches to the predetermined position, which is the position slightly lower than the position where each tire T of the vehicle body M comes in contact with the slat conveyor SC. When the lift-unit 3 reaches at the predetermined position, each chucking arm 65 is moved to the tire release position in compliance with the actuation of respective chuck cylinders 62 and 72 (see FIG. 3A and FIG. 3B). Next, each chucking arm 65 is slid to the outward in a left-and-right direction by the actuation of the cylinder 53, and is moved to the position (passing position) where the chucking arm 65 does not interfere with the vehicle body M. When the vehicle body M is conveyed to the outside of the gantry transfer apparatus 1, as shown in FIG. 8B, each chucking arm 65 is reversed to the initial position (tire support position) by the actuation of the cylinder 53. Simultaneously, each chucking arm 65 is changed to the closing condition (tire holding position), by which tire T is held, in compliance with the actuation of respective chuck cylinders 62 and 72 (see FIG. 3) to prepare for the next transfer of the vehicle body M (see FIG. 6). Here, if the wheel base of next vehicle body M to be transferred into the gantry transfer apparatus 1 is differing from the previous vehicle body M, the position of the rear tire supporter 7 is shifted in a fore-and-rear direction by the actuation of the supporter slide mechanism 8. Thereby, the distance between the front tire supporter 6 and the rear tire supporter 7 can be adjusted to the wheel base of the next vehicle body M. According to the present invention the benefits as follows can be obtained. (1) In the present invention, the vehicle body M is transferred while supporting tire T of the vehicle body M when the vehicle body M is transferred from the hanger-type conveyance line HL to the support-type conveyance line SL. Thus, the impact to be caused at the time of the transfer of the vehicle is mitigated by tire T. Thereby, the occurrence of the deformation of the flange of the side-sill can be prevented. (2) In the present invention, tire T is supported by a pair of chucking arms 65 in the condition that part of the bottom side of the tire T is positioning below the chucking arms 65. Thus, the vehicle body M is smoothly transferred to the support-type conveyance line SL when the vehicle body is transferred to a downward direction. This is because the tire T grounds in first with the support-type conveyance line SL and mitigates the impact due to the grounding. (3) Since each chucking arm 65 is being rotatable, the slide of the chucking arm 65 is not disturbed even if a load of the vehicle body M is acting on respective chucking arms 65. Thereby, each chucking arm 65 can easily be removed from the tire T. (4) In the present invention, the rear tire supporter 7 is being slidable along a fore-and-rear direction by the supporter slide mechanism 8. Thus, various kinds of vehicles, each is differing in wheel base, can be transferred using the same conveyance line. In the present invention, additionally, the distance between chucking arms 65 is being adjustable in compliance with the size of the tire T. Thus, various kinds of vehicle bodies, each are differing in the size of tire T, can be transferred using the same conveyance line. In the present invention, still furthermore, the front tire supporter 6 and the rear tire supporter 7 are allowed to move along a left-and-right direction with respect to the vehicle body by the slider unit 5. Thus, various kinds of vehicle bodies, each is differing in the distance between tires on both sides or differing in size of the width of the vehicle body M, can be transferred using the same conveyance line. As described above, various types of vehicle bodies, which each are differing in a wheel base, in a distance between tires of both sides, and in a size of tire, can be transferred using the same gantry transfer apparatus 1. Thus, since to provide the specific transfer apparatus to respective lines is not required, the same gantry transfer apparatus can be adopted to any kinds of conveyance line. Thereby, the manufacturing cost can be reduced. Although there have been disclosed what are the patent embodiment of the invention, it will be understood by person skilled in the art that variations and modifications may be made thereto without departing from the scope of the invention, which is indicated by the appended claims. In the above described embodiment, the gantry transfer apparatus, which transfers the vehicle body M to a support-type conveyance line SL disposed in a lower-side of a vehicle conveyance line from a hanger-type conveyance line disposed in an upper-side of the vehicle conveyance line, has been explained. But, the present invention is not limited to this. For example, the gantry transfer apparatus may transfer the vehicle body M to a hanger-type conveyance line disposed in an upper-side of the vehicle conveyance line from a support-type conveyance line SL disposed in a lower-side of a vehicle conveyance line. In the above described embodiment, furthermore, each chucking arm is being rotatable with respect to the support part 63d. But, each chucking arm may be un-rotatable. Additionally, only a fitting part between the chucking arm and the tire T may be made of rotatable roller.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to a vehicle transfer apparatus, which performs a transfer of a vehicle body between an upper-side conveyance line and a lower-side conveyance line that are installed in a vehicle assembly line. 2. Description of Relevant Art Conventionally, a vehicle assembly line includes a hanger-type conveyance line and a support-type conveyance line. The hanger-type conveyance line suspends a vehicle body using a conveyance hanger in order to install various parts, such as an engine, a transmission, an exhaust nozzle, and tires etc., which are normally installed from a bottom-side of the vehicle body. The support-type conveyance line holds the vehicle body using a slat conveyor from a bottom-side of the vehicle body in order to install exterior parts etc., which are normally installed from an upper-side of the vehicle body. In this kind of the assembly line, a vehicle body transfer apparatus, which transfers a vehicle body from the hanger-type conveyance line to the support-type conveyance line, is provided. As an example of this kind of the vehicle body transfer apparatus, the vehicle body transfer apparatus disclosed in Japanese unexamined Patent Publication No. H11-268823 has been discovered. The apparatus disclosed in this Japanese unexamined Patent Publication is composed of guide-stanchions positioned on both sides of a vehicle body to be transferred, a lift-unit which moves in an up-and-down direction along the guide-stanchion, and a support-base which moves in a horizontal direction from the lift-unit and changes the total length thereof in order to support the vehicle body. In this vehicle body transfer apparatus, a vehicle body is once passed to a support tool disposed on the support-base from the conveyance hanger at the upper-side of the vehicle body transfer apparatus. Then, the vehicle body is moved downwardly together with the lift-unit and is passed to a slat conveyor positioned in a lower-side of the vehicle body transfer apparatus. In this apparatus, normally, the vehicle body is transferred while supporting a flange of a side-sill of the vehicle body using the support tool, when performing the transfer of the vehicle body. This is because each jack-up point of the vehicle body is already being supported by the conveyance hanger in order to convey the vehicle body. In this conventional vehicle body transfer apparatus, since the flange of the side-sill of the vehicle body is held by the support tool, the impact, which is caused when the vehicle body is passed to the support tool from the conveyance hanger or when the lift-unit is stopped at the predetermined position, may cause the deformation on the flange of the side-sill. Therefore, the vehicle body transfer apparatus, by which a vehicle body is surely transferred between the upper-side conveyance line and the lower-side conveyance line without causing the deformation on the vehicle body, has been required.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to a vehicle transfer apparatus, which transfers a vehicle body between a conveyance line disposed in a lower-side of a vehicle conveyance line and a conveyance line disposed in an upper-side of the vehicle conveyance line. The vehicle transfer apparatus is composed of a pair of stanchions, a lift-unit, a tire supporter, a lift-unit driver, and a tire supporter driver. In this apparatus, a lift-unit is provided to respective stanchions, which are disposed on both sides of the vehicle body, and is allowed to slide in an up-and-down direction along the stanchion in compliance with the operation by the lift-unit driver. In this apparatus, additionally, the tire supporter, which supports the tire in the condition that the lower part of the tire is exposed under the tire supporter, is provided to each lift-unit, and this tire supporter is adapted to move between a tire support position and a passing position by a linear motion under the control of tire supporter driver. According to this vehicle transfer apparatus, when vehicle body is transferred to the conveyance line disposed in a lower-side from the conveyance line disposed in a upper-side of the vehicle conveyance line, the vehicle body, whose jack-up points are being held by conveyance hangers, respectively, is raised by the tire supporter of the lift-unit in the condition that each tire of the vehicle body is held by the tire supporter. Next, after disengaging each conveyance hanger from the vehicle body, the lift-unit, which is placing the vehicle body thereon, is moved downwardly till the tire of the vehicle body comes in contact with the conveyance line disposed in a lower-side. Then, after moving the tire supporter to the passing position in compliance with the actuation of the tire supporter driver, the vehicle body is conveyed by the conveyance line disposed in a lower-side. That is, in the present invention, the vehicle body is transferred while holding the tires of the vehicle body, when vehicle body is transferred to the conveyance line disposed in the lower-side from the conveyance line disposed in the upper-side of the vehicle conveyance line using the vehicle transfer apparatus. Therefore, since the impact to be caused during the transfer of the vehicle is mitigated by tire, the occurrence of the deformation of the vehicle body due to the impact can be prevented. In the present invention, additionally, when the vehicle body is passed to the conveyance line disposed in the lower side from the vehicle transfer apparatus, since each tire T is supported by the tire supporter in the condition that the lower part of the tire is exposed under the tire supporter, the tire T firstly comes in contact with the surface of the conveyance line disposed in the lower-side. Therefore, since the impact to be caused when the vehicle body is passed to the conveyance line disposed in the lower-side from the vehicle transfer apparatus is mitigated by tire, the occurrence of the deformation of the vehicle body due to the impact can be prevented. In the present invention, preferably but it is not necessary, the tire supporter includes a pair of chucking arms and an arm driver, which controls the position of the pair of chucking arms between a tire holding position and a tire release position. According to the vehicle transfer apparatus, when the vehicle body is passed from the vehicle transfer apparatus to the conveyance line disposed in a lower-side, the vehicle body is transferred while holding the tire by chucking arms placed at the tire holding position. Then, chucking arms are removed from the tire by changing the position of chucking arms to the tire release position after the tire comes in contact with the surface of the conveyance line disposed in the lower-side and the load due to the vehicle body is not received by chucking arms. Thereby, the vehicle body can be passed to the conveyance line disposed in the lower-side. That is, the hold and release of each tire of the vehicle body is controlled by changing the position of chucking arms between the tire holding position and the tire release position, when the vehicle body is passed from the vehicle transfer apparatus to the conveyance line disposed in the lower-side. Thus, chucking arms are easily removed from the tire. In the present invention, additionally, it is preferable that a part of the chucking arm that has contact with the tire is a rotatable roller. In this case, since the rotatable roller is provided, chucking arms can be removed from the tire even if the load due to the vehicle body is being applied to the chucking arms. This is because a frictional restriction between the tire and the chucking arm prevents the removing of the chucking arm from the tire, if the chucking arm is un-rotatable, in comparison with the case where the chucking arm is being rotatable. That is, when the vehicle body is passed to the conveyance line disposed in the lower-side from the vehicle conveyance line, the chucking arm can be removed from the tire due to the rotation of the roller even if the load caused by the vehicle body is applied to the chucking arm.

20060209

20081209

20061005

67679.0

B62D6518

BIDWELL, JAMES R

VEHICLE BODY TRANSFER APPARATUS

UNDISCOUNTED

ACCEPTED

B62D

ACCEPTED

Method For Rapid Identification of Alternative Splicing

Alternatively spliced RNA, along with their normally-spliced counterparts, can be rapidly identified by hybridizing cDNA from normal tissue to cDNA from an abnormal or test tissue. The two cDNA populations are separately tagged prior to hybridization, which allows isolation of double-stranded cDNA containing both normal and alternatively spliced molecules. Within this population, pairing of cDNA molecules representing an alternatively spliced mRNA with cDNA molecules representing the counterpart normally spliced mRNA will form double-stranded cDNA with single-stranded mismatched regions. The mismatched double-stranded cDNA are isolated with reagents that bind single-stranded nucleic acids. The strands of each mismatched double-stranded cDNA are then coupled and analyzed, simultaneously identifying both normal and alternatively spliced molecules.

1. A method of identifying an alternatively spliced RNA molecule in conjunction with a normally spliced counterpart RNA molecule, comprising the steps of: (1) obtaining a first population of cDNA molecules from a biological sample representing a first physiological condition and a second population of cDNA molecules from a biological sample representing an second physiological condition; (2) attaching a first selectable tag to cDNA molecules of the first cDNA population and a second selectable tag to cDNA molecules of the second cDNA population, wherein the first and second selectable tags are different; (3) denaturing and annealing cDNA molecules from both the first and second cDNA populations, to obtain a mixed population of cDNA molecules; (4) isolating double-stranded cDNA from the mixed population, wherein the double-stranded cDNA comprises the first and second selectable tags, and also comprises a cDNA molecule from the first cDNA population and a cDNA molecule from the second cDNA population; (5) selecting from the cDNA isolated in step (4) double-stranded cDNA which comprises at least one region of single-stranded nucleic acid; (6) coupling both strands of each double-stranded cDNA from step (5) to each other to obtain a coupled molecule; and (7) comparing both strands of the coupled molecule, wherein one strand of the coupled molecule represents the alternatively spliced RNA molecule, and the other strand represents the normally spliced counterpart RNA molecule. 2. The method of claim 1, wherein the first biological sample comprises normal tissue, and the second biological samples comprises diseased tissue. 3. The method of claim 1, wherein the first and second biological samples comprise tissue in different developmental states. 4. The method of claim 1, wherein the first biological sample comprises untreated tissue, and the second biological sample comprises tissue which has been treated with a therapeutic or toxic agent. 5. The first and second biological samples can also comprise tissue or cells from different species. 6. The method of claim 1, wherein the first and second biological samples are derived from a human. 7. The method of claim 2, wherein the second biological sample comprises tumor or neoplastic tissue. 8. The method of claim 7, wherein the tumor or neoplastic tissue is derived from a subject with acute promyelocytic leukemia; acute lymphoblastic leukemia; myeloblastic leukemia; uterine cancer; thyroid cancer; gastrointestinal tumors; dysplastic and neoplastic cervical epithelium; melanoma; breast cancer; prostate cancer; lung cancer; endometrial cancer; teratocarcinoma; colon cancer; brain and desmoplastic round cell tumors; epithelial neoplasias; gastric cancer; ovarian cancer or sarcomas, myomas, myxomas, ependymomas, fibromas, neurofibrosarcomas. 9. The method of claim 2, wherein the second biological sample comprises diseased tissue derived from a subject with infection, stress, disorders or conditions of the immune system; a metabolic disorder; a collagen disorder; a psychiatric disorder, a skin disorder, a liver disorder, a disorders of the arteries; an inherited red cell membrane disorder; thyroid hormone repression; endometrial hyperplasia; Alzheimer's disease; or alcoholism. 10. The method of claim 1, wherein the first and second cDNA populations are synthesized from RNA populations which have been enriched for polyA+ RNA. 11. The method of claim 1, wherein at least one cDNA population comprises double-stranded cDNA. 12. The method of claim 1, wherein the first and second cDNA populations comprise double-stranded cDNA. 13. The method of claim 1, wherein the first and second selectable tags are selected from the group consisting of: biotin; avidin; streptavidin; antigens; haptens; antibodies; hormones; vitamins; receptors; carbohydrates; lectins; metals; chelators; polynucleotides; cofactor or prosthetic groups; apoproteins; effector molecules; one member of a hydrophobic interactive pair; enzyme cofactors; enzymes; polymeric acids; polymeric bases; dyes; protein binders; peptides; protein binders; and enzyme inhibitors, provided that the first and second selectable tags are different. 14. The method of claim 1, wherein the first selectable tag comprises a biotin. 15. The method of claim 1, wherein the second selectable tag comprises a biotin. 16. The method of claim 1, wherein the first selectable tag comprises a polynucleotide. 17. The method of claim 1, wherein the second selectable tag comprises a polynucleotide. 18. The method of claim 16, wherein the polynucleotide comprises a restriction enzyme target site. 19. The method of claim 17, wherein the polynucleotide comprises a restriction enzyme target site. 20. The method of claim 1, wherein: 1) the first selectable tag comprises an oligonucleotide having a longer and a shorter strand each with a 5′ end, that when annealed form a six base pair double-stranded region and an 11 base 5′ single-stranded overhang, and wherein a biotin molecule is attached to the 5′ end of the longer oligonucleotide strand and the 5′ end of shorter oligonucleotide strand is phosphorylated at the 5′ end, and wherein the 11 base 5′ overhang comprises a six base nucleotide sequence which, when annealed with a single-stranded oligonucleotide comprising the complementary sequence, forms a Sma I restriction site; and 2) the second selectable tag comprises an oligonucleotide having a longer and a shorter strand each with a 5′ end, that when annealed form a six base pair double-stranded region and an 21 base 5′ single-stranded overhang, and wherein the 5′ end of shorter oligonucleotide strand is phosphorylated at the 5′ end, and wherein the 21 base 5′ overhang comprises a six base nucleotide sequence which, when annealed with a single-stranded oligonucleotide comprising a complementary sequence, forms a Pml I restriction site. 21. The method of claim 1, wherein in step (3) the cDNA molecules in the first and second cDNA populations are denatured separately, mixed, and annealed to obtain the mixed population of cDNA molecules. 22. The method of claim 1, wherein in step (3) the cDNA molecules in the first and second cDNA populations are mixed together, denatured, and annealed to obtain the mixed population of cDNA molecules. 23. The method of claim 1, wherein an excess of cDNA from one cDNA population relative to the other is used to obtain the mixed population of cDNA molecules. 24. The method of claim 2, wherein an excess of cDNA molecules from the first cDNA population relative to cDNA molecules from the second cDNA population is used to obtain the mixed population of cDNA molecules. 25. The method of claim 24, wherein a 20-fold excess of cDNA from the first cDNA population relative to cDNA molecules from the second cDNA population is used to obtain the mixed population of cDNA molecules. 26. The method of claim 1, wherein step (4) comprises: (i) selecting molecules comprising the first selectable tag from the mixed population to obtain a first selected population; and (ii) selecting molecules comprising the second selectable tag from the first selected population to obtain a second selected population, wherein the second selected population comprises the mixed population double-stranded cDNA comprising a cDNA molecule from the first cDNA population and a cDNA molecule from the second cDNA population. 27. The method of claim 1, wherein step (4) comprises: (i) selecting molecules comprising the second selectable tag from the mixed population to obtain a first selected population; and (ii) selecting molecules comprising the first selectable tag from the first selected population to obtain a second selected population, wherein the second selected population comprises double-stranded cDNA comprising the first and second selectable tags, and also comprises a cDNA molecule from the first cDNA population and a cDNA molecule from the second cDNA population. 28. The method of claim 1, wherein step (4) comprises contacting the mixed population with an affinity medium. 29. The method of claim 28, wherein the affinity medium comprises a compound selected from the group consisting of: biotin; avidin; streptavidin; antigens; haptens; antibodies; hormones; vitamins; receptors; carbohydrates; lectins; metals; chelators; polynucleotides; cofactor or prosthetic groups; apoproteins; effector molecules; one member of a hydrophobic interactive pair; enzyme cofactors; enzymes; polymeric acids; polymeric bases; dyes; protein binders; peptides; protein binders; and enzyme inhibitors 30. The method of claim 28, wherein the affinity medium comprises an affinity column. 31. The method of claim 28, wherein the affinity media comprises a solid carrier. 32. The method of claim 31, wherein the solid carrier is selected from the group consisting of: cellulose and cellulose derivatives; polyacrylamide; polystyrenes; polysaccharides; rubber; glass; nylon; polyacrylate; polyvinyltoluene; styrenebutadiamine copolymers; polyacrolein; polyurethane; poly (methyl methacrylate); and combinations thereof. 33. The method of claim 28, wherein the affinity medium comprises a magnetic particle. 34. The method of claim 1, wherein step (5) comprises contacting the double-stranded cDNA from step (4) with a reagent which binds regions of single-stranded DNA. 35. The method of claim 34, wherein the reagent which binds to regions of single-stranded DNA is selected from the group consisting of a resin which binds single stranded DNA, E. coli single-stranded binding protein; antibodies which bind to single-stranded DNA; and enzymes which bind to single-stranded DNA. 36. The method of claim 34, wherein the reagent which binds regions of single-stranded DNA is contained in an affinity column. 37. The method of claim 1, wherein step (6) comprises covalently linking both strands of each double-stranded cDNA from step (5) to each other to obtain a coupled molecule. 38. The method of claim 37, wherein both strands of each double-stranded cDNA from step (5) are covalently linked to each other with a polynucleotide linking moiety. 39. The method of claim 38, wherein the polynucleotide linking moiety comprises SEQ ID NO: 5. 40. The method of claim 1, wherein step (7) comprises determining at least a partial nucleotide sequence for each strand of the coupled molecule. 41. A kit for identifying an alternatively spliced RNA molecule in conjunction with a normally spliced counterpart RNA molecule, comprising at least two different selectable tags and their corresponding affinity media, a single-stranded DNA binding reagent, and a linking moiety. 42. A selectable tag comprising an oligonucleotide having a longer and a shorter strand each with a 5′ end, that when aimealed form a six base pair double-stranded region and an 11 base 5′ single-stranded overhang, and wherein a biotin molecule is attached to the 5′ end of the longer oligonucleotide strand and the 5′ end of shorter oligonucleotide strand is phosphorylated at the 5′ end, and wherein the 11 base 5′ overhang comprises a six base nucleotide sequence which, when annealed with a single-stranded oligonucleotide comprising the complementary sequence, forms a Sma I restriction site. 43. A selectable tag comprising an oligonucleotide having a longer and a shorter strand each with a 5′ end, that when annealed form a six base pair double-stranded region and an 21 base pair 5′ single-stranded overhang, and wherein the 5′ end of shorter oligonucleotide strand is phosphorylated at the 5′ end, and wherein the 21 base pair 5′ overhang comprises a six base nucleotide sequence which, when annealed with a single-stranded oligonucleotide comprising a complementary sequence, forms a Pml I restriction site. 44. A linking moiety comprising SEQ ID NO: 5.

FIELD OF THE INVENTION The present invention relates to a method for isolating and identifying alternatively spliced mRNA. BACKGROUND OF THE INVENTION The number of proteins produced by the human genome likely numbers in the hundreds of thousands. However, recent evidence indicates that the human genome contains only 30,000 to 45,000 different genes. Clearly, each gene is producing multiple proteins. Alternative splicing of primary RNA transcripts is a major mechanism for increasing production of proteins from the human genome. It is known that 30% to 60% of genes undergo alternative splicing to produce messenger RNA (mRNA). Modrek B et al. Nat. Genet. 30, 13-19 (2002). These alternatively spliced mRNA are translated into alternative splice form proteins that contain amino acid sequences different than the corresponding protein produced by normally spliced mRNA. Alternative splice form proteins are often expressed in a tissue-specific manner, or under certain physiologic or disease states. Modrek B et al., Nucl. Acids Res. 29, 2850-2859 (2001). Consequently, certain alternatively spliced mRNA are present in a limited number of cells in a subject suffering from a given disease or condition. For example, it is known that many types of cancer cells produce alternative splice forms which are not found in normal cells from the same subject. Cancer-associated genes such as CD44 (Rodriguez C et al., Int. J. Cancer 64, 347-354, 1995), estrogen receptor (Castles C G et al., Cancer Res. 53, 5934-5939, 1993), FGF receptor (Luqmani Y A et al., Int. J. Cancer 64, 274-279, 1995), DNA polymerase (Bhattacharyya N et al., DNA Cell Biol. 18, 549-554, 1999), cathepsin B (Gong Q et al., DNA Cell Biol. 12, 299-309, 1993), FHIT (Panagopoulos I. et al., Cancer Res. 56, 4871-4875, 1996), BRCA1 (Thakur S et al., Mol. Cell Biol. 17, 444-452, 1997) and BRCA2 (Bieche I et al., Cancer Res. 59, 2546-2550, 1999), produce alternatively spliced mRNA that are specifically expressed in cancerous tissues. Other disease states in which alternative splice forms are specifically produced in certain tissues include diabetes, Alzhiemer's disease and systemic lupus erythematosus (SLE). Drugs that target proteins specific to cancerous or other disease tissue have proven efficacious in the appropriate patient population. For example, successful treatment of breast cancer has been reported for drugs which target the estrogen receptor (Jordan C, Clin. Ther. 24 Suppl A, A3-16, 2002) or the HER-2 receptor (Thomssen C, Anticancer Drugs 12 Suppl 4, S19-S25, 2001; Yip Y L et al., Cancer Immunol. Immunother. 50; 569-587, 2002). The genetic alterations present in tumor-specific proteins, such as mutations in p53, BRCA 1 and BRCA2, provide another source of targets. Thus, the proteins produced from alternatively spliced mRNA produced specifically in cancers or other disease states are also attractive therapeutic targets. However, proteins produced from alternatively spliced mRNA have not been widely exploited as therapeutic targets. The major impediment to using such proteins as therapeutic targets has been the incidental or tedious nature by which alternatively spliced mRNA are found. Present methodologies are limited to either cDNA cloning (which is highly labor intensive) or RT/PCR (which focuses only on known portions of genes). In addition, most cloning- and RT/PCR-based methods are highly biased, as they require prior knowledge of the alternatively spliced mRNA sequence. An unbiased procedure for discovery of alternatively spliced mRNA has been reported in U.S. Pat. No. 6,251,590 of Schweighoffer et al. However, the Schweighoffer et al. method identifies only the region in the alternatively spliced mRNA that is different from the normally spliced mRNA. The cDNA corresponding to both the normal and alternatively spliced mRNA must be separately cloned in order to pinpoint the alternatively spliced region in the context of the full-length molecule. The sequencing of multiple cDNA clones is also required to determine the prevalence of a given alternatively spliced mRNA. The Schweighoffer et al. method thus required a substantial investment of both time and resources in order to identify alternatively spliced molecules. Thus, an unbiased method of rapidly and easily identifying alternatively spliced RNA in biological sample is needed, in which both the full-length normal and alternatively spliced mRNA are simultaneously isolated for comparison. Ideally, such a method would not rely on multiple cloning and sequencing steps for determining the identity and relative abundance of alternative splice forms in a given sample. SUMMARY OF THE INVENTION The present invention is directed to an unbiased method for isolating and identifying full-length alternatively spliced RNA, wherein the alternatively spliced RNA is isolated in conjunction with its counterpart normally spliced RNA. The practice of this method thus does not require foreknowledge of either the normal or alternatively spliced RNA sequences, or the nature of the alternative splice. The method also does not require multiple cloning or sequencing steps in order to identify the alternatively spliced RNA. The invention provides a method of identifying an alternatively spliced RNA by comparing populations of cDNA molecules obtained from two biological samples. One sample represents a first physiological condition, and the other sample represents a second physiological condition. The two cDNA populations are separately tagged with different compounds, and denatured portions of each tagged cDNA population are annealed to each other under conditions which allow the formation of a mixed population of cDNA molecules. This mixed population comprises single-stranded cDNA molecules from both populations, double-stranded cDNA comprising cDNA molecules from only the first or second cDNA populations, and double-stranded cDNA comprising cDNA molecules from both the first and second cDNA populations. Double-stranded cDNA comprising cDNA molecules from both the first and second cDNA populations are isolated from the mixed population by first selecting for those molecules comprising the tag specific to the first cDNA population, followed by selecting for molecules which also contain the tag specific to the second cDNA population. Alternatively, double-stranded cDNA comprising cDNA molecules from both the first and second cDNA populations can be isolated by selecting for molecules comprising the tag specific to the second cDNA population, followed by selecting for molecules comprising the tag specific to the first cDNA population. The double-stranded cDNA selected above comprises two types. The first type comprises two cDNA molecules with perfectly matched sequences, in which each cDNA molecule represents normally spliced mRNA. The second type comprises two cDNA molecules with at least one area of mismatched sequence. In the second type of double-stranded cDNA, one cDNA strand represents the alternatively spliced mRNA molecule and the other cDNA strand represents the normally spliced counterpart of the alternatively spliced mRNA. The mismatched sequence is unpaired with respect to the opposite strand and comprises a single-stranded region in the otherwise paired sequences. Such a double-stranded cDNA encompassing a mismatched sequence is then isolated with reagents which bind to regions of single-stranded nucleic acid. The two nucleic acid strands of said selected double-stranded cDNA are coupled, yielding a single molecule that can be analyzed to identify the normal and alternatively spliced molecules. A kit comprising some or all of the components and for performing the present method, along with instructions for their use, is also provided. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 is a flow chart of a method according to the invention. FIGS. 2A-2E are diagrams showing the isolation and identification of alternatively spliced RNA according to one embodiment of the invention. FIG. 3 is an agarose gel showing double stranded DNA with 20, 8 and 6 base mismatches either alone (lanes 1, 3 and 5, respectively) or after incubation with SOPE™ resin and removal of the resin by centrifugation (lanes 2, 4 and 6, respectively. DETAILED DESCRIPTION OF THE INVENTION The present method can be used to isolate and identify RNA molecules which are alternatively spliced in the cells of a first biological sample, as compared to RNA produced in the cells of a second biological sample. The alternatively spliced RNA molecule is simultaneously isolated with its normally spliced counterpart RNA molecule. As used herein, an “alternatively spliced RNA” is an RNA molecule transcribed from a gene in cells of one biological sample, which is spliced differently from an RNA molecule transcribed from the same gene in cells of a reference biological sample. The RNA molecule transcribed from the same gene in cells of the reference biological sample is the “normally spliced counterpart RNA molecule” of the alternatively spliced RNA. A biological sample typically contains a plurality of different alternatively spliced RNA molecules. Thus, the present method can simultaneously isolate and identify a plurality of alternatively spliced RNA molecules in conjunction with their normally spliced counterparts. A flow chart of the present method is provided in FIG. 1. With reference to the figure, first and second RNA populations comprising alternatively spliced RNA are obtained from first and second biological samples, respectively (step 100). The RNA populations are then converted to cDNA for subsequent manipulations (step 105). As the practice of the present method involves hybridization of complementary cDNA molecules from each cDNA population, preferably at least one, and more preferably both, cDNA populations comprise double-stranded cDNA. In step 110, selectable tags are attached to the molecules of the first and second cDNA populations. The selectable tags used for each population are different. Substantially all of the cDNA molecules from each tagged cDNA population are denatured and annealed, so that single-stranded cDNA molecules from one cDNA population hybridize with complementary single-stranded cDNA molecules from the other cDNA population (step 115). This step is also known as “cross-hybridization.” The double-stranded cDNA molecules which comprise one strand from each cDNA population also comprise both selectable tags. These molecules can therefore be isolated by selection for one tag, followed by selection for the other tag (step 120). The two strands of each double-stranded cDNA selected in step 120 have perfectly matched sequences, or have a mismatched sequence which represents an alternatively spliced region in one of the strands. The mismatched sequences manifest as single-stranded regions within the cDNA duplex. Double-stranded cDNA with mismatched sequences are therefore isolated by reagents which selectively bind single-stranded DNA (step 125). The strands of each cDNA duplex isolated in step 125 represent linked pairs of normal and alternatively spliced molecules. The two strands of each duplex isolated in step 125 are thus coupled together, so that the relationship of each pair of normal and alternatively spliced molecules is fixed (step 130). The coupled molecules produced in step 130 represent different pairs of alternatively spliced and normal molecules. Each coupled molecule can be expanded through cloning or the polymerase chain reaction. These coupled molecules can then be analyzed to obtain information about the molecules; e.g., sequence data, relative abundance, and the like. Any type of biological material comprising nucleic acids can be used as the first and second biological samples. For example, first and second biological samples can be derived from prokaryotes; lower eukaryotes (e.g., yeasts, flngi and the like); and higher eukaryotes such as birds, fish, reptiles, and mammals. Preferably, the biological samples are derived from mammals, especially canines, felines, rodents (e.g., mice and rats), bovines, ovines, porcines and primates (e.g., humans). In a particularly preferred embodiment, the biological samples are derived from humans. As used herein, “derived from” with respect to a biological sample includes tissue or cells obtained directly from a subject (e.g., blood or biopsy material), or cells or tissue which have been maintained ex vivo for any length of time, such as cell, tissue and organ cultures. The first and second biological samples can represent any two physiological or genetic states. For example, the first and second biological samples can comprise diseased and normal tissue, tissue in different developmental states, or tissue which has been treated with a therapeutic or toxic agent as compared with untreated tissue. The first and second biological samples can also comprise tissue or cells from different, but preferably related, species. The presence of alternatively spliced RNA in a particular biological sample as compared to another can thus be used as a marker of a given physiological condition, or can be used to develop therapeutic agents which target only the cells producing the alternatively spliced RNA. Generally, the first and second biological samples are derived from the same subject or from subjects of the same species, and represent alternative physiological states. Preferably, the first and second biological samples comprise cells from normal and diseased tissue, respectively. Diseased cells or tissue can be obtained, for example, from a subject with: infections or stress; cancers or neoplasias (e.g., acute promyelocytic leukemia; acute lymphoblastic leukemia; myeloblastic leukemia; uterine cancer; thyroid cancer; gastrointestinal tumors; dysplastic and neoplastic cervical epithelium; melanoma; breast cancer; prostate cancer; lung cancer; endometrial cancer; teratocarcinoma; colon cancer; brain or desmoplastic round cell tumors; epithelial neoplasias; gastric cancer; ovarian cancer; sarcomas, myomas, myxomas, ependymomas, fibromas, and neurofibrosarcomas); disorders or conditions of the imniune system (e.g., allergic response, x-linked agammaglobulinemia, immunity/inflammation, systemic lupus erythematosus, Goodpasture disease); metabolic disorders (e.g., phenylketonuria, non-insulin dependent diabetes); collagen disorders (e.g., osteogenesis imperfecta); psychiatric disorders; skin disorders, liver disorders; disorders of the arteries (atherosclerosis); inherited red cell membrane disorders (e.g., hereditary elliptocytosis); thyroid hormone repression; endometrial hyperplasia; Alzheimer's disease; and alcoholism. In a particularly preferred embodiment, the first and second biological samples comprise cells from normal and tumor or neoplastic tissue, respectively. Diseased cells or tissues can be readily identified by certain phenotypic abnormalities which are apparent to by those skilled in the art upon examination of the cells or tissue. See, for example, the pathology and histopathology of different cancers is described in Cancer: Principles and Practice of Oncology, (3rd edit., DeVita V T, Hellman S, and Rosenberg S A, eds.), 1989, J. B. Lipincott Co., Phila., PA. Cells which are tumorigenic or neoplastic can also be identified by certain growth characteristics and morphology exhibited by the cell in culture. Tumorigenic or neoplastic cells are insensitive to contact-induced growth inhibition, and the cells form foci in the culture vessel when cultured for extended periods. Tumorigenic or neoplastic cells also exhibit characteristic morphological changes, disorganized patterns of colony growth, and the acquisition of anchorage-independent growth. Tumorigenic or neoplastic cells also have the ability to form invasive tumors in susceptible animals, which can be assessed by injecting the cells, for example, into athymic mice or newborn animals of the same species using techniques well-known in the art. See, for example, Combes et al. (1999), “Cell Transformation Assays as Predictors of Human Carcinogenicity: The Report and Recommendations of ECVAM Workshop 39,” ATLA 27, 745-767. Other histological and cell culture-based techniques for identifying diseased cells are also within the skill in the art. In the practice of the invention, RNA populations are separately isolated from a first and a second biological sample. As used herein, a “population of RNA molecules” or “RNA population” refers to a group of individual RNA molecules which are representative of the RNA produced by cells in a biological sample, from which some or all of the RNA molecules are taken for further processing according to the present method. RNA populations for use in the present method can be obtained from a biological sample by techniques which are familiar to those skilled in the art. Such techniques generally comprise lysis of cells or tissues and recovery of RNA by means of extraction procedures. In particular, RNA populations can be obtained by treatment of biological samples with chaotropic agents such as guanidinium thiocyanate, followed by RNA extraction with solvents (e.g., phenol and chloroform). See, e.g., Sambrook J et al., Molecular Cloning: A Laboratory Manual; Second Edition, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1989. and Chomczynski et al., Anal. Biochem., 162, 156-159, 1987. Preferably, RNA populations for use in the present method are enriched for polyA+RNA by standard techniques, such as purification with oligo(dT) cellulose. As used herein, “polyA+RNA” refers to RNA which comprises a homopolymer of adenosine monophosphate residues (typically from 20-200 nucleotides in length) on the 3′ end. Generally, polyA+RNA comprises eukaryotic messenger RNA. Techniques for obtaining RNA populations from a biological sample can be readily implemented with commercially available kits, such as the RNeasy™ kit available from Qiagen, Inc. (Valencia, Calif.), the RiboPure™ kit available from Ambion (Austin, Tex.) and Eppendorf Phase Lock Gel available from Brinkmann Instruments, Inc. (Westbury, N.Y.). Techniques for obtaining RNA populations enriched for polyA+ RNA can be also readily implemented with commercially available kits, such the Poly(A)Pure™ kit available from Ambion (Austin, Tex.) or the polyA Spin™ mRNA isolation kit available from New England Biolabs, Inc. (Beverly, Mass.). RNA populations suitable for use in the present method can also be obtained directly from libraries or samples which have been prepared beforehand and stored under suitable conditions. It is understood that the RNA molecules comprising the RNA populations for use in the present method need not be in a fully pure state. For example, traces of genomic DNA, proteins or other cellular components (in as much as they do not significantly affect RNA stability) will not significantly affect the practice of the present method. RNA populations obtained from biological samples can be used immediately, or can be stored for later use. Suitable storage conditions for RNA are familiar to those skilled in the art, and include storage in the cold, preferably at −70° C. in an aqueous, RNase-free solution or in the RNA extraction buffer at temperatures from −20° C. to −70° C. The amount of RNA in RNA population can vary depending on the sample type and the extraction method used. Generally, total RNA populations for use in the present method comprises from about 0.1 microgram of to about 10 micrograms of RNA, preferably about 5 micrograms of RNA. Suitable polyA+ RNA-enriched populations for use in the present method generally comprise at least about 0.05 microgram of RNA to about 2 micrograms RNA, preferably about 1 microgram of RNA. RNA population comprising sufficient quantities of RNA molecules for use in the present method can be obtained from biological samples comprising from about 105 to about 108 cells, or biological samples comprising about 0.5 gram to about 5 grams of tissue. Because RNA is generally unstable once removed from the cellular environment, the present method is performed with RNA populations in which the RNA molecules, preferably only the polyA+ RNA molecules, have been converted into “complementary DNA” or “cDNA” by reverse-transcription. Conversion of the RNA molecules in an RNA population to cDNA creates a corresponding population of cDNA molecules. As used herein, a “population of cDNA molecules” or “cDNA population” refers to a group of individual cDNA molecules corresponding to individual RNA molecules from an RNA population, from which some or all of the cDNA molecules are taken for further processing according to the present method. Generally, cDNA populations for use in the present method are obtained by producing “first-strand” cDNA from the RNA molecules of an RNA or polyA+ RNA-enriched population. Each first-strand cDNA molecule is complementary to the RNA molecule from which is was reverse-transcribed. First-strand cDNA synthesis can be accomplished using an RNA-dependent DNA polymerase enzyme (also called a “reverse transcriptase”) and a suitable oligonucleotide primer, using standard techniques within the skill in the art; see, e.g., Sambrook et al., supra; Kotewicz et al., Gene 35, 249, 1985; Krug M M et al., Meth. Enzymol. 152, 316, 1987 and Gubler U et al., Gene 25, 263-269, 1983. Suitable primers for reverse-transcription of RNA include single-stranded DNA hexamers comprising random sequences and polydeoxythymidylic acid or “oligo(dT).” A preferred primer comprises oligo(dT) from about 12 to about 18 nucleotides in length, as such primers will reverse transcribe only the polyA+ RNA in an RNA population. Reverse transcriptases suitable for use in the present method are generally known in the art, and include those derived from Avian Myeloblastosis Virus (AMV) and from Moloney Murine Leukemia Virus (MMLV). AMV and MMLV reverse transcriptases and kits for generation of “first-strand” cDNA are commercially available, for example, from Invitrogen, Inc. (Carlsbad, Calif.), New England Biolabs, Inc. (Beverly, Mass.) and Promega Corp. (Madison, Wis.). Certain thermostable DNA polymerases, such as those isolated from Thermus flavus and Thermus thermophilus HB-8, also have reverse transcriptase activity. T. flavus and T. thermophilus HB-8 DNA polymerases are commercially available from Promega Corp. (Madison, Wis.). Preferred reverse-transcriptases are those which possess, or have been modified to possess, the ability to reverse transcribe RNA molecules over 3 kb in length. For example, MMLV reverse transcriptases which has been modified to remove the intrinsic RNase H activity allow the synthesis of cDNA up to 12 kb in length, with high fidelity to the original RNA sequence. Examples of such modified MMLV reverse transcriptases include the BioScript™ reverse transcriptase from Bioline USA, Inc. (Randolph, Mass.) and the SuperScript™ II RT from Invitrogen Life Technologies (Carlsbad, Calif.). First-strand cDNA can be used in the present method without further processing, or can be subjected to a second round of DNA synthesis to produce a “second-strand” cDNA. Each molecule of second-strand cDNA is complementary to the first-strand cDNA molecule from which is was synthesized. Under conditions which promote annealing of nucleic acids, complementary first- and second-strand cDNA molecules exist as a DNA duplex, which is hereinafter referred to as “double-stranded cDNA.” In the practice of the present method, the first strand cDNA molecules of at least one of the cDNA populations are converted into double-stranded cDNA. Techniques for synthesizing second-strand cDNA from first-strand cDNA are also within the skill in the art; see, e.g., Sambrook et al., 1989, supra and Gubler U et al., Gene 25, 263-269, 1983. In one such technique, the RNA template is removed from the first-strand cDNA with NaOH or RNase H. The 3′ end of the first-strand cDNA then forms a hairpin-like structure that primes synthesis of the second-strand cDNA by a DNA-dependent DNA polymerase. Suitable DNA-dependent DNA polymerases include E. coli DNA polymerase I (or the Klenow fragment); T4 DNA polymerase; and reverse transcriptases with DNA-dependent DNA polymerase activity such as AMV and MMLV reverse transcriptases. Another technique for synthesizing second-strand cDNA involves the “replacement synthesis” of second-strand cDNA. In this technique, an enzyme such as RNase H produces nicks and gaps in the RNA strand of the cDNA:RNA hybrid produced during first-strand cDNA synthesis. The nicked and gapped RNA strand is used as a series of primers by a DNA-dependent DNA polymerase for synthesis of the second-strand of cDNA. Double-stranded cDNA synthesized as described above can contain hairpin turns and single-stranded overhangs. In the practice of the present method, the double-stranded cDNA are preferably blunt-ended using standard enzymes and techniques familiar to those skilled in the art. For example, hairpin turns can be removed from double-stranded cDNA by treatment with nuclease S1 under standard conditions. Single-stranded overhangs on double-stranded cDNA molecules can be removed with enzymes which either degrade or fill in the single-stranded overhangs, or by restriction endonucleases which create blunt ends on digestion of double-stranded DNA. Examples of enzymes which degrade single-stranded overhangs on double-stranded DNA include mung bean nuclease; nuclease S1; Klenow fragment (degrades 3′ overhangs); and T4 DNA polymerase (degrades 3′ overhangs). Examples of enzymes which fill-in single-stranded overhangs on double-stranded DNA include Pfu polymerase; Klenow fragment in the presence of nucleotides (fills in 5′ overhangs); and T4 DNA polymerase (fills in 5′ overhangs). Examples of restriction endonucleases which create blunt ends on digestion of double-stranded DNA include Afe I; Alu I; BmgB I; BsaA I; BsrB I; BstU I; BstZ17 I; Dra I; Eco RV; Fsp I; Hae III; Hpa I; Hinc II; Msc I; Msp A1 I; Nae I, Nru I; Pme I; Pml I; Pvu II; Rsa I; Sca I; Sfo I; Sma I; SnaB I; Ssp I; Stu I; and Swa I. A preferred restriction endonuclease is Eco RV. In a particularly preferred embodiment, double-stranded cDNA molecules are digested with a restriction endonuclease to create blunt-ends comprising a naturally occurring nucleotide sequence. The cDNA populations for use in the present method can be used immediately, or can be stored for later use. Suitable storage conditions for cDNA are familiar to those skilled in the art, and include storage in the cold, preferably at −20° C. in an aqueous, DNase-free solution. After synthesis of cDNA populations as described above, a selectable tag is attached to the cDNA molecules of each cDNA population. The tag attached to the cDNA molecules of the first cDNA population is different from the tag attached to the cDNA molecules of the second cDNA population. The selectable tags can comprise any compound which allows differential separation of the cDNA molecules after cross-hybridization of molecules from the first and second cDNA populations. As is described in more detail below, these tags are used in subsequent steps to isolate double-stranded cDNA which comprise one cDNA molecule from the first cDNA population and one cDNA molecule from the second cDNA population. Generally, selectable tags useful in the present invention comprise one compound of an affinity pair. As used herein, an “affinity pair” refers to two compounds or structures with a specific affinity for each other. Suitable affinity pairs include biotin and avidin/streptavidin; antigens or haptens and their corresponding antibodies; hormones, vitamins, metabolites or pharmacological agents and their corresponding receptors; carbohydrates and lectins; metals and chelators; complementary polynucleotide sequences (including homopoly-nucleotides such as poly dG:poly dC, poly dA:poly dT, and poly dA:poly U); cofactor or prosthetic groups and apoproteins; effector molecules and their receptors; hydrophobic interactive pairs; enzyme cofactors and enzymes; polymeric acids and bases; dyes and protein binders; peptides and specific protein binders (e.g., ribonuclease, S-peptide and ribonuclease S protein); and enzyme inhibitors (reversible and irreversible) and enzymes. In one embodiment, the selectable tag comprises a lectin. Suitable lectins include C-type or Ca2+-dependent lectins, Gal-binding galectins, P-type Man 6-phosphate receptors, I-type lectins including sialoadhesins and other immunoglobulin-like sugar-binding lectins, and L-type lectins related in sequence to the leguminous plant lectins (see, e.g., Drickamer K, Curr. Opin. Struct. Biol. 5, 612-616, 1995; Drickamer et al., Annu. Rev. Cell Biol. 9, 237-264, 1993; and Powell L D et al., J. Biol. Chem. 270, 14243-14246, 1995). Preferably, the selectable tag comprises a biotin or avidin/streptavidin molecule, or a polynucleotide sequence. Techniques for attaching tags to cDNA molecules are within the skill in the art. For example, biotins can be attached to cDNA molecules by incorporating a nucleotide comprising the biotin molecule (e.g., biotin-11-dUTP) during first- or second-strand synthesis, according to standard techniques. Alternatively, biotin can be attached to cDNA molecules by a spacer arm, for example with one or more ε-aminocaproic acid moieties. Polynucleotide tags can be attached to the cDNA molecules by standard molecular biology techniques, for example by blunt-end ligation. See, e.g., Sambrook et al., 1989, supra. Preferably, selectable tags are releasable or comprise a portion which can be cleaved, for example by chemical, enzymatic or physical means. Physical cleavage includes cleavage by application of light or other electromagnetic radiation. Exposure of cDNA comprising a cleavable or releasable selectable tag to the appropriate conditions will cause separation of the tag (or a portion thereof) from the cDNA. For example, polynucleotide or polypeptide tags can comprise a specific chemical or enzymatic cleavage site, as are known in the art. Chemically cleavable and photocleavable biotins are also known, for example as described in U.S. Pat. No. 5,986,076, the entire disclosure of which is herein incorporated by reference. Examples of chemically cleavable biotins include NHS—SS-biotin, which can be linked to another molecule through a disulfide bond and an N-hydroxysuccinimide ester group that reacts selectively with primary amines. The biotin portion of NHS—SS-biotin can be removed by cleaving the disulfide bond with thiols. NHS—SS-biotin is commercially available as Immunopure NHS—SS-biotin from Pierce Chemical (Rockford, Ill.). If necessary, the cDNA molecules of the first and second cDNA populations are modified so that the molecules are not affected by the conditions or reagents which are used to cleave or release the selectable tags. Preferably, the cDNA molecules are modified prior to attachment of the selectable tags. For example, the cDNA molecules can be methylated by DNA methylase enzymes (e.g., CpG methylase) using standard techniques, prior to attachment of selectable tags comprising polynucleotide sequences. Methylation of cDNA protects the cDNA molecules from digestion by restriction enzymes which are subsequently used to cleave the selectable tags. In one embodiment, the selectable tag comprises an polynucleotide with an attached biotin molecule and a double-stranded region containing the sequence of a rare restriction endonuclease cut site. In another embodiment, the selectable tag comprises an oligonucleotide with a single-stranded overhang and a double-stranded region containing a rare restriction enzyme cut site. As used herein, a “rare restriction endonuclease cut site” comprises at least a five base-pair target sequence, and preferably comprises a six base-pair target sequence, for a restriction endonuclease. Examples of restriction endonucleases which cut a 5-base pair target sequence include Bbv I; Bce I; Eco RII; Fau I; and Hga I. Examples of restriction endonucleases which cut a 6-base pair target sequence include Ava I; Bam HI; Bgl II; Eco RI; Hind III; Hpa I; Kpn I; Pst I, Sma I; Sst I; Sal I; and Xma I. Other restriction endonucleases which target a rare restriction endonuclease cut site can be readily identified by those skilled in the art. In one embodiment, a first selectable tag for attachment to cDNA molecules of a first cDNA population comprises a 6-base pair double-stranded oligonucleotide defining a Sma I target site, which has a biotin molecule attached to the 5′-end of one of the oligonucleotide strands. This tag is represented schematically below: Biotin-5′CCCGGG 3′ GGGCCC -Sma I- In this embodiment, a second selectable tag for attachment to the cDNA molecules of a second cDNA population comprises an oligonucleotide that has a 6-base pair double-stranded region defining a Sal I target site, and a 15 base single-stranded 5′ overhang. This tag is represented schematically below: 5′GTCATGCATAGCAATTGTCGAC 3′ (SEQ ID NO: 1) ACAGCTG -Sal I- In a preferred embodiment, a first selectable tag for attachment to cDNA molecules of a first population comprises an oligonucleotide that has a six base pair double-stranded region and an 11 base 5′ single-stranded overhang. A biotin molecule is attached to the 5′ end of the longer oligonucleotide strand. The shorter oligonucleotide strand is phosphorylated at the 5′ end to allow for blunt-end ligation of the selectable tag to the molecules of the target cDNA population. The 11 base 5′ overhang comprises a six base nucleotide sequence which, when annealed with a single-stranded oligonucleotide comprising the complementary sequence, forms a Sma I restriction site. This selectable tag, hereinafter called “Tag 1,” is represented schematically below. In this schematic representation, the sequence that forms the Sma I site is underlined, and the 5′-phosphate on the shorter oligonucleotide strand is shown by a “P”. Biotin-5′TCCCCCGGGGGGAATCG 3′ (SEQ ID NO: 2) Sma I 3′CTTAGC-P 5′ In this embodiment, a second selectable tag for attachment to the cDNA molecules of a second cDNA population comprises and oligonucleotide that has a six base pair double-stranded region and a 21 base 5′ single-stranded overhang. The shorter oligonucleotide strand is phosphorylated at the 5′ end to allow for blunt-end ligation of the selectable tag to molecules of the target cDNA population. The 21 base 5′ overhang comprises a nucleotide sequence which, when annealed with a single-stranded oligonucleotide comprising the complementary sequence, forms a Pml I restriction site. This selectable tag, hereinafter called “Tag 2,” is represented schematically below. In this schematic representation, the sequence that forms the Pml I site is underlined, and the 5′-phosphate on the shorter oligonucleotide strand is shown by a “P”. 5′ATGCATAGCAACCTCACGTGTGAATCG 3′ (SEQ ID NO: 3) Pml I 3′CTTAGC-P 5′ Each of the tags described above can be attached to the cDNA molecules of the respective cDNA populations with standard blunt-end ligation techniques, for example as described in Sambrook et al., 1989, supra. Prior to attachment of the first and second selectable tags to the molecules of the respective cDNA populations, the cDNA molecules are preferably methylated by a DNA methylase as described above. Once selectable tags have been attached to the cDNA molecules, some or all of the molecules from the first and second cDNA population are denatured and annealed with each other. Annealing of cDNA molecules from one cDNA population with cDNA molecules from another population is also referred to herein as “cross-hybridization.” As used herein, to “denature” a double-stranded nucleic acid means to disrupting the hydrogen bonds between the purine and pyrimidine bases of both nucleic acid strands, so that the strands are separated. Denaturation of double-stranded nucleic acids can be achieved by heating or by exposing the nucleic acids to a low salt concentration. One skilled in the art can readily choose conditions under which the present double-stranded cDNA denatures. For purposes of the present invention, it is generally sufficient to heat aqueous solutions comprising cDNA to approximately 100° C. for at least one minute in water, TE buffer (10 mM Tris-HCl; 1 mM EDTA, pH 7.6), or the subtractive hybridization solution (50 mM HEPES, pH 7.6; 2 mM EDTA; 500 mM NaCl; 0.2% SDS) of Sive et al., Nucl. Acids. Res. 16: 10937, 1988. Because single-stranded cDNA can also form internal hydrogen bonds between complementary bases within the molecule, single-stranded cDNA molecules are preferably also denatured prior to cross-hybridization. In the practice of the present invention, the cDNA molecules of the first and second cDNA populations can be denatured separately and then mixed together, or can be mixed prior to denaturation. After denaturing, cDNA molecules from the first and second populations are annealed or “cross-hybridized,” so that cDNA molecules with sufficient compleriientarity form duplex DNA molecules. Annealing occurs upon removal of the conditions which caused denaturation; for example, by cooling or adding an appropriate amount of a salt to an aqueous solution comprising denatured cDNA molecules. As used herein, the “annealing” of denatured nucleic acids refers to the formation of hydrogen bonds between a sufficient number of purine and pyrimidine bases of two complementary nucleic acid strands, so that the two strands form a nucleic acid molecule with at least one double-stranded region. Cross-hybridization of cDNA molecules from the first and second cDNA populations can be carried out in solid or liquid phase, as is within the skill in the art. Preferably, cross-hybridization is carried out in the liquid phase. Liquid phase cross-hybridization is conveniently performed in any appropriate container, such as 0.5-1.5 ml plastic microcentrifuge tubes or microtiter plates. Generally, cross-hybridization is carried out in volumes ranging from 0.1 to 1000 microliters, for example from 1 to 50 microliters. The particular container as well as the final volumes used for cross-hybridization can be easily adapted by those skilled in the art to obtain the desired result. One skilled in the art can readily determine the appropriate amount of cDNA from each cDNA population to be used in performing the cross-hybridization. In general, amounts of cDNA from each population in the range of 0.1 to 100 micrograms can be used. Typically, the cross-hybridization is performed with an excess of cDNA from one cDNA population relative to the other. For example, a 1000-fold excess, preferably a 500-fold excess, more preferably a 100-fold excess, and particularly preferably a 20-fold excess of cDNA from one cDNA population relative to the other can be used for cross-hybridization. In one embodiment, four micrograms of cDNA from a first cDNA population is hybridized to 200 nanograms of cDNA from a second cDNA population. Preferably, an excess amount of cDNA from the biological sample which represents a standard or normal condition is cross-hybridized with the cDNA from a biological sample which represents a test or diseased condition. For example, if the first and second biological samples are derived from normal and tumor tissue, respectively, then an excess of cDNA from the normal sample is hybridized to cDNA from the tumor sample. Under such conditions essentially all the tumor cDNA anneals to complementary molecules from the normal cDNA population. Any sequence mismatches between hybridized cDNA are thus due to the presence of regions in the molecules from the tumor sample cDNA population which are different from the corresponding normal cDNA molecules. As is described in more detail below, the mismatched regions in the cross-hybridized double-stranded cDNA represent alternatively spliced regions in the original RNA molecule from which the cDNA was synthesized. The cross-hybridization of cDNA molecules from a first and second cDNA population creates a mixed population of tagged cDNA molecules. This mixed population comprises three subpopulations: 1) single-stranded cDNA molecules from both populations; 2) double-stranded cDNA comprising cDNA molecules from only the first or only the second cDNA populations; and 3) double-stranded cDNA comprising one cDNA molecule from the first cDNA population and one cDNA molecule from the second cDNA population. It is apparent that the cDNA molecules from only the first or only the second subpopulations described above comprise only one type of selectable tag. However, double-stranded cDNA from the third subpopulation comprises both selectable tag types. In the practice of the present method, double-stranded cDNA from the third subpopulation are isolated by selecting for one selectable tag to obtain a first selected population. The molecules of the first selected population are then subjected to a second isolation step, in which those molecules which also contain the other selectable tag are selected. This isolation process is illustrated below and in FIGS. 3A-3C with respect to a preferred embodiment of the invention, in which two RNA populations from different physiologic states are used. However, it is understood that the present method is not restricted to isolating alternative splice forms from RNA representing different physiological states, nor is the present method restricted to the particular selectable tags, affinity media or linking moieties described below. In step 1 of FIG. 2A, a first RNA population 200 is obtained from normal tissue, and a second RNA population 205 is obtained from tumor tissue. In step 2, molecules of the first and second RNA populations are then converted into first and second double-stranded cDNA populations 210 and 215, respectively, as described above. Double-stranded cDNA populations 210 and 215 are blunt-ended with Eco RV and methylated with CpG methylase. First cDNA population 210 is tagged with a first selectable tag 220 in step 3. First selectable tag 220 preferably comprises Tag 1 described above. Also in step 3, molecules of the second cDNA population 215 are tagged with a second selectable tag 225. The second selectable tag 225 preferably comprises Tag 2 described above. An excess of double-stranded cDNA molecules from first cDNA population 210 is mixed with cDNA molecules from second cDNA population 215 in step 4 of FIG. 2B. The mixed cDNA molecules are then denatured and annealed in step 5 to form a mixed population 230. Mixed population 230 comprises single-stranded cDNA molecules 235 and 235′ from the first and second cDNA populations, respectively; double-stranded cDNA 240 wherein both strands are from the first cDNA population; double-stranded cDNA 245 wherein both strands are from the second cDNA population; and double-stranded cDNA 250 and 250′ comprising one strand from the first cDNA population and one strand from the second cDNA population. The two strands in double-stranded cDNA 250 are perfectly matched, and the two strands in double-stranded cDNA 250′ comprise mismatched sequences representing an alternatively spliced region. In step 6a of FIG. 2C, the mixed population 230 is contacted with an affinity medium 255 comprising avidin, which selectively binds the biotin molecules of the first selectable tag 220. The affinity medium 255 thus retains the following molecules from the mixed population: single-stranded cDNA molecules 235 from the first cDNA population; double-stranded cDNA 240 in which both cDNA molecules are derived from the first cDNA population; and double-stranded cDNA 250 and 250′ in which one cDNA molecule is derived from the first cDNA population and the other cDNA molecule is derived from the second cDNA population. Single-stranded cDNA molecules 235′ from the second cDNA population and double-stranded cDNA 245 in which both strands are derived from the second cDNA population are not retained. The column material is then incubated with an oligonucleotide that hybridizes with the 11 base pair overhang of SEQ ID NO: 1 to form a Sma I restrictions site. This oligonucleotide is shown below: 5′ CGATTC The column is then washed to remove any unbound oligonucleotide. The molecules retained by the affinity medium 255 are released by digestion of the first selectable tag 220 with Sma I, to form a first selected population 260. The previous methylation of the cDNA molecules from the first cDNA population 210 and second cDNA population 215 prevents cleavage of the cDNA molecules at any internal Sma I site. In step 6b of FIG. 2C, the first selected population 260 is contacted with an affinity medium 265 comprising a polynucleotide complementary to the 21-base pair 5′ overhang of the second selectable tag 225. The sequence of the polynucleotide comprising affinity medium 265 is shown below: ACACGTGAGGTTGCTATGCAT (SEQ ID NO: 4) Hybridization of affinity medium 265 to the 21 base pair 5′ overhang of the second selectable tag 225 creates a Pml I restriction site. The affinity medium 265 thus retains double-stranded cDNA 250 and 250′, in which one cDNA molecule is derived from the first cDNA population and the other cDNA molecule is derived from the second cDNA population. Single-stranded cDNA molecules 235 from the first cDNA population and double-stranded cDNA 240 in which both cDNA molecules are derived from the first cDNA population are not retained. The double-stranded cDNA 250 and 250′ are then separated from the affinity medium 265 by digestion of the second selectable tag 225 with Pml I to produce a second selected population 270. The previous methylation of the cDNA molecules from the first cDNA population 200 and second cDNA population 210 prevents cleavage of the cDNA molecules at any internal Pml I site. It is understood that order in which the mixed population 230 is contacted with the affinity media 255 and 265 is not critical. Thus, double-stranded cDNA 250 and 250′ can also be isolated by first contacting the mixed population 230 with affinity medium 265 to obtain a first selected population comprising single-stranded cDNA molecules 235′ from the second cDNA population and double-stranded cDNA 250 and 250′. The first selected population can then be contacted with affinity medium 255 to select for double-stranded cDNA 250 and 250′. As stated above, affinity media 255 and 265 are exemplary. In the practice of the present method, the affinity media can comprise any moiety which selectively binds to one of the selectable tags attached to the cDNA molecules. In one embodiment, the affinity media comprises a solid carrier comprising the other compound of an affinity pair as described above. Suitable solid carriers can comprise, for example, cellulose and cellulose derivatives; polyacrylamide; polystyrenes; polysaccharides such as dextran or agarose; rubber; glass; nylon; polyacrylate; polyvinyltoluene; styrenebutadiamine copolymers; polyacrolein; polyurethane; poly (methyl methacrylate); and combinations thereof. In preferred embodiments, the material comprising the affinity media comprises a multiplicity of functionalities; e.g., amino, carboxy, imino, or the like, to which one member of an affinity pair can be bonded. Materials comprising affinity media can comprise free particles. Affinity media comprising particles are conveniently in the form of beads or microspheres, and preferably have an average diameter of from about 0.2 to about 20 microns. Such particles or microspheres can be readily prepared by standard techniques, or are commercially available. Alternatively, the affinity media can be affixed to an apparatus such as an affinity chromatography column, filter, or a plastic or glass surface (e.g., microtiter plates, dipstick systems or test tubes). A preferred apparatus for performing separations with the affinity media is an affinity chromatography column. Moieties capable of selectively binding to selectable tags can be readily attached to affinity media. For example, biotin derivatives can be prepared with functionalities which are reactive towards amines, phenols, imidazoles, aldehydes, carboxylic acids and thiols. Haptens and other biological molecules can be coupled to agarose and polyacrylamides as described, for example, Cuatrecasas, J Biol. Chem. 245, 3059-3065, 1970 and Jacoby W B et al., Meth. Enzymol., Volume 34, Academic Press, New York, 1974. The affinity media can comprise materials other than a solid carrier. For example, affinity media can comprise a substance whose chemical or physical characteristics allow separation of bound material by electric or magnetic fields, phase extraction, or precipitation. In a preferred embodiment, such affinity media comprise magnetic particles. Moieties capable of binding to selectable tags can be readily attached to magnetic particles, for example as disclosed in U.S. Pat. No. 5,512,439, the entire disclosure of which is herein incorporated by reference. Magnetic particles can also be derivatized by providing a surface coating of a polymer carrying functional groups such as: polyurethane together with a polyglycol to provide hydroxyl groups; a cellulose derivative to provide hydroxyl groups; a polymer or copolymer of acrylic acid or methacrylic acid to provide carboxyl groups; or an aminoalkylated polymer to provide amino groups, as described in U.S. Pat. No. 4,654,267, the entire disclosure of which is herein incorporated by reference. Moieties which bind to selectable tags are then attached to these functional groups. In a preferred embodiment, affinity media comprising magnetic particles are prepared by attaching avidin or streptavidin attached to the particles; e.g., via a hydroxyl group. In a particularly preferred embodiment, affinity media comprising magnetic particles are prepared; e.g., by linking a nucleic acid to the particles by forming a phosphoramidate linkage between the nucleic acid and an amino group on the particle. As described above, EDNA comprising a selectable tag is contacted with an affinity medium comprising the appropriate binding partner, under conditions suitable for effecting binding between the selectable tag and the affinity medium. One skilled in the art can readily determine the conditions under which this binding can be effected. For example, if the selectable tag and affinity medium each comprise a polynucleotide, conditions similar to those described above for cross-hybridization of cDNA molecules should also allow hybridization between the tag and affinity medium. The cDNA molecules which are bound to the affinity medium by a selectable tag are separated from unbound material by methods appropriate to the particular type of affinity medium used. For example, if the affinity medium comprises free particles, separation of bound material can be accomplished by centrifugation or filtration of the particles from the general solution. If the affinity medium comprises an affinity chromatography column, the bound material can be conveniently separated by washing the unbound material from the column with a suitable buffer. Recovery of the bound material from affinity media is accomplished by subjecting the affinity media to conditions suitable for cleaving or separating the selectable tag (or a portion thereof) from the cDNA molecule. Alternatively, the affinity medium is subjected to conditions suitable for reversing the binding of the selectable tag to the medium. In another embodiment, the moiety attached to the affinity medium which specifically binds to the selectable tag (or a portion thereof) is cleavable or removable from the affinity medium itself. Moieties bound to the affinity media which are cleavable or removable can comprise a specific chemical or enzymatic cleavage site as described above for the selectable tags. As discussed above, the sequential contact of a mixed cDNA population with the affinity media produces a selected population comprising double-stranded cDNA, in which each double-stranded cDNA comprises one EDNA molecule derived from the first cDNA population and one cDNA molecule derived from the second cDNA population. Of these double-stranded cDNA, some comprise cDNA molecules with perfectly matched nucleotide sequences and some comprise cDNA molecules with mismatched nucleotide sequences. The mismatched sequences represent alternatively spliced regions in one of the cDNA molecules. The other cDNA molecule of the double-stranded cDNA represents the normally spliced molecule. Thus, it is from this population of double-stranded cDNA that a plurality of molecules representing alternatively spliced RNA can be isolated, in conjunction with their normally spliced counterparts. The mismatched sequences in these double-stranded cDNA result in at least one portion of the cDNA being single-stranded. The single-stranded portions can comprise a single-base mismatch or can comprise a mismatch between plurality of nucleotides. It is understood that the single-stranded portion or portions present in these double-stranded cDNA cannot be so large as to prevent formation of a stable DNA duplex. In the practice of the present method, double-stranded cDNA comprising cDNA molecules with mismatched sequences are isolated with reagents which bind single-stranded regions of DNA. Suitable reagents which bind to regions of single-stranded DNA include, E. coli single-stranded binding protein (see Webster G et al., FEBS Lett. 411, 313-316, 1997); antibodies which bind to single-stranded DNA; enzymes (e.g., resolvases) which bind to single-stranded DNA, and ion exchange resins capable of binding single stranded nucleic acids, such as are described in U.S. Pat. No. 6,504,021 of Kristyanne et al., the entire disclosure of which is herein incorporated by reference. A suitable ion exchange resin capable of binding single stranded nucleic acids is the Solid Phase Oligo/Protein Elimination (SOPE™) resin available from Edge Biosystems, Gaithersburg, Md. Preferably, enzymes which bind to single-stranded DNA for use in the present methods lack any catalytic activity, or are used under conditions which do not allow catalytic activity to occur, such as are described in U.S. Pat. No. 6,110,684, the entire disclosure of which is herein incorporated by reference. One skilled in the art can readily determine the conditions under which double-stranded cDNA comprising mismatched sequences can bind to and be separated from the reagents which bind single-stranded DNA. The reagents which bind single-stranded DNA can be incorporated into materials such as those described above which comprise the affinity media. In a preferred embodiment, double-stranded cDNA comprising mismatched sequences is isolated on an affinity column comprising a reagent which binds single-stranded DNA. Preparation of such affinity columns are within the skill in the art. Suitable affinity columns comprising a reagent which binds single-stranded DNA are also available commercially. For example, an affinity column comprising an antibody which binds single-stranded DNA is available from Biomol Research Laboratories, Inc. (Plymouth Meeting, Pa.). In a preferred embodiment, DNA is bound to SOPE™ resin for 30 min. at room temperature in H2O. As shown in Example 1 below and in FIG. 3, double-stranded DNA with a base mismatch of 6-8 bases can be precipitated with the SOPE™ resin. The double-stranded cDNA isolated by the single-stranded DNA binding reagent comprises one cDNA molecule which represents an alternatively spliced RNA. The other cDNA molecule in this double-stranded cDNA represents the normally spliced counterpart of the alternatively spliced RNA. A plurality of such mismatched double-stranded cDNA are isolated, representing different pairs of alternatively spliced and normal molecules. In the practice of the invention, the two cDNA molecules in each mismatched double-stranded cDNA duplex are coupled. As used herein, “coupled” means that the two cDNA molecules in the double-stranded cDNA are linked such that their association is preserved in subsequent analysis steps. Preferably, coupling of the cDNA molecules comprises covalent linking of the two strands by a chemical bond or a linking moiety. Suitable linking moieties can comprise polypeptides or polynucleotides. The isolation of double-stranded cDNA comprising mismatch regions, and the coupling of strands in each double-stranded duplex so isolated is illustrated below and in FIG. 2D with respect to one preferred embodiment of the invention. However, it is understood that the present method is not restricted to the particular single-stranded DNA binding reagents or linking agents described below. In step 7 FIG. 2D, double-stranded cDNA 250 and 250′ as shown in FIG. 2C is applied to an affinity column 272 comprising a single-stranded DNA binding reagent 275. In a preferred embodiment, the single-stranded DNA binding reagent comprises SOPE™ resin obtained from Edge Biosystems (Gaithersburg, M.D.)). Double-stranded cDNA 250′ (comprising mismatched sequences) is retained on the column and is separated from double-stranded cDNA 250 (which comprises perfectly matched sequences). After elution of double-stranded cDNA 250′ from affinity column 272, both strands of each cDNA are coupled with linking moiety 280 in step 8 of FIG. 2D to form coupled molecules 285. In a preferred embodiment, linking moiety 280 comprises polynucleotide “GN”, which can form a DNA hairpin wherein the free ends form a complementary end with the overhang from SEQ ID NO: 3 following its annealing with its SEQ ID NO: 4 and digestion with Pml I. This polynucleotide can be ligated to the GTGT “sticky end” overhang protruding from the double-stranded cDNA which was formed by digestion of the second selectable tag 215 as described above, to covalently link the two cDNA strands. The primary nucleotide sequence of polynucleotide GN is given below: (SEQ ID NO: 5) 5′-ACA CCG CAG ATG TCC GCA GTT ATT CCT TTT TTG GAA TAA CTG CGG ACA TCT GCG-3′ Coupled molecules 285 comprise a plurality of molecules which represent different linked pairs of full-length alternatively spliced and normally spliced RNA molecules from the first and second biological samples. Analysis of these linked pairs can now be performed, for example to obtain information about the relative abundance of an alternatively spliced molecule, or the sequence of both normal and alternatively spliced molecules. Performance of such analyses is within the skill in the art. In one embodiment, the relative abundance of a given molecule in the final population is determined by PCR amplification of either or both strands of a coupled molecule. In a further embodiment, the sequence of both strands of a coupled molecule is determined by standard DNA sequencing techniques. For example, the coupled molecules can be sequenced directly, or PCR amplification products of either or both strands can be performed. The coupled molecules can be modified to facilitate the analyses discussed above. For example, polynucleotide sequences representing targets for PCR primers can ligated to the ends of the coupled molecules. Denaturation of such molecules produces a linear polynucleotide comprising the (as yet) unknown normal and alternatively spliced sequences flanked by known sequences. This is illustrated in step 8 of FIG. 2D, which shows the blunt-end ligation of short double-stranded polynucleotide sequences 290. Polynucleotide sequences 290 comprise a target for PCR primers to the free end of coupled molecules 285. Denaturation and subsequent PCR amplification of these coupled molecules as shown in FIG. 2E produces one fragment from each coupled molecule. Each amplified fragment comprises the sequences of the normally spliced molecule and the alternatively spliced molecule from a particular coupled molecule, which flank the sequence of the linker moiety. These amplification products are then run on an agarose gel 295 under standard conditions and stained with ethidium bromide. Assuming that fluorescence of the individual fragments is proportional to length, the relative abundance of each fragment (and thus of each alternatively spliced/normal pair) will be apparent from the gel. Individual bands can then be excised from the gel and sequenced. Preferably, the predominant species (as determined, e.g., by relative fluorescence on the gel) are excised sequenced. It is apparent that the linker moiety serves as the divider between the normal and alternatively spliced molecules. Upon sequencing, sequences of the normal and alternatively spliced molecules can be easily identified and compared; e.g., to determine what constitutes the alternative splice and to predict the reading frame. If desired, further analysis of the normal and alternatively spliced molecules can be carried out. For example, alternatively spliced molecules can be searched against sequence databases (such as the NCBI or EMBL databases) to determine if the molecule corresponds to any known nucleotide or protein sequence. PCR primers flanking the alternatively spliced region can also be generated and used to confirm expression of the alternatively spliced RNA in tissue samples. Preferably, quantitative PCR methods are used to confirm that the alternatively spliced molecule is more expressed more abundantly in one tissue sample as compared to another. Some or all of the components and reagents for performing the present method can be conveniently provided as a kit. For example, reagents and components for performing RNA isolation (including reverse-transcriptase and oligonucleotide primers) and reagents and components for performing cDNA synthesis (including DNA polymerase) can be provided, along with instructions for their use. A kit according to the invention can also comprise, for example, reagents and components for cross-hybridizing cDNA populations, along with instructions for their use. A kit according to the invention can also comprise at least two different selectable tags and their corresponding affinity media, along with reagents and instructions for attaching the tags to cDNA molecules and separating the tagged cDNA molecules with the affinity media. A single-stranded DNA binding reagent for isolating double-stranded cDNA with sequence mismatches, or a linking moiety for coupling the strands of the mismatched double-stranded cDNA together, can also be provided in the present kits, along with instructions for their use. The invention will now be illustrated by the following non-limiting example. EXAMPLE 1 Retention of Mismatched Double-Stranded DNA by SOPE™ Resin Oligonucleotide molecules were synthesized that were otherwise complementary except for a 4, 8, or 20 base insertion relative to one strand. After annealing, the double stranded DNA containing the mismatched regions were incubated with SOPE™ resin (Edge Biosystems, Gaithersburg, Md.) in H2O at room temperature, according to the manufacturer's instructions. Lanes 1, 3, and 5 of FIG. 3 show annealed DNA containing 20, 8 and 4 base mismatch regions, respectively, prior to binding to SOPE™ resin. SOPE™ resin was then added to the DNA. The DNA remaining in the supernatant after pelleting of the SOPE™ resin with bound DNA by centrifugation is shown in FIG. 3 (lane 2; 20 base mismatch, lane 4; 8 base mismatch, lane 6; 6 base mismatch). As can be seen from the figure, all of the double stranded DNA with a 20 base mismatch and approximately 90% of the double-stranded DNA with an 8 base mismatch was bound to the SOPE™ resin. The SOPE™ resin also appeared to bind a significant portion of the double stranded DNA with a 6 base mismatch. All documents referred to herein are incorporated by reference in their entirety. While the present invention has been described in connection with the preferred embodiments and the various figures, it is to be understood that other similar embodiments may be used or modifications and additions made to the described embodiments for performing the same function of the present invention without deviating therefrom. Therefore, the present invention should not be limited to any single embodiment, but rather should be construed in breadth and scope in accordance with the recitation of the appended claims.

<SOH> BACKGROUND OF THE INVENTION <EOH>The number of proteins produced by the human genome likely numbers in the hundreds of thousands. However, recent evidence indicates that the human genome contains only 30,000 to 45,000 different genes. Clearly, each gene is producing multiple proteins. Alternative splicing of primary RNA transcripts is a major mechanism for increasing production of proteins from the human genome. It is known that 30% to 60% of genes undergo alternative splicing to produce messenger RNA (mRNA). Modrek B et al. Nat. Genet. 30, 13-19 (2002). These alternatively spliced mRNA are translated into alternative splice form proteins that contain amino acid sequences different than the corresponding protein produced by normally spliced mRNA. Alternative splice form proteins are often expressed in a tissue-specific manner, or under certain physiologic or disease states. Modrek B et al., Nucl. Acids Res. 29, 2850-2859 (2001). Consequently, certain alternatively spliced mRNA are present in a limited number of cells in a subject suffering from a given disease or condition. For example, it is known that many types of cancer cells produce alternative splice forms which are not found in normal cells from the same subject. Cancer-associated genes such as CD44 (Rodriguez C et al., Int. J. Cancer 64, 347-354, 1995), estrogen receptor (Castles C G et al., Cancer Res. 53, 5934-5939, 1993), FGF receptor (Luqmani Y A et al., Int. J. Cancer 64, 274-279, 1995), DNA polymerase (Bhattacharyya N et al., DNA Cell Biol. 18, 549-554, 1999), cathepsin B (Gong Q et al., DNA Cell Biol. 12, 299-309, 1993), FHIT (Panagopoulos I. et al., Cancer Res. 56, 4871-4875, 1996), BRCA1 (Thakur S et al., Mol. Cell Biol. 17, 444-452, 1997) and BRCA2 (Bieche I et al., Cancer Res. 59, 2546-2550, 1999), produce alternatively spliced mRNA that are specifically expressed in cancerous tissues. Other disease states in which alternative splice forms are specifically produced in certain tissues include diabetes, Alzhiemer's disease and systemic lupus erythematosus (SLE). Drugs that target proteins specific to cancerous or other disease tissue have proven efficacious in the appropriate patient population. For example, successful treatment of breast cancer has been reported for drugs which target the estrogen receptor (Jordan C, Clin. Ther. 24 Suppl A, A3-16, 2002) or the HER-2 receptor (Thomssen C, Anticancer Drugs 12 Suppl 4, S19-S25, 2001; Yip Y L et al., Cancer Immunol. Immunother. 50; 569-587, 2002). The genetic alterations present in tumor-specific proteins, such as mutations in p53, BRCA 1 and BRCA2, provide another source of targets. Thus, the proteins produced from alternatively spliced mRNA produced specifically in cancers or other disease states are also attractive therapeutic targets. However, proteins produced from alternatively spliced mRNA have not been widely exploited as therapeutic targets. The major impediment to using such proteins as therapeutic targets has been the incidental or tedious nature by which alternatively spliced mRNA are found. Present methodologies are limited to either cDNA cloning (which is highly labor intensive) or RT/PCR (which focuses only on known portions of genes). In addition, most cloning- and RT/PCR-based methods are highly biased, as they require prior knowledge of the alternatively spliced mRNA sequence. An unbiased procedure for discovery of alternatively spliced mRNA has been reported in U.S. Pat. No. 6,251,590 of Schweighoffer et al. However, the Schweighoffer et al. method identifies only the region in the alternatively spliced mRNA that is different from the normally spliced mRNA. The cDNA corresponding to both the normal and alternatively spliced mRNA must be separately cloned in order to pinpoint the alternatively spliced region in the context of the full-length molecule. The sequencing of multiple cDNA clones is also required to determine the prevalence of a given alternatively spliced mRNA. The Schweighoffer et al. method thus required a substantial investment of both time and resources in order to identify alternatively spliced molecules. Thus, an unbiased method of rapidly and easily identifying alternatively spliced RNA in biological sample is needed, in which both the full-length normal and alternatively spliced mRNA are simultaneously isolated for comparison. Ideally, such a method would not rely on multiple cloning and sequencing steps for determining the identity and relative abundance of alternative splice forms in a given sample.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is directed to an unbiased method for isolating and identifying full-length alternatively spliced RNA, wherein the alternatively spliced RNA is isolated in conjunction with its counterpart normally spliced RNA. The practice of this method thus does not require foreknowledge of either the normal or alternatively spliced RNA sequences, or the nature of the alternative splice. The method also does not require multiple cloning or sequencing steps in order to identify the alternatively spliced RNA. The invention provides a method of identifying an alternatively spliced RNA by comparing populations of cDNA molecules obtained from two biological samples. One sample represents a first physiological condition, and the other sample represents a second physiological condition. The two cDNA populations are separately tagged with different compounds, and denatured portions of each tagged cDNA population are annealed to each other under conditions which allow the formation of a mixed population of cDNA molecules. This mixed population comprises single-stranded cDNA molecules from both populations, double-stranded cDNA comprising cDNA molecules from only the first or second cDNA populations, and double-stranded cDNA comprising cDNA molecules from both the first and second cDNA populations. Double-stranded cDNA comprising cDNA molecules from both the first and second cDNA populations are isolated from the mixed population by first selecting for those molecules comprising the tag specific to the first cDNA population, followed by selecting for molecules which also contain the tag specific to the second cDNA population. Alternatively, double-stranded cDNA comprising cDNA molecules from both the first and second cDNA populations can be isolated by selecting for molecules comprising the tag specific to the second cDNA population, followed by selecting for molecules comprising the tag specific to the first cDNA population. The double-stranded cDNA selected above comprises two types. The first type comprises two cDNA molecules with perfectly matched sequences, in which each cDNA molecule represents normally spliced mRNA. The second type comprises two cDNA molecules with at least one area of mismatched sequence. In the second type of double-stranded cDNA, one cDNA strand represents the alternatively spliced mRNA molecule and the other cDNA strand represents the normally spliced counterpart of the alternatively spliced mRNA. The mismatched sequence is unpaired with respect to the opposite strand and comprises a single-stranded region in the otherwise paired sequences. Such a double-stranded cDNA encompassing a mismatched sequence is then isolated with reagents which bind to regions of single-stranded nucleic acid. The two nucleic acid strands of said selected double-stranded cDNA are coupled, yielding a single molecule that can be analyzed to identify the normal and alternatively spliced molecules. A kit comprising some or all of the components and for performing the present method, along with instructions for their use, is also provided.

20070618

20110405

20080626

72082.0

C12Q168

WILDER, CYNTHIA B

METHOD FOR RAPID IDENTIFICATION OF ALTERNATIVE SPLICING

SMALL

ACCEPTED

C12Q

ACCEPTED

Pulmonary evaluation device

Pulmonary evaluation device has sensor means adapted to sense fluctuations in a user's lung operation and feedback means, driven by said sensor means, for determining successive values representative of the user's lung fluctuations and adapted to translate said values into appropriate lung-evaluating information. Optionally, the sensor means comprises or forms part of an item suitable to be worn by or carried adjacent the user so as to follow body movements caused by the user's lung operation to evaluate the user's lung operation.

1-9. (canceled) 10. A pulmonary evaluation device comprising: an item worn over the user's body for following body movements caused by the user's lung operation; a sensor for sensing fluctuations in a user's lung operation; and a feedback, driven by said sensor, for determining successive values representative of the user's lung fluctuations and for translating said values into appropriate lung-evaluating information; wherein the item has at least one chamber formed between one inner wall and at least one outer wall, said at least one chamber is so sized and shaped to span the entire lung region of the user's body, whereby as the user's body displaces due to respiration said at least one inner wall follows the displacement and said sensor senses the pressure within said at least one chamber. 11. A device according to claim 10, wherein at least one chamber contains a gas. 12. A device according to claim 11, comprising a seal for sealing said at least one chamber; whereby the volume of gas contained by said at least one chamber remains constant and as the body displaces during respiration, a measurable change in internal chamber pressure occurs as the chambers' wall displaces. 13. A device according to claim 10, incorporating an array of chambers locating a chamber over a separate region of the user's lung. 14. A device according to claim 10, wherein said at least one inner wall is substantially resilient and said at least one outer wall is substantially rigid in relation to said inner wall; whereby the inner wall may follow, in use, the movement caused by the user's lung operation whilst the outer wall remains substantially rigid.

FIELD OF THE INVENTION The present invention relates to pulmonary evaluation devices. BACKGROUND TO THE INVENTION The main function of the lungs is to provide continuous gas exchange between inspired air and the blood in the pulmonary circulation, supplying oxygen and removing carbon dioxide, which is then cleared from the lungs by subsequent expiration. Survival is dependent upon this process being reliable, sustained and efficient, even when challenged by disease or an unfavourable environment. Lung function tests evaluate how much air lungs can hold, how quickly air moves in and out of the lungs, and how well lungs add oxygen to and remove carbon dioxide from the blood. Such tests can help diagnose lung diseases and measure the severity of lung problems that prevent normal breathing. Lung function tests are done to: Help determine the cause of breathing problems; Measure the amount of lung function in a person who has a lung disease and monitor the effectiveness of treatment; Identify people at high risk of developing lung disease (especially smokers); Evaluate a person's ability to breathe before surgery; Monitor the lung function of a person who is regularly exposed to substances that can damage the lungs. Several different types of tests can provide information about lung function. Such tests include spirometry, gas dilution tests, body plethysmography, carbon monoxide diffusing capacity and arterial blood gases. Spirometry measures the volume of air inspired or expired as a function of time and is the standard method for measuring most relative lung volumes; however, it is incapable of providing information about absolute volumes of air in the lung. Thus a different approach is required to measure residual volume, functional residual capacity and total lung capacity. Two methodologies most commonly used for determination of absolute lung volume are gas dilution and body plethysmography. Gas dilution tests measure the amount of air that remains in the lungs after the subject has exhaled as completely as possible (residual volume). Body plethysmography measures the total amount of air that lungs can hold. During body plethysmography, the subject sits in an airtight box (body plethysmograph, or ‘body box’) of known volume and breathes through a mouthpiece connected to a shutter. The pressure is monitored in two places, in the box and at the subject's airways, the latter via a side-port of the mouthpiece. At end-expiration the airways are momentarily occluded by the shutter, and the subject makes an inspiratory effort against the occlusion. The increase in their chest volume slightly reduces the box volume whilst slightly increasing the pressure in the box. Monitoring changes in pressure in the box and applying a series of well documented derivation techniques, body plethysmography allows a number of pulmonary measurements to be obtained such as for example thoracic gas volume and airways resistance. Drawbacks associated with body plethysmography: Mental confusion, muscular incoordination, body casts or other conditions that prevent the subject from entering the plethysmograph cabinet or adequately performing the required manoevours (i.e. panting against a closed shutter); Claustrophobia may be aggravated by entering the plethysmography cabinet; Presence of devices or other conditions such as continuous I.V infusions with pumps or other equipment that will not fit into the plethysmograph that should not be discontinued, or that might interfere with pressure changes (eg. chest tube or ruptured eardrums); Continuous oxygen therapy that should not be temporarily discontinued; Over estimation of thoracic gas volumes in subjects with severe obstruction or induced bronchospasm unless a slow ‘panting’ speed is maintained; Erroneous measurement of thoracic gas volume, airways resistance, or specific airways conductance due to improper panting technique. Excessive pressure fluctuations or signal drift during panting may invalidate thoracic gas volume, airways resistance or specific airways conductance; Whole-body plethysmographs are expensive and usually found in pulmonary function laboratories, cardiopulmonary laboratories, clinics and specialist pulmonary offices. An object of the present invention is to provide a cost effective and easy to use, pulmonary evaluation device which does away with the requirement of the patient having to be placed in an air-tight box so that, for example, it can be used at the General Practice (GP) level. A further object of the invention is to provide a pulmonary evaluation device that can be used by a variety of subjects or users. Such subjects including neonatal, paediatric, geriatric, disabled, the mentally frail and animals. SUMMARY OF THE INVENTION According to the broadest independent aspect of the invention there is provided a pulmonary evaluation device comprising:— sensor means adapted to sense fluctuations in a user's lung operation; and feedback means, driven by said sensor means, for determining successive values representative of the user's lung fluctuations and adapted to translate said values into appropriate lung-evaluating information; characterised by the feature that the sensor means comprises or forms part of an item suitable to be worn by or carried adjacent the user. This combination of features is advantageous because it eliminates the requirement of using an enclosure to obtain results useful in pulmonary evaluation. Due to its versatility it is also particularly advantageous because a variety of subjects (even animals) may benefit from its use. It is also advantageous because it may be used to obtain results without requiring the patient to be sitting in the enclosure. He/she may for example be sitting on his/her hospital bed. One of the advantages of this particular configuration is in allowing the user to freely move around and change position rather than being static and seated during use. This may for example be particularly useful in assessing pulmonary function during motion or even exercise. Pulmonary evaluation may be obtained for athletes, greyhounds and horses. This enables a range of measurements to be taken during both inactive and active periods to obtain a more detailed and precise profile of the user's lung operation. According to a subsidiary aspect of the present invention there is provided a device, wherein the item engages the user's body, when in use, so as to follow body movements caused by the user's lung operation. One of the advantages of such an arrangement is that having the item in engagement allows more accurate measurements to be obtained. A further advantage of such an arrangement is that compliance measurements may be obtained for specific body parts for example, differentiation between the individual's lungs and/or differentiation between the lungs and the abdomen. According to a subsidiary, aspect of the present invention there is provided a device, wherein said sensing means incorporate: an inner wall and an outer wall forming a chamber therebetween; and at least one sensor adapted to sense pressure values within said chamber. Such a configuration is advantageous in that pressure readings are obtained without the need for an enclosure. The result of this device will therefore generate results which can be readily interpreted by the skilled man in the art without requiring extensive training from his/her knowledge of prior art pulmonary evaluation devices. In a further subsidiary aspect of the present invention there is provided a device wherein the inner wall is substantially resilient and the outer wall is substantially rigid in relation to the inner wall, whereby the inner wall may follow, in use, the movement caused by the user's lung operation whilst the outer wall remains substantially rigid. One of the advantages of such an arrangement is that, in use, the user's movements are not restricted. A further advantage of this particular configuration is that the user may wear the device over its clothing. Another advantage is that multiple users of differing shapes and sizes may use the device without adjustment. In a further subsidiary aspect of the present invention, said item is a vehicle seatbelt. This configuration is particularly advantageous because the tension and/or lack of tension apparent on the seat belt whilst breathing may provide an alternative useable measure of the user's lung operation. In a further subsidiary aspect of the present invention there is provided a device, wherein said sensor means is a camera whereby said camera captures successive images of the user's lung fluctuations. Thus a completely non-contact evaluation can be obtained beneficial to, for example, burns victims and/or patients requiring an environment free from contaminants. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1a and 1b show a front view of a pulmonary evaluation device in accordance with a first embodiment of the invention. FIGS. 2a-c show cross-sectional views of a pulmonary evaluation device at rest, during inspiration and during expiration. FIGS. 3a-b show front views of a pulmonary evaluation device in accordance with a first embodiment of the invention having an array of chambers. DETAILED DESCRIPTION OF THE DRAWINGS FIG. 1a presents a pulmonary evaluation device 10 in the form of an over-the-head item or garment 10 having a front panel 11, rear panel 12 and side panels 13, 14. FIG. 1b shows device 10 comprising head aperture 15, arm or upper torso apertures 16, 17, lower torso aperture 18, upper adjustment means 19, 20 and/or side adjustment means 21, 22 and securing means 23 for securing between the legs of a patient forming leg apertures 24, 25 in use. The various apertures are so sized and shaped by the person skilled in the art to allow relatively unrestrained movement of the various body members. The lower torso aperture 18 is so sized and shaped to allow entry of the user's upper body when donning the garment 10. Adjustment means 19, 20, 21, 22 are provided between the upper front panel 11, the upper rear panel 12, and side panels 13, 14 such that the user can adjust the garment 10 in use to become more or less form fitting. These may be selected by the skilled man from known alternatives such as VELCRO®. Securing means 23 is fixably attached at a first end to either the lower front panel 11 or the lower rear panel 12 and releasably connected to the opposing panel 12, 11 at a second end. Once secured the lower torso aperture 18 and securing means 23 provide leg apertures 24, 25 allowing unrestricted movement of the user's legs. The material forming the garment 10 may be lightweight, supple and form fitting. When donned the garment 10 covers the anterior chest wall and at least the upper abdomen. The adjustment means 19, 20, 21, 22 provide adjustment ensuring that the necessary region is in sufficient contact with the garment 10. FIGS. 2a-c presents the internal configuration of the garment 10 comprising an inner wall 110 substantially in contact with the user and an outer wall 120 connected to the inner wall 110 and forming a chamber 130 between the inner wall 110 and outer wall 120. Sensor means 140 are located between the two walls 110, 120. Feedback means 145 are connected to the sensor means 140 to capture and evaluate successive readings. Such feedback means may include for example, a microprocessor, a computer or a data logger. In use, the wearer inserts their head, arms and upper torso through the lower torso aperture 18 until the head exits the head aperture 15 and the arms exit the arm apertures 16, 17. The user and/or assistant adjusts the garment 10 ensuring that the anterior chest wall and the upper abdomen is enclosed by the garment 10. The securing means 23 is secured so as not to restrict the movement of the user's legs or movement of the garment 10 perpendicular to the user's spine whilst restricting the movement of the garment 10 parallel to the user's spine. The movement of the wearer's chest wall during breathing is followed by the garment 10. FIGS. 2a to 2c relate the use of the garment 10 to the breathing cycle: FIG. 2a shows the device 10 at rest; FIG. 2b shows the device 10 during inspiration wherein the inner wall 110 of the garment 10 follows the movement of the chest. Whereas the outer wall 120 does not. The fixed volume of gas between the inner and outer wall is compressed as the inner wall 110 is pushed towards the outer wall 120 due to the expansion of the lung(s). The volume of gas within the garment 10 does not change whilst the wearer is breathing unlike the pressure of the gas. The sensor means 140 is positioned to note the pressure changes. FIG. 2c shows the device 10 during expiration, as the lung and chest volume decrease, the inner wall 110 relaxes whilst still following the movement of the chest and the pressure exerted on the gas by the inner wall 110 decreases. During exercise or rigorous movement the securing means 23 ensures that the garment 10 is correctly located during use. FIGS. 3a-b present possible configurations of the garment 10 comprising an array of chambers 103a, 130b, 130a′, 130a″, 130b′, 130b″. FIG. 3a shows the device 10 having two chambers 130a, 130b which may be used to differentiate between each lung. Alternatively the front panel 11 may comprise an upper and a lower chamber which may be used to differentiate measurements between the upper rib regions and the lower rib regions. FIG. 3b shows the device 10 having four chambers 130a′, 130a″, 130b′, 130b″ which may be used to differentiate measurements between the upper and lower rib region of each lung. The rear panel 12 may have a similar array of chambers as just described. The number and location of the array of chambers 130a, 130b, 130a′, 130a″, 130b′, 130b″ permit localised measurements to be obtained. In a second embodiment the pulmonary evaluation device may take the form of a vehicle seat belt having a pulmonary contact region enclosing the torso and sensor means within the pulmonary contact region capable of measuring tension within the contact region, all being connected to a microprocessor which stores and evaluates the obtained results. Alternatively the sensor means may comprise a dual wall structure having a sensor therebetween as previously described. Such a vehicle seat belt variant would enable heart compliance measurements to be obtained if the contact region was located over the heart. In a third embodiment, the pulmonary evaluation device utilises a camera monitoring lung fluctuation/displacement. As the user breathes a number of images of the user's chest wall profile can be captured and then processed to determine displacement during breathing.

<SOH> BACKGROUND TO THE INVENTION <EOH>The main function of the lungs is to provide continuous gas exchange between inspired air and the blood in the pulmonary circulation, supplying oxygen and removing carbon dioxide, which is then cleared from the lungs by subsequent expiration. Survival is dependent upon this process being reliable, sustained and efficient, even when challenged by disease or an unfavourable environment. Lung function tests evaluate how much air lungs can hold, how quickly air moves in and out of the lungs, and how well lungs add oxygen to and remove carbon dioxide from the blood. Such tests can help diagnose lung diseases and measure the severity of lung problems that prevent normal breathing. Lung function tests are done to: Help determine the cause of breathing problems; Measure the amount of lung function in a person who has a lung disease and monitor the effectiveness of treatment; Identify people at high risk of developing lung disease (especially smokers); Evaluate a person's ability to breathe before surgery; Monitor the lung function of a person who is regularly exposed to substances that can damage the lungs. Several different types of tests can provide information about lung function. Such tests include spirometry, gas dilution tests, body plethysmography, carbon monoxide diffusing capacity and arterial blood gases. Spirometry measures the volume of air inspired or expired as a function of time and is the standard method for measuring most relative lung volumes; however, it is incapable of providing information about absolute volumes of air in the lung. Thus a different approach is required to measure residual volume, functional residual capacity and total lung capacity. Two methodologies most commonly used for determination of absolute lung volume are gas dilution and body plethysmography. Gas dilution tests measure the amount of air that remains in the lungs after the subject has exhaled as completely as possible (residual volume). Body plethysmography measures the total amount of air that lungs can hold. During body plethysmography, the subject sits in an airtight box (body plethysmograph, or ‘body box’) of known volume and breathes through a mouthpiece connected to a shutter. The pressure is monitored in two places, in the box and at the subject's airways, the latter via a side-port of the mouthpiece. At end-expiration the airways are momentarily occluded by the shutter, and the subject makes an inspiratory effort against the occlusion. The increase in their chest volume slightly reduces the box volume whilst slightly increasing the pressure in the box. Monitoring changes in pressure in the box and applying a series of well documented derivation techniques, body plethysmography allows a number of pulmonary measurements to be obtained such as for example thoracic gas volume and airways resistance. Drawbacks associated with body plethysmography: Mental confusion, muscular incoordination, body casts or other conditions that prevent the subject from entering the plethysmograph cabinet or adequately performing the required manoevours (i.e. panting against a closed shutter); Claustrophobia may be aggravated by entering the plethysmography cabinet; Presence of devices or other conditions such as continuous I.V infusions with pumps or other equipment that will not fit into the plethysmograph that should not be discontinued, or that might interfere with pressure changes (eg. chest tube or ruptured eardrums); Continuous oxygen therapy that should not be temporarily discontinued; Over estimation of thoracic gas volumes in subjects with severe obstruction or induced bronchospasm unless a slow ‘panting’ speed is maintained; Erroneous measurement of thoracic gas volume, airways resistance, or specific airways conductance due to improper panting technique. Excessive pressure fluctuations or signal drift during panting may invalidate thoracic gas volume, airways resistance or specific airways conductance; Whole-body plethysmographs are expensive and usually found in pulmonary function laboratories, cardiopulmonary laboratories, clinics and specialist pulmonary offices. An object of the present invention is to provide a cost effective and easy to use, pulmonary evaluation device which does away with the requirement of the patient having to be placed in an air-tight box so that, for example, it can be used at the General Practice (GP) level. A further object of the invention is to provide a pulmonary evaluation device that can be used by a variety of subjects or users. Such subjects including neonatal, paediatric, geriatric, disabled, the mentally frail and animals.

<SOH> SUMMARY OF THE INVENTION <EOH>According to the broadest independent aspect of the invention there is provided a pulmonary evaluation device comprising:— sensor means adapted to sense fluctuations in a user's lung operation; and feedback means, driven by said sensor means, for determining successive values representative of the user's lung fluctuations and adapted to translate said values into appropriate lung-evaluating information; characterised by the feature that the sensor means comprises or forms part of an item suitable to be worn by or carried adjacent the user. This combination of features is advantageous because it eliminates the requirement of using an enclosure to obtain results useful in pulmonary evaluation. Due to its versatility it is also particularly advantageous because a variety of subjects (even animals) may benefit from its use. It is also advantageous because it may be used to obtain results without requiring the patient to be sitting in the enclosure. He/she may for example be sitting on his/her hospital bed. One of the advantages of this particular configuration is in allowing the user to freely move around and change position rather than being static and seated during use. This may for example be particularly useful in assessing pulmonary function during motion or even exercise. Pulmonary evaluation may be obtained for athletes, greyhounds and horses. This enables a range of measurements to be taken during both inactive and active periods to obtain a more detailed and precise profile of the user's lung operation. According to a subsidiary aspect of the present invention there is provided a device, wherein the item engages the user's body, when in use, so as to follow body movements caused by the user's lung operation. One of the advantages of such an arrangement is that having the item in engagement allows more accurate measurements to be obtained. A further advantage of such an arrangement is that compliance measurements may be obtained for specific body parts for example, differentiation between the individual's lungs and/or differentiation between the lungs and the abdomen. According to a subsidiary, aspect of the present invention there is provided a device, wherein said sensing means incorporate: an inner wall and an outer wall forming a chamber therebetween; and at least one sensor adapted to sense pressure values within said chamber. Such a configuration is advantageous in that pressure readings are obtained without the need for an enclosure. The result of this device will therefore generate results which can be readily interpreted by the skilled man in the art without requiring extensive training from his/her knowledge of prior art pulmonary evaluation devices. In a further subsidiary aspect of the present invention there is provided a device wherein the inner wall is substantially resilient and the outer wall is substantially rigid in relation to the inner wall, whereby the inner wall may follow, in use, the movement caused by the user's lung operation whilst the outer wall remains substantially rigid. One of the advantages of such an arrangement is that, in use, the user's movements are not restricted. A further advantage of this particular configuration is that the user may wear the device over its clothing. Another advantage is that multiple users of differing shapes and sizes may use the device without adjustment. In a further subsidiary aspect of the present invention, said item is a vehicle seatbelt. This configuration is particularly advantageous because the tension and/or lack of tension apparent on the seat belt whilst breathing may provide an alternative useable measure of the user's lung operation. In a further subsidiary aspect of the present invention there is provided a device, wherein said sensor means is a camera whereby said camera captures successive images of the user's lung fluctuations. Thus a completely non-contact evaluation can be obtained beneficial to, for example, burns victims and/or patients requiring an environment free from contaminants.

20060209

20100209

20061207

93563.0

A61B508

NATNITHITHADHA, NAVIN

PULMONARY EVALUATION DEVICE

SMALL

ACCEPTED

A61B

ACCEPTED

Start-up assistance coaxial gear reducer with increasing ratio up to direct drive

The invention concerns a decreasing reduction start-up phase coaxial mechanical reducer using constantly variable radius gears, with a final direct drive 1:1 ratio obtained without internal movement component.

1. A coaxial mechanical reduction gearset with a continuously decreasing reduction ratio employing a plurality of variable-radius gears for a phase of starting up a rotary machine, wherein said gears have uniformly varying radii, the reduction ratio at the end of the start-up phase is 1:1 in direct drive, and the reduction gearset at that point then no longer has any internal moving part. 2. The reduction gearset as claimed in claim 1, wherein the variable-radius gears are symmetric, and wherein the reduction gearset comprises two pinions which have axes common to said gears, the ratio between said pinions being the same as the ratio between the extrema of the radii of the gears. 3. The reduction gearset as claimed in claim 2, comprising a device which blocks the rotation of the wheels at the end of the start-up phase at the minimum reduction point of 1:1 and releases it for reengagement at the point of maximum reduction. 4. The reduction gearset as claimed in claim 1, wherein the variable radii of the gears have rates of variation that are functions of their angular positions. 5. The reduction gearset as claimed in claim 1, comprising a plurality of gears offset longitudinally and distributed about the common input and output axis.

Coaxial reduction gearset to aid with start-up having a ratio that increases up to direct drive. The present invention relates to the field of rotary machinery requiring frequent restarts. One problem that has been solved only in part is that of the work needed to bring the machine up to speed during the start-up phase in the course of which the reduction ratio between an input shaft and an output shaft, usually ideal for steady state operation, is inappropriate. Gearbox, bicycle derailleur or variable-cheek pulley systems are known. The disadvantages with these systems are that they are complex or that they are always in operation, even during steady state operation. What is therefore missing is a simple system with a continuously decreasing reduction ratio culminating in a final ratio of 1:1—direct drive—where there is no longer any internal moving part. This object is achieved by a coaxial mechanical reduction gearset with a continuously decreasing reduction ratio employing a plurality of variable-radius gears for a phase of starting up a rotary machine, characterized in that said gears have uniformly varying radii, in that the reduction ratio at the end of the start-up phase is 1:1—direct drive—and in that the reduction gearset at the end of the start-up phase then no longer has any internal moving part. Gears with variable radii and constant distance between centers are well known in the field of pumps, compressors and flow meters, but their reference or pitch curve is generally closed to allow for continuous rotation. This leads to increasing and decreasing variations in said radius, and therefore to a reduction ratio that varies in the same way. The present invention uses gears with uniformly varying radii, leading to a reduction ratio which is also uniformly variable. On account of their design, such gears have a discontinuity in the radius preventing continuous rotation. By contrast, they are perfectly able to operate for a transient period. To optimize the useful angular amplitude, the invention in a preferred form anticipates pairs of gears able both to operate over one complete revolution, which entails symmetric gear pairs and the possibility of reengaging the teeth, also known as remeshing, after stopping at the point of the discontinuity. These said gears are reminiscent of the shape of a portion of a spiral limited to one polar revolution with radii which, for equal curved abscissa values at the points corresponding to them, measured from the closest end, need to exhibit a constant sum equal to the distance between centers. It may be pointed out that a logarithmic spiral portion the radius of which is an exponential function of the polar angle, limited to a variation of 360° of this angle, satisfies this condition, and has the special feature that its velocity vector has an angle that remains constant with the radius. The reduction ratio of such a pair of gears varies continuously from r/R to R/r with r and R corresponding to the minimum and to the maximum of the value of the radius, which values lie at the discontinuity. It is sensible to have this pair of gears driven by a couple of fixed-radius pinions exhibiting a ratio of R/r. This then yields a reduction ratio that varies from R/r×R/r=(R/r)2 for the starting position, to R/r×r/R=1 on approaching the discontinuity. The large pinion and the driving gear are axially secured together in order to afford the aforementioned drive. It must be pointed out that the final gearset performs one complete revolution for a rotation R/r times as much and in the same direction as the small input pinion. In order to produce a system which, at the end of the phase, no longer has any internal moving part, the invention provides for this common intermediate axis to be able to rotate about the axis of the small driving pinion, for example with a wheel carrier plate, with a device preventing it from rotating in the opposite direction, and for the distances between centers to have the same length. This device may be a ratchet wheel, a wedging system, a retainer, or any other system known per se. The axis of the output gear is therefore the same as that of the small input pinion, which at the end of the phase leads to the entirety rotating in direct drive with no internal relative movement. The end of the transient phase corresponds to the end of a rotation through 360° of the variable-radius gears and of the large pinion. A rotation-blocking device, which may be positioned with no particular preference on any one of these three wheels, then stops the mechanism and the whole entity then rotates about the common input and output axis. Temporary deactivation of this device allows the system to reposition itself in the starting position for a further transient phase, which is once again stopped after it has rotated through another 360°. It is also possible to maintain permanent blocking at the end of the phase and to return partially or fully to the transient phase by rotating the input pinion in the opposite direction if the output gear is able also to rotate in the opposite direction, or by rotating the intermediate axis in the direction of operation with the output gear blocked, the input pinion then rotating in the opposite direction to the direction in which it previously rotated. Another way of blocking the end of the transient phase may be achieved without the use of a dedicated device if the final overall transmission ratio becomes slightly step-up because the system then encourages direct drive shortly before the discontinuity. This is achieved by choosing the ratio of the driving pinions slightly smaller than R/r. Unblocking in order to reposition the system in the starting position is achieved by a device which provides the small necessary amount of additional internal rotation. The next paragraph deals with the first and second derivatives of the radius of the gears with respect to the polar angle at the point lying on their pitch curve. The variation in radii of the gears may be uniform in order to generate a uniform variation in the reduction ratio, but may also be modulated as a function of their rotation in order to obtain different rates of variation of said ratio. That may be dependent on the input torque when such torque is variable. A bicycle bottom bracket assembly for example receives a different torque according to the position of the cranks, the torque being maximum when these are horizontal and practically zero at top dead center and bottom dead center. In this case, the reduction ratio decreases more quickly when the available torque is higher. The general shapes of the gears are still spirals, but on which there are local variations in radius. To improve the balance of the device it is possible to increase the number of wheels other than the input pinion by distributing them in a circle about the common input and output axis and offsetting the variable-radius gears longitudinally. That makes it possible also to increase the amount of torque that can be transmitted. The invention will be better understood in the light of the detailed description which will follow, with reference to the attached drawing in which the figures depict one particular embodiment of the invention. FIG. 1 depicts a view of the active part of the reduction gearset from the output side, operating in the clockwise direction. The small pinion 1 is the input pinion. It acts on the large pinion 2, in this example depicted with a reduction ratio of 3 and which is axially secured to a driving gear 3 which in turn drives a driven gear 4 symmetric with the gear 3 and having a pitch curve which is a portion of a logarithmic spiral the ends of which have been smoothed using arcs of a circle. The radii at the point of discontinuity are also in a ratio of 3 and the rule of the sum of the radii remaining constant and equal to the distance between centers for equal curved abscissa values from the ends is met. The gear 4 is the output gear. A circular plate 5 acts as a wheel carrier for the wheels 2 and 3 and can rotate only in the clockwise direction by virtue of a device which has not been depicted. The small input pinion 1, the wheel carrier plate 5 and the output gear 4 are not secured to the main axis. The large pinion 2 and the gear 3 are secured to the intermediate shaft guided freely by the plate 5. The position depicted in FIG. 1 corresponds to an intermediate position with a reduction ratio of 3×2=6. FIG. 2 depicts the position of the discontinuity corresponding both to the start of the start-up phase with a reduction ratio of 3×3=9 and to the final blocked position with a reduction ratio of 3×⅓=1.

20061023

20100803

20070222

61477.0

F16H3500

LEWIS, TISHA D

START-UP ASSISTANCE COAXIAL GEAR REDUCER WITH INCREASING RATIO UP TO DIRECT DRIVE

SMALL

ACCEPTED

F16H

ACCEPTED

Bone seperator

A bone spreader includes two tubular pin holders which are connected to one another by a parallel guide system, and two pins that are configured to be connected to the bone parts that are to be spread apart. In order to give the bone parts that are to be spread apart a more secure position in relation to one another, at least one of the pin holders is provided with a locking device for a pin located in the pin holder. This locking device includes a locking finger which is movable tangentially with respect to the pin holder and which, in the locking position, engages in a transverse groove of the associated pin and can be formed by a pivotably mounted hook.

1. A bone spreader for spreading bone parts apart, comprising two tubular pin holders which are connected to one another by a parallel guide system and are configured to receive two pins that are configured to be connected to the bone parts that are to be spread apart, and at least one pin holder having a locking device for a pin located therein thereon, wherein the pins have at least one transverse groove formed therein and the locking device comprises a locking finger which is guided between a locking position and a release position in a transverse movement tangentially with respect to the pin holder. 2. The bone spreader as claimed in claim 1, wherein the locking finger is in the form of a hook which is mounted at an open end of the pin holder closer to the parallel guide system and is pivotable about an axis extending approximately parallel to said pin holder.

FIELD AND BACKGROUND OF THE INVENTION The invention relates to a bone spreader for spreading bone parts apart including two parallel tubular pin holders, which are connected to one another by a parallel guide system, and two pins to be connected to the bone parts that are to be spread apart. In connection with the invention, this term also includes screws. The pins are introduced parallel to one another into the bone parts that are to be spread apart. Their free sections are introduced into the pin holders. When these are now moved away from one another or moved closer to one another by means of the parallel guide system, this movement is transmitted to the bone parts. This type of spreader is especially suitable for distraction of two cervical vertebral bodies for the purpose of implantation of a cervical intervertebral prosthesis, as the vertebral bodies are guided parallel to one another during the distraction. However, this parallel attribute applies only with respect to the direction of the pin holders. Two degrees of freedom remain. These are, on the one hand, a rotation of the bone parts about the pin axis, which for various reasons is of no consequence in normal circumstances, and, on the other hand, a displacement in the direction of the pin holders, which displacement can be prevented by a locking device. For this purpose, a first known design of this locking device, disclosed in WO03/024344, uses a friction clamp, which in many cases is not secure enough. A second known design, disclosed in U.S. Pat. No. 6,340,363, uses a clamping screw or some kind of clamp. A clamping screw, however, cannot be maneuvered, or may be maneuvered only with difficulty, deep within the operating site. The issue remains, furthermore, of how a clamp can be designed so that it is both secure and easy to operate. SUMMARY OF THE INVENTION According to the invention, this disadvantage is remedied by the fact that the locking device is designed in the form of a locking finger which is guided between a locking position and a release position in a transverse movement tangentially with respect to the pin holder and at least one transverse groove in the pin, into which groove the locking finger engages in the locking position. Several transverse grooves may also be provided, one of which is chosen for the engagement of the locking finger. To ensure that the locking finger cannot be lost as a separate part, according to a further feature of the invention, it is designed as a hook which is mounted so as to be pivotable about an axis extending approximately parallel to the pin holder. The arrangement is especially simple and clear if the hook is arranged at the open end of the pin holder closer to the parallel guide system. BRIEF DESCRIPTION OF THE DRAWINGS The invention is explained in more detail below with reference to the drawing which depicts an advantageous illustrative embodiment and in which: FIG. 1 shows an overall view of the spreader, and FIGS. 2 and 3 show partial views of the spreader in different stages of its operation. DETAILED DESCRIPTION OF THE INVENTION A first spreader body 2 is arranged rigidly at the end of a guide bar 1 of noncircular cross section. A second spreader body 3 with a guide tube 4 is arranged parallel to the spreader body 2 on the guide bar 1 and is displaceable in the longitudinal direction of said guide bar 1, but not rotatable. The displacement is effected using a toggle 5 which is connected to a pinion (not shown) engaging in a toothing 6 of the guide bar 1. In addition, any kind of locking means can be connected to the spreader body 3 or to the guide tube 4 so as to secure the distance between the spreader bodies 2 and 3. Arranged at the free ends of the spreader bodies 2 and 3 there are tubular pin holders 7 which are set at an angle in relation to the spreader bodies 2, 3. They extend parallel to one another in planes which are perpendicular to the guide bar. They are used for receiving two pins, each one of which is connected respectively to one of the two bones or fragments that are to be distracted. By operating the toggle 5, it is possible for these bone parts or fragments to be spread apart from one another or guided toward one another, in which process they are held parallel to one another in relation to the axes of the two pin holders 7. To this extent, the bone spreader can be regarded as being known. Whereas in known bone spreaders of this kind the hole inside the pin holder is closed at the rear end connected to the associated spreader body 2, 3, according to the invention, it is continued right through at this location, such that it opens out at 8. Adjacent to the opening 8, a hook plate 9 is mounted pivotably by way of a screw 10. It lies in a plane extending substantially perpendicular to the axis of the pin holder. It contains a hook cutout 11 which is outwardly delimited by a hook finger 12 whose direction extends tangentially with respect to the axis of the pin holder. The associated pins 13 have, at least at their rear end, one or more peripheral grooves 14 whose width (measured in the longitudinal direction of the pin) is slightly greater than the thickness of the plate 9 or hook finger 12. When a pin is located in the pin holder in such a way that its rear end protrudes outward at the rear, as is shown in FIG. 2, the plate 9 can be pivoted in such a way that the hook finger 12 engages in one of the grooves 14 and in this position, which is illustrated in FIG. 3, prevents the pin 13 from moving in its longitudinal direction. The hook finger 12 can be designed such that it locks in the closed position (FIGS. 1 and 3) so as not to inadvertently come loose from here under the action of slight forces. Instead of this, or in addition, the pivot bearing of the plate 9 can be provided with a spring or catch mechanism which satisfies this purpose. The invention has the effect that the pins received in the pin holders 7 can be secured in the pin holder by means of a rapid and simple movement by the operator. In this way, the secured bone parts are prevented from executing a relative movement in the direction of the pin holders.

<SOH> FIELD AND BACKGROUND OF THE INVENTION <EOH>The invention relates to a bone spreader for spreading bone parts apart including two parallel tubular pin holders, which are connected to one another by a parallel guide system, and two pins to be connected to the bone parts that are to be spread apart. In connection with the invention, this term also includes screws. The pins are introduced parallel to one another into the bone parts that are to be spread apart. Their free sections are introduced into the pin holders. When these are now moved away from one another or moved closer to one another by means of the parallel guide system, this movement is transmitted to the bone parts. This type of spreader is especially suitable for distraction of two cervical vertebral bodies for the purpose of implantation of a cervical intervertebral prosthesis, as the vertebral bodies are guided parallel to one another during the distraction. However, this parallel attribute applies only with respect to the direction of the pin holders. Two degrees of freedom remain. These are, on the one hand, a rotation of the bone parts about the pin axis, which for various reasons is of no consequence in normal circumstances, and, on the other hand, a displacement in the direction of the pin holders, which displacement can be prevented by a locking device. For this purpose, a first known design of this locking device, disclosed in WO03/024344, uses a friction clamp, which in many cases is not secure enough. A second known design, disclosed in U.S. Pat. No. 6,340,363, uses a clamping screw or some kind of clamp. A clamping screw, however, cannot be maneuvered, or may be maneuvered only with difficulty, deep within the operating site. The issue remains, furthermore, of how a clamp can be designed so that it is both secure and easy to operate.

<SOH> SUMMARY OF THE INVENTION <EOH>According to the invention, this disadvantage is remedied by the fact that the locking device is designed in the form of a locking finger which is guided between a locking position and a release position in a transverse movement tangentially with respect to the pin holder and at least one transverse groove in the pin, into which groove the locking finger engages in the locking position. Several transverse grooves may also be provided, one of which is chosen for the engagement of the locking finger. To ensure that the locking finger cannot be lost as a separate part, according to a further feature of the invention, it is designed as a hook which is mounted so as to be pivotable about an axis extending approximately parallel to the pin holder. The arrangement is especially simple and clear if the hook is arranged at the open end of the pin holder closer to the parallel guide system.

20060210

20110419

20061019

70965.0

A61B1758

COMSTOCK, DAVID C

BONE SEPARATOR

UNDISCOUNTED

ACCEPTED

A61B

ACCEPTED

Blade-pitch-angle control device and wind power generator

A blade-pitch-angle control device includes a memory unit in which predetermined parameters that affect the load fluctuation of blades, azimuth angles, and pitch-angle command values are stored in association with each other; an azimuth-angle detecting unit that detects the azimuth angle of each of the blades; a parameter-detecting unit that detects the predetermined parameters; a command-value receiving unit that receives pitch-angle command values for each of the blades from the memory unit, the pitch-angle command values being selected on the basis of the azimuth angle of each blade detected by the azimuth-angle detecting unit and the predetermined parameters detected by the parameter-detecting unit; and a pitch-angle-control command-value generating unit that generates pitch-angle-control command values for individually controlling the pitch-angle of each blade on the basis of the pitch-angle command values and a common-pitch-angle command value.

1. A blade-pitch-angle control device used for a wind power generator having a plurality of blades, the blade-pitch-angle control device comprising: a memory device in which predetermined parameters that affect the load fluctuation of the blades, azimuth angles, and pitch-angle command values are stored in association with each other; an azimuth-angle detecting device that detects the azimuth angle of each of the blades; a parameter-detecting device that detects the predetermined parameters; a command-value receiving device that receives the pitch-angle command values for each of the blades from the memory device, the pitch-angle command values being selected on the basis of the azimuth angle of each blade detected by the azimuth-angle detecting device and the predetermined parameters detected by the parameter-detecting device; and a pitch-angle-control command-value generating device that generates pitch-angle-control command values for individually controlling the pitch-angle of each blade on the basis of the pitch-angle command values received by the command-value receiving device and a common-pitch-angle command value that is common to each blade, the common-pitch-angle command value being determined by output information of the wind power generator. 2. The blade-pitch-angle control device according to claim 1, wherein the pitch-angle command values stored in the memory device are set to values in which the wind shear characteristics at the installation location of the wind power generator are reflected. 3. The blade-pitch-angle control device according to claim 1, wherein the predetermined parameters comprise the wind speed, and the parameter-detecting device is a wind-speed estimating device that includes a characteristic table relating the wind speed and an output of the wind power generator and that estimates the wind speed by reading out a wind speed corresponding to the output of the wind power generator from the characteristic table. 4. The blade-pitch-angle control device according to claim 1, further comprising: a frequency-component extraction device that extracts a frequency component corresponding to an integral multiple of the number of blades from any one of the power generation output of the wind power generator, the number of revolutions of the power generator, and the number of rotor revolutions; and a calculation device that calculates a pitch-angle for eliminating the load fluctuation due to the frequency fluctuation on the basis of the extracted frequency-component, wherein the pitch-angle-control command-value generating device causes the pitch-angle calculated by the calculation device to be reflected in the pitch-angle-control command value. 5. A wind power generator having a plurality of blades, comprising: a blade-pitch-angle control device including a memory device in which predetermined parameters that affect the load fluctuation of the blades, azimuth angles, and pitch-angle command values are stored in association with each other; an azimuth-angle detecting device that detects the azimuth angle of each of the blades; a parameter-detecting device that detects the predetermined parameters; a command-value receiving device that receives the pitch-angle command values for each of the blades from the memory device, the pitch-angle command values being selected on the basis of the azimuth angle of each blade detected by the azimuth-angle detecting device and the predetermined parameters detected by the parameter-detecting device; and a pitch-angle-control command-value generating device that generates pitch-angle-control command values for individually controlling the pitch-angle of each blade on the basis of the pitch-angle command values received by the command-value receiving device and a common-pitch-angle command value that is common to each blade, the common-pitch-angle command value being determined by output information of the wind power generator. 6. A blade-pitch-angle control device used for a wind power generator having a plurality of blades, the blade-pitch-angle control device comprising: load-measuring devices that measure a load applied to the blades or mechanical parts constituting a windmill at predetermined azimuth angles; an adjusting pitch-angle command-value generating device that generates an adjusting pitch-angle command value for each blade for reducing the load measured with each of the load-measuring devices; and a pitch-angle-control command-value generating device that generates a pitch-angle-control command-value for each blade by causing the adjusting pitch-angle command value generated for each blade to be reflected in a common-pitch-angle command value for equally controlling the blades. 7. A blade-pitch-angle control device used for a wind power generator having a plurality of blades, the blade-pitch-angle control device comprising: load-measuring devices that measure a load applied to the blades or mechanical parts constituting a windmill at predetermined azimuth angles; a calculation device that calculates a periodic fluctuation of the load on the basis of the measured values measured by the load-measuring devices; an adjusting pitch-angle command-value generating device that generates an adjusting pitch-angle command value for each blade for reducing a load fluctuation on the basis of the calculation results of the calculation device; and a pitch-angle-control command-value generating device that generates a pitch-angle-control command-value for each blade by causing the adjusting pitch-angle command value generated for each blade to be reflected in a common-pitch-angle command value for equally controlling the blades. 8. The blade-pitch-angle control device according to claim 6, wherein each of the load-measuring devices includes an azimuth-angle measuring device that measures the azimuth angle of each blade at predetermined time intervals, a trigger-generating device that generates a trigger signal when the measurement result matches a predetermined azimuth angle, and a measuring device that measures a load on the basis of the trigger signal. 9. The blade-pitch-angle control device according to claim 6, wherein each of the load-measuring devices includes an encoder that generates a trigger when the azimuth angle reaches a predetermined angle, and a measuring device that measures a load on the basis the trigger. 10. A wind power generator having a plurality of blades, comprising: a blade-pitch-angle control device including load-measuring devices that measure a load applied to the blades or mechanical parts constituting a windmill at predetermined azimuth angles; an adjusting pitch-angle command-value generating device that generates an adjusting pitch-angle command value for each blade for reducing the load measured with each of the load-measuring devices; and a pitch-angle-control command-value generating device that generates a pitch-angle-control command-value for each blade by causing the adjusting pitch-angle command values generated for each blade to be reflected in a common-pitch-angle command value for equally controlling the blades.

CROSS-REFERENCE TO RELATED APPLICATIONS The present application is based on International Application No. PCT/JP/2004/03144 filed on Sep. 9, 2004, which in turn corresponds to Japanese Application Number 2003-318312 filed Sep. 10, 2003 and Japanese Application Number 2004-143642 filed May 13, 2004, and priority is hereby claimed under 35 USC § 119 based on these applications. Each of these applications are hereby incorporated by reference in their entirety into the present application. TECHNICAL FIELD The present invention relates to a wind power generator, and in particular, to a blade-pitch-angle control device for controlling a blade-pitch-angle of a windmill. BACKGROUND ART As shown in a schematic view in FIG. 11, a known propeller windmill used in wind power generators includes, for example, three blades composed of a first blade 1, a second blade 2, and a third blade 3, a rotor 5 serving as a link mechanism for linking the three blades, a tower 4, and so on. In general, each of the blades of such a propeller windmill is controlled depending on the wind conditions so as to obtain a predetermined rotational speed and output of a power generator. FIG. 12 shows an example of the structure of a known pitch-angle control device. As shown in the figure, the known pitch-angle control device includes a common-pitch-angle command-value generating unit 15 for generating a common-pitch-angle command value on the basis of the difference between a preset value of a rotational speed or output of a power generator and a controlled value at that time. Actuators control each blade so as to have identical pitch-angles on the basis of the common-pitch-angle command value generated by the common-pitch-angle command-value generating unit 15, thus controlling the pitch-angle of the blades. The inflow wind speed to a windmill is affected by the ground, as shown in FIG. 13A (the wind speed characteristics affected by the ground are hereinafter referred to as “wind shear characteristics”), or by the tower supporting the windmill, as shown in FIG. 13B (the wind speed characteristics affected by the tower are hereinafter referred to as “tower characteristics”). Spatial disorder and temporal disorder of the wind speed are added to the effects described above, resulting in an uneven wind speed distribution in the blade rotation area, as shown in FIG. 13C. Under such uneven wind speed conditions, since the instantaneous values of the aerodynamic output from each of the blades are different from each other, the values of the thrust, the moment, and the like of the blades are also different from each other. As a result, a load fluctuation in each blade occurs, thereby shortening the lifetime of the blades. To overcome this problem, for example, PCT Japanese Translation Patent Publication No. 2001-511497 discloses a technology in which the angle of attack of wind flowing to each blade and the load are measured, and the blades are individually controlled on the basis of these values. PCT Japanese Translation Patent Publication No. 2001-511497. PCT Publication No. WO01/86141 pamphlet DISCLOSURE OF INVENTION In the invention disclosed in PCT Japanese Translation Patent Publication No. 2001-511497, the load applied to each part of a wind power generator, the angle of attack of wind flowing to the blades, and the like are instantaneously calculated on the basis of detected values from a plurality of sensors, and the pitch-angle is controlled so as to decrease the instantaneous load fluctuation. In order to effectively decrease the load fluctuation, a series of processes from detection by the sensors to feedback control must be performed substantially in real time. However, according to the above invention, since the instantaneous load is obtained by calculation based on each of the detected values, the process disadvantageously becomes complex and the instantaneous load cannot be rapidly obtained. Such an increase in the processing time also causes a delay in the feedback control and decreases the accuracy of the pitch-angle control. Furthermore, in the above invention, a plurality of wind power sensors and strain gauges must be provided for each of the blades. Since high reliability is required for these sensors, expensive sensors must be used, resulting in the problem of high cost. In addition, since the wind speed is measured with an anemometer disposed in the airflow behind the blades, the measurement is affected by wind speed fluctuations due to the rotation of the blades. Therefore, the wind speed cannot be accurately detected. The present invention has been made in order to solve the above problems, and it is an object of the present invention to provide a pitch-angle control device in which a load fluctuation generated in a wind power generator can be further decreased by improving the accuracy of pitch-angle control. In order to solve the above problems, the present invention provides the following solutions. The present invention provides a blade-pitch-angle control device used for a wind power generator having a plurality of blades, the blade-pitch-angle control device including a memory device in which predetermined parameters that affect the load fluctuation of the blades, azimuth angles, and pitch-angle command values are stored in association with each other; an azimuth-angle detecting device that detects the azimuth angle of each of the blades; a parameter-detecting device that detects the predetermined parameters; a command-value receiving device that receives the pitch-angle command values for each of the blades from the memory device, the pitch-angle command values being selected on the basis of the azimuth angle of each blade detected by the azimuth-angle detecting device and the predetermined parameters detected by the parameter-detecting device; and a pitch-angle-control command-value generating device that generates pitch-angle-control command values for individually controlling the pitch-angle of each blade on the basis of the pitch-angle command values received by the command-value receiving device and a common-pitch-angle command value that is common to each blade, the common-pitch-angle command value being determined by output information of the wind power generator. According to the present invention, the optimum pitch-angle command values which are related to various parameters affecting the load fluctuation of the blades are stored in advance in the memory device. Accordingly, during control, the command-value receiving device just reads out from the memory device the optimum pitch-angle command values selected based on the various parameters, thereby performing pitch-angle control that is optimum for the operational state of the windmill. Thus, since the optimum pitch-angle command values can be immediately obtained from various parameters without performing a process for calculating the load fluctuation of the blades or the like, the process can be simplified and rapidly performed. In this case, since the pitch angles can be controlled in real time, this device can immediately cope with dynamic changes of the operational state of the wind power generator and the load fluctuation can be further reduced. Consequently, the lifetime of each blade can be maintained for a long period and a stable power generation output can be achieved. The pitch-angle-control command-value generating device causes the optimum pitch-angle command values, which are received by the command-value receiving device and which are determined in consideration of the operational state of the windmill, to be reflected in the common-pitch-angle command value, which is generated for performing feedback control of the power generation output of the wind power generator and which is used as a common pitch-angle command value in each blade. Thus, the pitch-angle-control command-value generating unit generates pitch-angle-control command-values for controlling the blade pitch-angle of each blade. Accordingly, each blade can be controlled so as to have the optimum pitch-angle, considering the output fluctuation and the operational state of the wind power generator. In the above blade-pitch-angle control device, the pitch-angle command values stored in the memory device are preferably set to values in which the wind shear characteristics at the installation location of the wind power generator are reflected. Wind speed, air density, the output of the wind power generator, and the like are dynamically changed according to the conditions. In contrast, the wind shear is uniquely determined depending on the site conditions of the wind power generator. Thus, in the information stored in the memory device, not only parameters that dynamically change but also information such as the wind shear, which is uniquely determined depending on the site conditions, are considered. Therefore, the pitch-angle can be controlled with very high accuracy. In the above blade-pitch-angle control device, the predetermined parameters may include the wind speed, and the parameter-detecting device is preferably a wind-speed estimating device that includes a characteristic table relating the wind speed and an output of the wind power generator and that estimates the wind speed by reading out a wind speed corresponding to the output of the wind power generator from the characteristic table. The wind speed is one of the important parameters required for selecting the pitch-angle command values. Whether load fluctuation and output fluctuation can be precisely reduced or not significantly depends on the detection accuracy of the wind speed, and therefore, the wind speed must be detected with high accuracy. However, in the conventional method in which the wind speed is measured with an anemometer disposed in the airflow behind a windmill, the measurement is directly affected by wind speed fluctuations due to the rotation of the blades. Consequently, the wind speed cannot be accurately measured. According to the present invention, the wind speed is measured not physically by the wind-speed detecting device but by a simple process in software on the basis of the output of the wind power generator, which has a close relationship with the wind speed. Thereby, highly accurate wind speed can be obtained, and in addition, the cost can be reduced. Instead of such wind-speed estimating device, an anemometer (such as a laser Doppler anemometer) that measures the wind speed before the wind flows to the windmill may be used. Since this configuration is not affected by the airflow behind the blades, highly accurate wind speed can be obtained. When the laser Doppler anemometer is used, a device for supplying tracer particles from upstream of the windmill toward the windmill is provided. Alternatively, dust or water vapor mixed in air that flows to the windmill may be used as a tracer to obtain scattered light from the dust or the water vapor, and thus laser Doppler measurement may be performed. In this case, the device for supplying tracer particles need not be separately provided. The above blade-pitch-angle control device preferably includes a frequency-component extraction device that extracts a frequency component corresponding to an integral multiple of the number of blades from any one of the power generation output of the wind power generator, the number of revolutions of the power generator, and the number of rotor revolutions; and a calculation device that calculates a pitch-angle for eliminating the load fluctuation due to the frequency fluctuation on the basis of the extracted frequency-component, wherein the pitch-angle-control command-value generating device preferably causes the pitch-angle calculated by the calculation device to be reflected in the pitch-angle-control command value. Even when pitch-angle control values are determined in consideration of fluctuations of various parameters such as the wind speed, it is difficult to completely eliminate the load fluctuation and the fluctuation of power generation output because of an error or a time-lag due to feedback control. On the other hand, it is known that the frequency band in which the output fluctuation significantly occurs depends on the number of blades. Accordingly, a pitch-angle for eliminating such a significant output fluctuation is determined and the resulting pitch-angle is reflected in the blade-pitch-angle-control command value, thereby further decreasing the output fluctuation. That is, in a wind power generator using a constant-speed windmill, the frequency-component extraction device extracts a frequency component corresponding to an integral multiple of the number of blades from the output of the wind power generator. On the other hand, in a wind power generator using a variable-speed windmill, the frequency-component extraction device extracts a frequency component corresponding to an integral multiple of the number of blades from the number of revolutions of the power generator or the number of rotor revolutions. For example, the calculation device calculates the frequency component extracted by the frequency-component extraction device on the basis of a predetermined algorithm to calculate fluctuating pitch-angles in the frequency domain. Furthermore, the calculation device performs an inverse frequency analysis using the fluctuating pitch-angles to obtain fluctuating pitch-angles in the time domain. The fluctuating pitch-angles thus obtained serve as pitch-angles for eliminating a significant load fluctuation. The pitch-angle-control command-value generating device causes the pitch-angles for canceling out the significant output fluctuation to be reflected in the pitch-angle-control command values. Thus, the fluctuation of power generation output that significantly occurs can be eliminated at a single point and more stable power generation output can be achieved. The present invention provides a wind power generator having a plurality of blades, the wind power generator including a blade-pitch-angle control device including a memory device in which predetermined parameters that affect the load fluctuation of the blades, azimuth angles, and pitch-angle command values are stored in association with each other; an azimuth-angle detecting device that detects the azimuth angle of each of the blades; a parameter-detecting device that detects the predetermined parameters; a command-value receiving device that receives the pitch-angle command values for each of the blades from the memory device, the pitch-angle command values being selected on the basis of the azimuth angle of each blade detected by the azimuth-angle detecting device and the predetermined parameters detected by the parameter-detecting device; and a pitch-angle-control command-value generating device that generates pitch-angle-control command values for individually controlling the pitch-angle of each blade on the basis of the pitch-angle command values received by the command-value receiving device and a common-pitch-angle command value that is common to each blade, the common-pitch-angle command value being determined by output information of the wind power generator. The present invention provides a blade-pitch-angle control device used for a wind power generator having a plurality of blades, the blade-pitch-angle control device including load-measuring devices that measure a load applied to the blades or mechanical parts constituting a windmill at predetermined azimuth angles; an adjusting pitch-angle command-value generating device that generates an adjusting pitch-angle command value for each blade for reducing the load measured with each of the load-measuring devices; and a pitch-angle-control command-value generating device that generates a pitch-angle-control command-value for each blade by causing the adjusting pitch-angle command value generated for each blade to be reflected in a common-pitch-angle command value for equally controlling the blades. Since the load-measuring devices measure the load not at predetermined time intervals but at predetermined azimuth-angles, the load-measuring devices can be applied not only to constant-speed windmills but also to variable-speed windmills in which the rotational speed of the blades changes depending on the operational state. For example, the adjusting pitch-angle command-value generating device calculates the optimum pitch-angle for each blade for reducing the load measured by each of the load-measuring devices to generate adjusting pitch-angle command-values. The pitch-angle-control command-value generating device causes these adjusting pitch-angle command-values to be reflected in the pitch-angle-control command-values for controlling the pitch angles of the blades. Thereby, the load fluctuation can be decreased. The present invention provides a blade-pitch-angle control device used for a wind power generator having a plurality of blades, the blade-pitch-angle control device including load-measuring devices that measure a load applied to the blades or mechanical parts constituting a windmill at predetermined azimuth angles; a calculation device that calculates a periodic fluctuation of the load on the basis of the measured values measured by the load-measuring devices; an adjusting pitch-angle command-value generating device that generates an adjusting pitch-angle command value for each blade for reducing a load fluctuation on the basis of the calculation results of the calculation device; and a pitch-angle-control command-value generating device that generates a pitch-angle-control command-value for each blade by causing the adjusting pitch-angle command value generated for each blade to be reflected in a common-pitch-angle command value for equally controlling the blades. The present inventors focus on the fact that a significant load fluctuation of the blades periodically occurs. Consequently, the load-measuring devices and the calculation device are provided as devices that detect the load fluctuation during one revolution of a rotor. The load-measuring devices measure a load applied to each of the blades at predetermined azimuth angles. Thus, since the load is measured not at predetermined time intervals but at predetermined azimuth-angles, the load-measuring devices can be applied to variable-speed windmills in which the rotational speed of the blades changes. The calculation device obtains measured values measured with the load-measuring devices at each azimuth angle, the measured values corresponding to a predetermined period (for example, corresponding to one revolution), and determines the characteristics of the load on the basis of the measured values. Thus, information on the load fluctuation in each blade can be obtained. The adjusting pitch-angle command-value generating device calculates the adjusting pitch-angle command values for eliminating the load fluctuation, and the pitch-angle-control command-value generating device causes these adjusting pitch-angle command values to be reflected in the control of the pitch angle of each blade. Thereby, the significant load fluctuation that periodically occurs can be reduced. Thus, since the load fluctuation is decreased by focusing on the load fluctuation that periodically occurs, the load fluctuation can be efficiently decreased by a process much simpler than the conventional pitch-angle control that decreases instantaneous load fluctuations. Consequently, each blade can be controlled so as to have the optimum pitch-angle, and the lifetime of the blades and mechanical parts constituting the windmill can be extended. In the present invention, since measured values corresponding to at least one cycle are obtained and feedback control based on these measured values is then performed, a time-lag occurs. However, the load fluctuation that is focused on by the present invention periodically occurs at substantially the same azimuth angle. Therefore, even when the time-lag due to the feedback control occurs, the load fluctuation can be eliminated with high accuracy. In the above blade-pitch-angle control device, each of the load-measuring devices preferably includes an azimuth-angle measuring device that measures the azimuth angle of each blade at predetermined time intervals, a trigger-generating device that generates a trigger signal when the measurement result matches a predetermined azimuth angle, and a measuring device that measures a load on the basis of the trigger signal. Thus, since the load-measuring devices include generally well known mechanisms, the load-measuring devices can be achieved simply and at low cost. Examples of the measuring device include a strain gauge, a load cell, and an optical fiber sensor. In the above blade-pitch-angle control device, each of the load-measuring devices preferably includes an encoder that generates a trigger when the azimuth angle reaches a predetermined angle and a measuring device that measures a load on the basis the trigger. The encoder and the measuring device are generally well known mechanisms. Thus, since the load-measuring devices include generally well known mechanisms, the load-measuring devices can be achieved simply and at low cost. Examples of the measuring device include a strain gauge, a load cell, and an optical fiber sensor. The present invention provides a blade-pitch-angle control device used for a wind power generator having a plurality of blades, the blade-pitch-angle control device including an acceleration-measuring device that measures the acceleration applied to the blades or mechanical parts constituting a windmill at predetermined azimuth angles; an adjusting pitch-angle command-value generating device that generates an adjusting pitch-angle command value for each blade for reducing the acceleration measured with the acceleration-measuring device; and a pitch-angle-control command-value generating device that generates a pitch-angle-control command-value for each blade by causing the adjusting pitch-angle command value generated for each blade to be reflected in a common-pitch-angle command-value for equally controlling the blades. The adjusting pitch-angle command-value generating device, for example, calculates the optimum pitch-angle for each blade for reducing the acceleration measured with the acceleration-measuring device and generates adjusting pitch-angle command values. The pitch-angle-control command-value generating device causes these adjusting pitch-angle command values to be reflected in the pitch-angle-control command values that control the pitch-angles of the blades, thereby reducing the acceleration. Since the acceleration and the load fluctuation are correlated, a decrease in the acceleration can also decrease the load fluctuation. The present invention provides a wind power generator having a plurality of blades, the wind power generator including a blade-pitch-angle control device including load-measuring devices that measure a load applied to the blades or mechanical parts constituting a windmill at predetermined azimuth angles; an adjusting pitch-angle command-value generating device that generates an adjusting pitch-angle command value for each blade for reducing the load measured with each of the load-measuring devices; and a pitch-angle-control command-value generating device that generates a pitch-angle-control command-value for each blade by causing the adjusting pitch-angle command values generated for each blade to be reflected in a common-pitch-angle command value for equally controlling the blades. Since the wind power generator includes such a blade-pitch-angle control device, each blade can be controlled so as to have the optimum pitch-angle and a wind power generator including long-life blades and mechanical parts constituting a windmill can be realized. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 a block diagram showing the structure of a blade-pitch-angle control device according to a first embodiment of the present invention. FIG. 2 a view illustrating an azimuth angle. FIG. 3 a graph showing an example of a characteristic table relating wind speed and output of a wind power generator. FIG. 4 a graph showing an example of a characteristic table under steady wind conditions (having a temporally constant and two-dimensionally uniform wind speed). FIG. 5 a graph showing an example of a characteristic table including a waveform of a pitch-angle correction value for canceling out the effect of a tilt angle on the wind when the wind speed is varied and a waveform in which the correction value is reflected. FIG. 6 a graph showing an example of a characteristic table including a waveform of a pitch-angle correction value for canceling out the effect of a deviation of wind direction when the wind speed is varied and a waveform in which the correction value is reflected. FIG. 7 a graph showing an example of a characteristic table when air density is used as a variable. FIG. 8 a graph showing an example of a characteristic table when the output of the wind power generator is used as a variable. FIG. 9 a diagram showing the structure of an output-fluctuation eliminating device that is employed when a constant-speed windmill is used. FIG. 10 a block diagram showing the structure of a blade-pitch-angle control device according to a second embodiment of the present invention. FIG. 11 a schematic view of a propeller windmill used in a wind power generator. FIG. 12 a block diagram showing an example of the structure of a blade-pitch-angle control device according to a known art. FIG. 13 views illustrating wind shear characteristics, tower shadow characteristics, and wind speed distribution. BEST MODE FOR CARRYING OUT THE INVENTION Embodiments according to the present invention will now be described with reference to the drawings in the order of a first embodiment and a second embodiment. First Embodiment FIG. 1 is a block diagram showing the structure of a blade-pitch-angle control device that is applied to a wind power generator using a constant-speed windmill. As shown in FIG. 1, the blade-pitch-angle control device according to this embodiment includes a memory unit (memory device) 10, an azimuth-angle detecting unit (azimuth-angle detecting device) 11, a parameter-detecting unit (parameter-detecting device) 12, a command-value receiving unit (command-value receiving device) 13, a pitch-angle-control command-value generating unit (pitch-angle-control command-value generating device) 14, and a common-pitch-angle command-value generating unit (common-pitch-angle command-value generating device) 15. In the memory unit 10, predetermined parameters that affect the load fluctuation of blades, for example, wind speed, temperature, and output of the wind power generator; azimuth angles; and pitch-angle command values are stored in association with each other. As shown in FIG. 2, the azimuth angle represents an angle formed relative to the vertical direction of the windmill. The azimuth angle when a blade is located at the top of the windmill is defined as 0°, and the azimuth angle when the blade is located at the bottom of the windmill is defined as 180°. The detailed contents stored in the memory unit 10 are described below. The azimuth-angle detecting unit 11 detects the azimuth angle of each blade at predetermined intervals and outputs it to the command-value receiving unit 13. For example, the azimuth angle can be determined from an output of a rotary encoder provided on a rotation axis. The parameter-detecting unit 12 includes a wind-speed detecting unit (wind-speed detecting device) 121 that detects wind speed, an air-density detecting unit 122 that detects air density, and a wind-power-generator-output detecting unit 123 that detects the output of the wind power generator. The wind-speed detecting unit 121 includes a characteristic table (refer to FIG. 3) in which wind speed is related with the output of the wind power generator. The wind-speed detecting unit 121 receives the output of the wind power generator from the wind-power-generator-output detecting unit 123 at predetermined intervals. A wind speed corresponding to the output is read out from the characteristic table to estimate the wind speed. The estimated wind speed is output to the command-value receiving unit 13. Instead of such a method of estimating the wind speed, an anemometer (such as a laser Doppler anemometer) that measures the wind speed before the wind flows to the windmill may be used. Since this configuration is not affected by the airflow behind the blades, highly accurate wind speed can be obtained. When the laser Doppler anemometer is used, a device for supplying tracer particles from upstream of the windmill toward the windmill is provided. Alternatively, dust or water vapor mixed in air that flows to the windmill may be used as a tracer to obtain scattered light from the dust or the water vapor, and thus laser Doppler measurement may be performed. In this case, the device for supplying tracer particles need not be separately provided. The air-density detecting unit 122 measures air temperature and air pressure at predetermined intervals, and determines the air density from the measured values on the basis of the characteristics of the air density, the air temperature, and the air pressure. The air density can be uniquely determined by the air temperature and the air pressure. For example, the air-density detecting unit 122 has a map in which air temperature, air pressure, and air density are related with each other in advance. An air density selected by measured values of air temperature and air pressure is obtained from the map, thus determining the air density. Alternatively, the air-density detecting unit 122 may have a relational expression including air temperature, air pressure, and air density. The air density may be calculated by substituting measured values of air temperature and air pressure in the relational expression. The command-value receiving unit 13 receives pitch-angle command values from the memory unit 10. The pitch-angle command values are selected on the basis of azimuth angles of the blades input from the azimuth-angle detecting unit 11 and various parameters (such as wind speed, air density, and power generation output) input from the parameter-detecting unit 12. The command-value receiving unit 13 outputs the pitch-angle command values of the blades, i.e., a first-blade-pitch-angle command value, a second-blade-pitch-angle command value, and a third-blade-pitch-angle command value, to the pitch-angle-control command-value generating unit 14. The common-pitch-angle command-value generating unit 15 calculates a common-pitch-angle command value for commonly controlling pitch-angles of the three blades, i.e., the first blade to the third blade, from the difference between the preset values of the number of revolutions of the power generator (information on power generation output) or the power generation output (information on power generation output) and the controlled value at that time so that the power generation output of the wind power generator corresponds with the rated output (preset value), and outputs the common-pitch-angle command value to the pitch-angle-control command-value generating unit 14. For example, the common-pitch-angle command-value generating unit 15 is composed of a known PID control system. The pitch-angle-control command-value generating unit 14 generates pitch-angle-control command values for individually controlling the pitch-angles of the blades on the basis of the pitch-angle command value for each blade input from the command-value receiving unit 13 and the common-pitch-angle command value input from the common-pitch-angle command-value generating unit 15. Specifically, the pitch-angle-control command value for each blade is generated by adding each of the pitch-angle command values to the common-pitch-angle command value. Subsequently, the pitch-angle-control command-value generating unit 14 outputs the pitch-angle-control command values that are individually obtained for each of the blades to actuators, which are devices for controlling the pitch-angles of the blades. The actuator is a known mechanism such as a hydraulic cylinder or an electric motor that is installed in each blade. The content stored in the memory unit 10 will now be described in detail. First, wind speed, air density, output of the wind power generator, and the like are used as parameters and various values are set for these parameters. Thus, the optimum pitch-angle in various test patterns is determined by a computer simulation. For example, as a test pattern, the wind speed is set to A (m/s), the air density is set to B (g/cm3), and the power generation output is set to C (kW). Data about the fluctuating load when the pitch-angle is varied under these conditions is collected. Subsequently, the resulting data is checked to select a pitch-angle that provides the minimum fluctuating load. A characteristic table relating the selected pitch-angle and the azimuth angle is prepared. The above operation is repeated while values of the parameters (wind speed A (m/s), air density B (g/m3), and power generation output C (kW)) are varied to prepare characteristic tables for various conditions. These characteristic tables are related with the preset values of each of the parameters (preset values of wind speed, air density, power generation output, and the like) in the test patterns and written in the memory unit 10. Thus, by determining values of the parameters, a pitch-angle that is the most suitable for the conditions can be obtained. In the above simulation, more appropriate pitch-angle can be obtained by setting the wind shear characteristics and the tower shadow characteristics (refer to FIGS. 13A and 13B) as fixed values in advance. For example, the above-described parameters, such as wind speed, dynamically change depending on the conditions. On the other hand, the wind shear characteristics and the tower shadow characteristics are uniquely determined depending on the location of the windmill or the windmill structure. By performing the simulation in consideration of these characteristics, the optimum pitch-angle for the windmill can be obtained. Consequently, more accurate control of the blade-pitch-angles can be performed. The characteristic table will now be described more specifically by way of an example. First, FIG. 4 shows a characteristic table under steady wind conditions (having a temporally constant and two-dimensionally uniform wind speed). As shown in the figure, the characteristic table includes an abscissa indicating the azimuth angle (deg) and an ordinate indicating the pitch-angle (deg). The characteristic table shows a cosine wave in which the maximum pitch-angle (for example, 1°) is located at an azimuth angle of 0° and the minimum pitch-angle (for example, −1°) is located at an azimuth angle of 180°. The angles in the figure represent relative values. This indicates the following: At an azimuth angle of 0°, where the wind speed at the blade becomes the maximum, the pitch-angle must be increased to decrease the aerodynamic performance. On the other hand, at an azimuth angle of 180°, where the wind speed at the blade becomes the minimum, the pitch-angle must be decreased to improve the aerodynamic performance. Characteristic tables under various conditions obtained by the above simulation also have a fundamental shape substantially the same as that of the characteristic table shown in FIG. 4, but have different amplitude and phase. For example, when the air density and the power generation output of the wind power generator are set as fixed values and only the wind speed is varied, as the wind speed increases, the effect of the load fluctuation of the blade increases (the load is proportional to the square of the wind speed). Accordingly, when the wind speed is varied, as the wind speed increases, the amplitude of the cosine wave shown in FIG. 4 also increases. A blade of the windmill basically forms an upward angle, expressed as a “tilt angle” (generally about 5°), so that a clearance is provided for preventing the blade from hitting the tower. Because of the effect of this tilt angle, the wind flowing to the windmill generally blows upward. Under low wind speed conditions, the above effect of the wind speed itself is small and need not be considered. However, an increase in the wind speed increases the effect of the tilt angle. A pitch-angle correction value for canceling out the effect of the tilt angle on the wind exhibits the characteristics shown in FIG. 5. In FIG. 5, line A shows a waveform of the fundamental pitch-angle shown in FIG. 4, line B shows a waveform of the correction value for canceling out the effect of the tilt angle, and line C shows a waveform of a pitch-angle command value obtained by adding the correction value of line B to the waveform of line A. Thus, the characteristic table obtained when the wind speed is increased in the simulation is a characteristic table in which the upward-blowing wind due to the tilt angle is considered, and has characteristics different from those shown in FIG. 4, not only in terms of the amplitude but also in terms of the phase. The wind direction also affects the load fluctuation of the blade. For example, when an observer stands facing the windward side at the position of the windmill and the wind flows from the left side, the effect of the wind received increases at an azimuth angle of 0° and the effect of the wind received decreases at an azimuth angle of 180°. Accordingly, a pitch-angle correction value for canceling out the effect of a deviation in wind direction exhibits the characteristics shown in FIG. 6. In FIG. 6, line A shows a waveform of the fundamental pitch-angle shown in FIG. 4, line B shows a waveform of the correction value for canceling out the effect of the deviation in wind direction, and line C shows a waveform of a pitch-angle command value obtained by adding the correction value of line B to the waveform of line A. Thus, the characteristic table obtained when the wind direction is varied in the simulation is a characteristic table in which the amplitude of the fundamental pitch-angle shown in FIG. 4 changes in the vertical direction. Next, when the wind speed and the power generation output of the wind power generator are set as fixed values and only the air density is varied, as the air density increases, the effect of the load fluctuation of the blade increases. Accordingly, in the case where the air density is varied in the simulation, as the air density increases, a characteristic table having an amplitude larger than the amplitude of the characteristic shown in FIG. 4 is obtained. FIG. 7 shows a characteristic table when the air density is used as a variable. In FIG. 7, line A shows a waveform of the pitch-angle command value when the air density is high, and line B shows a waveform of the pitch-angle command value when the air density is low. Next, when the wind speed and the air density are set as fixed values and only the output of the wind power generator is varied, and the output is higher than the preset value (required output), a large aerodynamic force is applied to the blade, and furthermore, a large fluctuating aerodynamic force load is applied, compared with the case where the operation is performed with the required output. Accordingly, in the case where the output is higher than the required output, a characteristic table having an amplitude larger than the amplitude of the fundamental pitch-angle shown in FIG. 4 is obtained. FIG. 8 shows a characteristic table when the output of the wind power generator is used as a variable. In FIG. 8, line A shows a waveform of the pitch-angle command value when the output is high, and line B shows a waveform of the pitch-angle command value when the output is low. The operation of the blade-pitch-angle control device according to the above-described embodiment will now be described. First, when the command-value receiving unit 13 receives an azimuth angle from the azimuth-angle detecting unit 11 and receives the wind speed, air density, and power generator output from the parameter-detecting unit 12, the command-value receiving unit 13 then receives a characteristic table from the memory unit 10, the characteristic table being selected based on the wind speed, the air density, and the power generator output. Subsequently, in the characteristic table received, pitch-angle command values corresponding to the azimuth angle of each blade input from the azimuth-angle detecting unit 11 are received. Thus, pitch-angle command values corresponding to each of the first blade, the second blade, and the third blade can be obtained. The command-value receiving unit 13 outputs these pitch-angle command values thus obtained to the pitch-angle-control command-value generating unit 14. The pitch-angle-control command-value generating unit 14 generates pitch-angle-control command values for each of the blades by adding the pitch-angle command values input from the command-value receiving unit 13 to the common-pitch-angle command value based on the power generation output of the wind power generator, the common-pitch-angle command value being input from the common-pitch-angle command-value generating unit 15. The pitch-angle-control command-value generating unit 14 outputs these pitch-angle-control command values to the respective actuators provided on the corresponding blades. Thus, the pitch-angle of each blade is controlled so as to be the most suitable angle for the operational state of the wind power generator at that time. When the memory unit 10 does not store a characteristic table that completely corresponds with parameter values input from the parameter-detecting unit 12, a characteristic table that most closely approximates the parameter values may be selected. Alternatively, a plurality of approximate characteristic tables may be read out and these characteristic tables may be interpolated to determine the pitch-angle command values. A blade-pitch-angle control device that is applied to a wind power generator using a constant-speed windmill has been described, but the blade-pitch-angle control device of the present invention can also be applied to a wind power generator using a variable-speed windmill. A blade-pitch-angle control device that is applied to a wind power generator using a variable-speed windmill will now be described. When a variable-speed windmill is used, the number of rotor revolutions is controlled according to the output of the wind power generator. The load fluctuation of each blade is also changed by varying the rotational speed (the number of revolutions). Therefore, when such a variable-speed windmill is used, the number of rotor revolutions must also be considered as a parameter. Specifically, with the configuration of the blade-pitch-angle control device shown in FIG. 1, the number of rotor revolutions is added as a parameter input to the command-value receiving unit 13, and the memory unit 10 stores characteristic tables in which the number of rotor revolutions is also considered. The command-value receiving unit 13 receives a characteristic table from the memory unit 10, the characteristic table being selected by the wind speed, the air density, the power generator output, and the number of rotor revolutions that are input. In the characteristic table received, pitch-angle command values corresponding to the azimuth angle of each blade input from the azimuth-angle detecting unit 11 are received. Each of the pitch-angle command values is then output to the pitch-angle-control command-value generating unit 14. The subsequent processes are the same as those of the first embodiment described above. Although the above-described blade-pitch-angle control device can significantly reduce the load fluctuation generated in the blades, the device still generates not insignificant output fluctuation. It is known that the frequency band in which such an output fluctuation significantly occurs depends on the number of blades. Accordingly, a pitch-angle for eliminating such a significant output fluctuation is determined and the resulting pitch-angle is reflected in the blade-pitch-angle-control command value, thereby further decreasing the output fluctuation. In this embodiment, an output-fluctuation eliminating device having the following function is added to the blade-pitch-angle control device shown in FIG. 1. FIG. 9 shows the structure of the output-fluctuation eliminating device that is employed when a constant-speed windmill is used. As shown in FIG. 9, the output-fluctuation eliminating device includes a frequency analysis unit (frequency-component extraction device) 21, a control algorithm (calculation device) 22, an inverse frequency analysis unit (calculation device) 23, and a calculation unit 24. The frequency analysis unit 21 extracts a frequency component corresponding to an integral multiple of the number of blades from the output of the wind power generator and outputs the extracted frequency component. For example, when a windmill including three blades is used, a 3N component (N=integer) is extracted. The control algorithm 22 obtains the frequency component output from the frequency analysis unit 21 and the azimuth angle detected by the azimuth-angle detecting unit 11 shown in FIG. 1 as input information. The control algorithm 22 calculates the information on the basis of a predetermined algorithm to calculate a fluctuating pitch-angle Δθ(ω) in the frequency domain, and outputs the fluctuating pitch-angle Δθ(ω). The inverse frequency analysis unit 23 obtains the fluctuating pitch-angle Δθ(ω) calculated by the control algorithm 22 as input information, calculates a fluctuating pitch-angle Δθ(t) in the time domain by performing an inverse frequency analysis, and outputs the fluctuating pitch-angle Δθ(t). The calculation unit 24 obtains the fluctuating pitch-angle Δθ(t) in the time domain calculated by the inverse frequency analysis unit 23 and the common-pitch-angle command value output from the common-pitch-angle command-value generating unit 15 (refer to FIG. 1) as input information, adds these values so as to finely adjust the common-pitch-angle command value, and outputs the finely adjusted common-pitch-angle command value to the pitch-angle-control command-value generating unit 14 (refer to FIG. 1). As described above, the frequency analysis unit 21 extracts a frequency component that significantly affects the load fluctuation of each blade from the output of the wind power generator. The control algorithm 22 and the inverse frequency analysis unit 23 calculate a pitch-angle at which such a frequency component is eliminated. The calculation unit 24 reflects the fluctuating pitch-angle output from the inverse frequency analysis unit 23 in the common-pitch-angle command value. Thereby, only the significant output fluctuation can be eliminated at a single point and a stable power generation output can be maintained. When a variable-speed windmill is used, in the output-fluctuation eliminating device in FIG. 9, the number of rotor revolutions is input as an input signal. In other words, since the output is controlled by the number of rotor revolutions in the variable-speed windmill, the fluctuating pitch-angle Δθ(t) is calculated by performing a frequency analysis of the number of rotor revolutions instead of the output. Thus, the blade-pitch-angles can be controlled more precisely even in variable-speed windmills. The blade-pitch-angle control device according to the first embodiment of the present invention has been described in detail with reference to the drawings. The specific structure is not limited to this embodiment, however, and may also include design changes and the like within the spirit and the scope of the present invention. For example, the various parameters are not limited to the above-described wind speed, air density, output of the wind power generator, and rotor speed (the number of revolutions), but may include any parameter that affects the output and the like during wind power generation. Among these parameters, a pitch-angle obtained by considering fluctuations of all the parameters may be used. Alternatively, a pitch-angle obtained by considering some of the parameters (for example, only wind speed) may be controlled. Furthermore, the parameters are not limited to those that are synchronously detected. For example, the wind speed and the azimuth angle may be detected at predetermined intervals, and the air density and the like, whose temporal change is small, may be detected at time intervals longer than those used for the wind speed and the azimuth angle. Second Embodiment A blade-pitch-angle control device according to a second embodiment of the present invention will now be described. FIG. 10 is a block diagram showing the structure of a blade-pitch-angle control device that is applied to a wind power generator used in a variable-speed windmill. As shown in FIG. 10, the blade-pitch-angle control device according to the present embodiment includes load-measuring units (load-measuring devices) 30, a frequency analysis unit (calculation device) 31, an adjusting pitch-angle generating unit (adjusting pitch-angle command-value generating device) 32, a pitch-angle-control command-value generating unit (pitch-angle-control command-value generating device) 36, and a common-pitch-angle command-value generating unit 15. Each of the load-measuring units 30 measures a load applied to a corresponding blade at predetermined azimuth angles (for example, every 6°), and outputs the measurement results as an electrical signal. The load-measuring unit 30 includes, for example, an azimuth-angle measuring instrument (azimuth-angle measuring device), a trigger-generating circuit (trigger-generating device), and a sensor (measuring device). The azimuth-angle measuring instrument measures the azimuth angles of each blade at predetermined time intervals. The trigger-generating circuit generates a trigger signal when the measurement result of the azimuth-angle measuring instrument matches a predetermined azimuth angle (for example, an angle that is a multiple of 6°). The sensor measures the load on the basis of the trigger signal of the trigger-generating circuit. Examples of the sensor for measuring the load include a strain gauge, a load cell, and an optical fiber sensor that are installed in the blade base portion or a part of the windmill. The frequency analysis unit 31 obtains measured values (loads) measured at predetermined azimuth angles as input signals from the load-measuring units 30, and calculates a periodic fluctuation of the load applied to each blade on the basis of the measured values. Specifically, when measured values corresponding to one revolution are obtained, azimuth-angle characteristics of the load are calculated using the following computational expressions (1.1) and (1.2). The azimuth-angle characteristics can be expressed by a cosine component Zic and a sine component Zis of the load. { Z ic } n = 2 K ⁢ ∑ k = 1 K ⁢ zi ⁡ ( nk ⁢ ⁢ Δψ ) ⁢ cos ⁡ ( nk ⁢ ⁢ Δ ⁢ ⁢ ψ ) ( 1.1 ) { Z is } n = 2 K ⁢ ∑ k = 1 K ⁢ zi ⁡ ( nk ⁢ ⁢ Δ ⁢ ⁢ ψ ) ⁢ sin ⁡ ( nk ⁢ ⁢ Δ ⁢ ⁢ ψ ) ( 1.2 ) In expressions (1.1) and (1.2), symbol i represents the blade number. When a wind power generator includes three blades, i=1, 2, or 3. Symbol n represents an integer that is varied according to the cycle of the load fluctuation to be considered. When n=3, it means that the fluctuating load is considered three times during one revolution of a rotor. Symbol K represents the number of measurements in the azimuth angle range from 0° to 360°. For example, “K=12” means that the load is measured 12 times while the rotor 5 rotates once. Symbol Δψ represents a value obtained by dividing 360° by K. Symbol zi(nkΔψ) represents a load value measured at each azimuth angle, which is an input signal from the load-measuring unit 30. Subsequently, the adjusting pitch-angle command-value generating unit 32 obtains the analysis results of the frequency analysis unit 31 as input information, and generates an adjusting pitch-angle command value for reducing the load fluctuation for each blade on the basis of the analysis results. The adjusting pitch-angle command-value generating unit 32 includes an adjusting command-value calculation unit 33 and an inverse frequency analysis unit 34. The adjusting command-value calculation unit 33 obtains the cosine components Zic and the sine components Zis of the load fluctuation, which are calculated by the frequency analysis unit 31, as input signals, and calculates the input signals Zic and Zis using a predetermined transfer function. Thereby, an adjusting command value θdem for eliminating a significant load fluctuation that periodically occurs is calculated for each blade. The adjusting command values θ1dem, θ2dem, and θ3dem that are calculated here are values in the frequency domain. An example of a method for determining the transfer function used in the adjusting command-value calculation unit 33 is a method in which a simulation is performed while various load fluctuations are assumed, the optimum adjusting command values are obtained by analyzing the simulation results, and a transfer function is determined from the results. Alternatively, a plurality of transfer functions may be defined according to the operational state of the windmill. The optimum transfer function may be selected according to the operational state of the windmill and used. Thus, more suitable adjusting command values can be determined. Subsequently, the inverse frequency analysis unit 34 converts the adjusting command values θ1dem, θ2dem, and θ3dem, which are calculated by the adjusting command-value calculation unit 33 and which are values in the frequency domain, into values in the time domain. In other words, originally, these adjusting command values are values calculated on the basis of the loads measured by the load-measuring units 30 at predetermined azimuth angles. Therefore, information handled by the frequency analysis unit 31 and the adjusting command-value calculation unit 33 includes characteristics and adjusting command values that are obtained by the change in angle. In contrast, a common-pitch-angle command value determined by the common-pitch-angle command-value generating unit 35, which will be described below, is a command value obtained by the change in time, that is, a time-base command value. Therefore, these command values must be consistent with each other. Accordingly, the inverse frequency analysis unit 34 converts the adjusting command values θ1dem, θ2dem, and θ3dem into values θ1(t), θ2(t), and θ3(t), respectively, in the time domain using information on the azimuth angle at that time and a predetermined function. The inverse frequency analysis unit 34 transmits the converted adjusting command values θ1(t), θ2(t), and θ3(t) as adjusting pitch-angle command values to the pitch-angle-control command-value generating unit 36. The adjusting pitch-angle command values for reducing the load fluctuation are input from the adjusting pitch-angle command-value generating unit 32 to the pitch-angle-control command-value generating unit 36. The common-pitch-angle command value is also input as a feedback control value for matching the output at that time with a target value from the common-pitch-angle command-value generating unit 36 to the pitch-angle-control command-value generating unit 36. This common-pitch-angle command value is a command value that is common to each blade. The pitch-angle-control command-value generating unit 36 adds the input common-pitch-angle command value to each of the adjusting pitch-angle command values θ1(t), θ2(t), and θ3(t) for each blade, thereby generating pitch-angle-control command values for individually controlling the pitch angle of each blade. The pitch-angle-control command-value generating unit 36 then outputs the pitch-angle-control command values to the actuators that control the pitch-angle of each blade. Consequently, the pitch-angle of each blade is controlled by the corresponding actuator on the basis of the control command value. As described above, the blade-pitch-angle control device according to this embodiment provides the following advantages. First, since the load-measuring units 30 measure the load at predetermined azimuth angles regardless of the rotational speed of the blades, this device can be advantageously applied not only to a constant-speed windmill but also to a variable-speed windmill, in which the rotational speed of the blades changes depending on the operational state. Second, the load-measuring units 30 measure the load applied to each blade at predetermined azimuth angles, the frequency analysis unit 31 analyzes the periodic fluctuation characteristics of the load, the adjusting pitch-angle command-value generating unit 32 determines the adjusting pitch-angle command values for eliminating the load fluctuation on the basis of the analysis results, and the pitch-angle-control command-value generating unit 36 causes these adjusting pitch-angle command values to be reflected in the control of the pitch-angle of each blade. Thus, a significant load fluctuation that periodically occurs can be reduced. Third, this device focuses on the fact that a significant load fluctuation of the blades periodically occurs and aims at reducing the periodic load fluctuation. Therefore, even when a time-lag due to the feedback control occurs, the fluctuating load can be eliminated with high accuracy. Thereby, the load fluctuation can be efficiently reduced by a process much simpler than the conventional pitch-angle control that reduces instantaneous load fluctuations. Consequently, each blade can be controlled so as to have the optimum pitch-angle and the lifetime of the blades and mechanical parts constituting the windmill can be extended. Fourth, since the load-measuring unit 30 includes an azimuth-angle measuring instrument that measures the azimuth angle of each blade at predetermined time intervals, a trigger-generator that generates a trigger signal when the measurement result matches a predetermined azimuth angle, and a sensor that measures the load on the basis of the trigger signal, the load-measuring unit 30 can be simply realized. Alternatively, the load-measuring unit 30 may include, for example, an encoder that generates a trigger when the azimuth angle reaches a predetermined angle and a sensor that measures the load on the basis the trigger. Since such an encoder and a sensor are generally well known mechanisms, the load-measuring device can be simply realized. The second embodiment of the present invention has been described in detail with reference to the drawings. The specific structure is not limited to this embodiment, however, and may also include design changes and the like within the spirit and the scope of the present invention. First, instead of the load-measuring units 30 of the above embodiment, by employing acceleration-measuring units that measure the acceleration of the blades, the acceleration of the blades at predetermined azimuth angles may be measured to calculate the optimum pitch-angle for reducing the acceleration. Thus, the acceleration of the blades or mechanical parts constituting the windmill can be reduced. In addition, upon receiving a load fluctuation, the blades or the mechanical parts constituting the windmill vibrate and generate acceleration. Because of this correlation, the load fluctuation can also be reduced by reducing the acceleration in the above-described manner. Second, the case in which the blade-pitch-angle control device is applied to a variable-speed windmill has been described in the above embodiment, but the blade-pitch-angle control device according to the above embodiment can also be applied to a wind power generator using a constant-speed windmill. In such a constant-speed windmill, information input to the common-pitch-angle command-value generating unit 15 is not the rotational speed of the power generator but the output of the power generator, and the common-pitch-angle command value is determined so that the output of the power generator matches the target value. Third, the processes performed by the above frequency analysis unit 31, the adjusting command-value calculation unit 33, the inverse frequency analysis unit 34, the common-pitch-angle command-value generating unit 15, and the pitch-angle-control command-value generating unit 36 may be realized with a single computer device. This is performed by recording a program for realizing the function of each unit on a recording medium that can be read by a computer, reading the program recorded on the recording medium by a computer system, and executing the program.

<SOH> BACKGROUND ART <EOH>As shown in a schematic view in FIG. 11 , a known propeller windmill used in wind power generators includes, for example, three blades composed of a first blade 1 , a second blade 2 , and a third blade 3 , a rotor 5 serving as a link mechanism for linking the three blades, a tower 4 , and so on. In general, each of the blades of such a propeller windmill is controlled depending on the wind conditions so as to obtain a predetermined rotational speed and output of a power generator. FIG. 12 shows an example of the structure of a known pitch-angle control device. As shown in the figure, the known pitch-angle control device includes a common-pitch-angle command-value generating unit 15 for generating a common-pitch-angle command value on the basis of the difference between a preset value of a rotational speed or output of a power generator and a controlled value at that time. Actuators control each blade so as to have identical pitch-angles on the basis of the common-pitch-angle command value generated by the common-pitch-angle command-value generating unit 15 , thus controlling the pitch-angle of the blades. The inflow wind speed to a windmill is affected by the ground, as shown in FIG. 13A (the wind speed characteristics affected by the ground are hereinafter referred to as “wind shear characteristics”), or by the tower supporting the windmill, as shown in FIG. 13B (the wind speed characteristics affected by the tower are hereinafter referred to as “tower characteristics”). Spatial disorder and temporal disorder of the wind speed are added to the effects described above, resulting in an uneven wind speed distribution in the blade rotation area, as shown in FIG. 13C . Under such uneven wind speed conditions, since the instantaneous values of the aerodynamic output from each of the blades are different from each other, the values of the thrust, the moment, and the like of the blades are also different from each other. As a result, a load fluctuation in each blade occurs, thereby shortening the lifetime of the blades. To overcome this problem, for example, PCT Japanese Translation Patent Publication No. 2001-511497 discloses a technology in which the angle of attack of wind flowing to each blade and the load are measured, and the blades are individually controlled on the basis of these values. PCT Japanese Translation Patent Publication No. 2001-511497. PCT Publication No. WO01/86141 pamphlet

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 a block diagram showing the structure of a blade-pitch-angle control device according to a first embodiment of the present invention. FIG. 2 a view illustrating an azimuth angle. FIG. 3 a graph showing an example of a characteristic table relating wind speed and output of a wind power generator. FIG. 4 a graph showing an example of a characteristic table under steady wind conditions (having a temporally constant and two-dimensionally uniform wind speed). FIG. 5 a graph showing an example of a characteristic table including a waveform of a pitch-angle correction value for canceling out the effect of a tilt angle on the wind when the wind speed is varied and a waveform in which the correction value is reflected. FIG. 6 a graph showing an example of a characteristic table including a waveform of a pitch-angle correction value for canceling out the effect of a deviation of wind direction when the wind speed is varied and a waveform in which the correction value is reflected. FIG. 7 a graph showing an example of a characteristic table when air density is used as a variable. FIG. 8 a graph showing an example of a characteristic table when the output of the wind power generator is used as a variable. FIG. 9 a diagram showing the structure of an output-fluctuation eliminating device that is employed when a constant-speed windmill is used. FIG. 10 a block diagram showing the structure of a blade-pitch-angle control device according to a second embodiment of the present invention. FIG. 11 a schematic view of a propeller windmill used in a wind power generator. FIG. 12 a block diagram showing an example of the structure of a blade-pitch-angle control device according to a known art. FIG. 13 views illustrating wind shear characteristics, tower shadow characteristics, and wind speed distribution. detailed-description description="Detailed Description" end="lead"?

20061020

20081118

20070222

95937.0

B64C1106

NGUYEN, NINH H

BLADE-PITCH-ANGLE CONTROL DEVICE AND WIND POWER GENERATOR

UNDISCOUNTED

ACCEPTED

B64C

ACCEPTED

Crosslinking Within Coordination Complexes

Crosslinked proteins, proteins and polymers, and polymers and methods of making the same are disclosed. In one illustrative embodiment, a method is provided comprising the steps of attaching a chelator to one or more polymers; creating a coordination complex between the first protein, the second protein, and a metal ion; and crosslinking the first and second proteins by exposing the coordination complex to an oxidant.

1. A method of crosslinking a first and a second moiety comprising the steps of: attaching a metal ligand to the first moiety; attaching a metal ligand to the second moiety; adding a metal ion to form a coordination complex between the first moiety and the second moiety; which in the presence of an oxidizing agent leads to the formation of at least one covalent crosslink between phenolic groups or phenolic derivatives attached to each of the first and second moieties. 2. The method of claim 1, wherein the coordination complex actives the oxidizing agent. 3. The method of claim 1, wherein the oxidizing agent is activated by a metalloenzyme. 4. The method of claim 3, wherein the metalloenzyme is selected from the group consisting of a peroxidase, a tyrosinase, a laccase, and a catechol oxidase. 5. The method of claim 4 wherein the peroxidase is horseradish peroxidase. 6. The method of claim 1, wherein the oxidizing agent is generated electrochemically at a surface of an electrode. 7. The method of claim 1, wherein the phenolic groups or phenolic derivatives are each selected from the group consisting of tyrosine, dihydroxyphenylalanine, and polyphenolic compounds. 8. The method of claim 1, wherein the second moiety comprises at least one phenolic group positioned such that in the coordination complex the phenolic group is located between 1 and 100 angstroms from the metal ion. 9. The method of claim 1, wherein the first moiety comprises at least one phenolic group positioned such that in the coordination complex the phenolic group is located between 1 and 100 angstroms from the metal ion. 10. The method of claim 9, wherein the phenolic group is a tyrosine residue located on the first moeity. 11. The method of claim 9, wherein the phenolic group is a tyrosine residue located within the metal ligand on the first moiety and positioned such that in the coordination complex the tyrosine is located between the metal ion and the first polymer. 12. The method of claim 1, wherein the covalent crosslink is a substituted phenolic adduct. 13. The method of claim 1, wherein the covalent crosslink is formed by a chemical bond between the phenolic group or phenolic derivative on the first moiety and the phenolic group or phenolic derivative on the second moiety. 14. The method of claim 1, wherein the covalent crosslink is dityrosine and isomers thereof. 15. The method of claim 1, wherein the first moiety and second moiety are both polymers. 16. The method of claim 15, wherein the first moiety and second moiety are both biopolymers. 17. The method of claim 15, wherein the first moiety and second moiety are both synthetic polymers. 18. The method of claim 15, wherein the first moiety is a biopolymer and the second moiety is a synthetic polymer. 19. The method of claim 1, wherein at least one of the first and second moieties is a biopolymer selected from the group consisting of protein, polysaccharide, poly-nucleic acid, lipid, and combinations thereof. 20. The method of claim 1, wherein at least one of the first and second moieties is a synthetic polymer selected from the group consisting of polyethylene glycol, polypropylene glycol, polyesters, and polyethylene glycol and polypropylene glycol block copolymers. 21. The method of claim 1, wherein the first moiety is a polymer and the second moiety is a small molecule. 22. The method of claim 21, wherein the small molecule has a molecular weight from 50 g/mol to 800 g/mol. 23. The method of claim 21, wherein the small molecule is an oligomer with a degree of polymerization from 1 to 10. 24. The method of claim 21, wherein the small molecule is comprised of epitope labels or fluorophores. 25. The method of claim 21, wherein the small molecule is selected from the group consisting of digoxigenin, biotin, fluorescein, rhodamine, CY-3, CY-5, and derivatives thereof. 26. The method of claim 1, wherein one of the first and second moieties is attached to a solid surface. 27. The method of claim 26, wherein the solid surface is selected from the group consisting of a polymer, a metal, a ceramic, a composite, a biopolymer, a bioceramic, and a colloidal particle. 28. The method of claim 27, wherein the solid surface is a metal and is coated with a polymer. 29. The method of claim 27, wherein the solid surface is a colloidal particle and the colloidal particle is composed of a material selected from the group consisting of gold, silver, silica, semiconductors, fluorescent semiconductors, polystyrene, polymeric micelles, dendrimers, liposomes, and viruses. 30. The method of claim 27, wherein the surface is a colloidal gold particle and the colloidal particle has a diameter of from 1 nm to 100 μM. 31. The method of claim 1, wherein both the first and second moieties are attached to a solid surface. 32. The method of claim 31, wherein the first and second moieties are attached to different solid surfaces and the crosslinking is used to adhere two solids. 33. The method of claim 32, wherein the two solid surfaces are biological tissues. 34. The method of claim 32, wherein each of the solid surfaces are independently selected from the group consisting of polymers, metals, ceramics, composites, biopolymers, bioceramics, colloidal particles, and combinations thereof. 35. The method of claim 34, wherein at least one of the solid surfaces is a colloidal particle, and the colloidal particle is composed of a material selected from the group consisting of gold, silver, silica, semiconductors, fluorescent semiconductors, polystyrene, polymeric micelles, dendrimers, liposomes, and viruses. 36. The method of claim 35, wherein the colloidal particle has a diameter from 1 nm to 100 M. 37. The method of claim 1, wherein at least one of the first moiety and the second moiety is biodegradable. 38. The method of claim 1, wherein at least one of the first moiety and the second moiety contains a therapeutic agent. 39. The method of claim 38, wherein the therapeutic agent is a protein. 40. The method of claim 1, wherein the first moiety is an HY-tag. 41. The method of claim 40, wherein the first moiety contains plurality of tyrosine residues interdispersed through out the HY-tag. 42. The method of claim 40, wherein the HY-tag comprises a plurality of histidine residues. 43. The method of claim 1, wherein the metal ion is selected from the group consisting of nickel, copper, zinc, and cobalt, gadolinium, iron, osmium, palladium, rhodium, ruthenium, samarium, selenium, silver, strontium, tantalum, thulium, tin, tungsten, vanadium, yttrium, and zinc. 44. The method of claim 43, wherein more than one metal ion is present in the coordination complex. 45. A method of crosslinking a first and a second protein comprising the steps of: attaching a first HY-tag to a first protein; attaching a second HY-tag to a second protein; creating a coordination complex between the first protein, the second protein, and a metal ion; and crosslinking the first and second proteins at or adjacent to the HY-tags by exposing the coordination complex to an oxidizing agent to form a covalent crosslink. 46. The method of claim 45, wherein the coordination complex is catalytic or redox active. 47. The method of claim 45, wherein the oxidizing agent is a mild oxidizing agent and crosslinking occurs without significant non-specific crosslinking. 48. The method of claim 47, wherein the oxidizing agent is provided as Na2SO3. 49. The method of claim 45, wherein the oxidizing agent is a peroxide. 50. The method of claim 49, wherein the peroxide is H2O2. 51. The method of claim 47, wherein the oxidizing agent is O2. 52. The method of claim 45, wherein the first and second HY-tags each comprise a tyrosine residue located between a plurality of histidine residues and the protein. 53. The method of claim 53, wherein the covalent crosslink is a substituted dityrosine. 54. A method of conjugating a protein with a synthetic polymer comprising the steps of: attaching a metal-binding peptide to a selected protein; attaching a second ligand to a selected polymer; forming a coordination complex between the protein, the polymer, and a metal ion; and crosslinking the protein and polymer by exposing the coordination complex to an oxidizing agent. 55. The method of claim 54, wherein the coordination complex is redox active. 56. The method of claim 54, wherein the polymer is a synthetic polymer. 57. The method of claim 54, wherein the polymer is polyethylene glycol. 58. The method of claim 54, wherein the metal ion is selected from the group consisting of nickel, copper, zinc, and cobalt. 59. The method of claim 54, wherein the oxidizing agent is Na2SO3 or O2. 60. The method of claim 54, wherein the oxidizing agent is a peroxide. 61. The method of claim 58, wherein the oxidizing agent is H2O2. 62. The method of claim 54, wherein the oxidizing agent is a mild oxidizing agent and crosslinking occurs without significant non-specific crosslinking. 63. The method of claim 54, wherein one of the metal-binding peptide is a HY-tag and the second ligand is a synthetic chelator. 64. A method of immobilizing a protein on a polymer surface under conditions that preserve protein structure and activity, comprising the steps of: modifying a polymeric surface such that the polymeric surface comprises a synthetic ligand; attaching a metal-binding peptide to a protein; forming a coordination complex between the polymeric surface, the protein, and a metal ion; and immobilizing the protein to the polymeric surface by exposing the coordination complex to an oxidizing agent, thus causing the crosslinking of the polymer and the protein. 65. The method of claim 64, wherein the polymer surface is further comprised of a synthetic polymer. 66. The method of claim 64, wherein the polymer is polyethylene glycol. 67. The method of claim 64, wherein the metal ion is selected from the group consisting of nickel, copper, zinc, and cobalt, gadolinium, iron, osmium, palladium, rhodium, ruthenium, samarium, selenium, silver, strontium, tantalum, thulium, tin, tungsten, vanadium, yttrium, and zinc. 68. The method of claim 64, wherein the oxidizing agent is a mild oxidating agent. 69. The method of claim 64, wherein the metal-binding peptide is a HY-tag. 70. A crosslinked polymer material produced by crosslinking a polymer having a synthetically-placed chelator in a mixture comprising the polymer, a metal, and an oxidant. 71. The crosslinked polymer material of claim 70, wherein the polymer is a protein. 72. The crosslinked polymer material of claim 71, wherein the synthetically-placed chelator is a HY-tag. 73. The crosslinked polymer material of claim 72, wherein the protein comprises two HY-tags and the protein is polymerized by the crosslinking. 74. The crosslinked polymer material of claim 71, wherein the mixture further comprises a synthetic polymer comprising a chelator, and wherein the synthetic polymer is crosslinked to the protein. 75. The crosslinked polymer material of claim 70, wherein the mixture comprises a plurality of identical polymers each having the synthetically-placed chelator. 76. The crosslinked polymer material of claim 70, wherein the mixture comprises a second polymer having a synthetically-placed chelator, the second polymer being different from the first polymer and crosslinked thereto. 77. The crosslinked polymer material of claim 76, wherein the polymer is a protein and the second polymer is a synthetic polymer. 78. The crosslinked polymer material of claim 77, wherein the second polymer is a polymeric surface. 79. The crosslinked polymer material of claim 70 wherein the oxidant is a mild oxidant.

US GOVERNMENT RIGHTS This invention was made with United States Government support under NSF Grant No. BES9807287 and NIH Grant No. GM49860. The United States Government has certain rights in the invention. BACKGROUND AND SUMMARY OF THE INVENTION Complex networks of highly crosslinked biopolymers are common materials in living tissues. Familiar examples of these are the networks of collagen fibers that form the matrices of skin, bones, and connective tissues. The crosslinking found in these materials gives them their tensile strength, elasticity, and other valuable characteristics. In nature, the crosslinking, which is so critical to the function of these tissues, is accomplished by enzymatic oxidation of specific amino acid side chains of the protein materials involved, thus creating reactive intermediates which spontaneously form crosslinks. In the case of collagen and elastin, the s-amino group of specific lysine residues are oxidatively deaminated by lysyl oxidase into reactive aldehyde groups that spontaneously condense with neighboring peptidyl aldehydes or s-amino groups (Kagan, H. M. et al., J Cell Biochem, 2003. 88(4): p. 660-72). Another widely occurring mechanism of biomolecule crosslinking is oxidative coupling through phenols. Examples are the formation of lignin, which is a major structural component of plant cell walls, the formation of melanin pigments, the curing of tree sap into hard lacquers, the formation of peptidic natural products that exhibit high biological activity, such as vancomycin (Jung, G., Letters in Peptide Science, 2001. 8(3-5): p. 259-265; Malnar, I. et al. Tetrahedron Letters, 2000. 41(12): p. 1907-1911; Nishiyama, S., et al., Tetrahedron Letters, 1994. 35(45): p. 8397-8400) and bouvardin (Boger, D. L., et al. JACS, 1994. 116(19): p. 8544-56), through the formation of dityrosine protein crosslinks. Dityrosine protein linkages have been found in many structural proteins including elastin (LaBella, F., et al., Biochem Biophys Res Commun., 1967. 26(6): p. 748-53; Malanik, V. et al., Connect Tissue Res, 1979. 6(4): p. 235-40), silk (Raven, D. J., C. Earland, et al., Biochim Diophys Acta, 1971. 251(1): p. 96-99), plant cell wall extensin (Fry, S. C., Biochem J, 1982. 204(2): p. 449-55; Brady, J. D., et al. Biochem J, 1996. 315(Pt 1): p. 323-7), and in hardened fertilization membranes of insect and sea urchin eggs (Foerder, C. A. et al., PNAS (USA), 1977. 74(10): p. 4214-8). These oxidative phenolic coupling processes are catalyzed by a large number of structurally and mechanistically distinct metalloenzymes, including peroxidases, tyrosinases, and laccases. Peroxidases crosslink tyrosines by extracting a single electron from the phenol side chain to create a radical that then reacts with a vicinal phenol side chain to form dityrosine or isodityrosine (Michon, T., et al., Biochemistry, 1997. 36(28): p. 8504-13; Eickhoff, H., et al., Tetrahedron, 2001. 57(2): p. 353-364). Tyrosinases may crosslink tyrosine residues in two steps: first, the phenol side chain is hydroxylated forming 3,4-dihydroxyphenyl-L-alanine (DOPA); second, DOPA is further oxidized to form reactive o-quinones that spontaneously crosslink (Sanchez-Ferrer, A., et al., Biochim Biophys Acta, 1995. 1247(1): p. 1-11; Espin, J. C., et al., Eur J Biochem, 2000.267(5): p. 1270-9). These natural oxidative protein crosslinking mechanisms are mediated by transition metal-peptidyl coordination complexes. The redox active metal complexes come in many forms. Lysyl oxidase contains a single copper (II) atom and an organic co-factor formed by the intermolecular crosslinking of a lysine &amine and a tyroxyl quinone (Kagan, H. M. et al., J Cell Biochem, 2003. 88(4): p. 660-72). Tyrosinases (Sanchez-Ferrer, A., et al., Biochim Biophys Acta, 1995. 1247(1): p. 1-11) and laccases (Thurston, C. F., Microbiology, 1994. 140: p. 19-26) are multi-copper enzymes that transfer electrons to molecular oxygen. Peroxidases that crosslink tyrosines are iron-heme proteins that transfer single electrons from phenols to H2O2 (Michon, T., et al., Biochemistry, 1997. 36(28): p. 8504-13; Oudgenoeg, C., et al., J. Agric. Food Chem., 2001.49(5): p. 2503-10). Nature has found many distinct metal-mediated pathways for extracting electrons to crosslink phenolic compounds. Another particularly intriguing example of crosslinking through tyrosine derivatives occurs in mussel byssal threads, which are specialized ligaments that bond the animals to an external substrate. The byssal threads contain several proteins and are heavily diDOPA crosslinked (Rzepecki, L. M., et al., Mol Mar Bid Biotechmol, 1991. 1(1): p. 78-88; McDowell, L. M., et al., J Biol Chem, 1999. 274(29): p. 20293-5). The thread proteins include three unusual collagens with blocky primary structures; a central collagen block is flanked by either elastin-like blocks (pre-ColP) (Coyne, K. J., et al., Science, 1997. 277(5333) p. 1830-2), silk-like blocks (pre-ColD) (Qin, X X., et al., J Biol Chem, 1997. 272(51): p. 32623-7), or amorphous glycine-rich blocks (pre-ColNG) (Qin, X X. et al., PNAS (USA), 1998. 95(18): p. 10517-22). All three have histidine- and DOPA-rich domains at the amino- and carboxyl-termini. The histidine blocks likely chelate the several metal ions found associated with byssal threads. Chelate complexes are thought to participate in non-covalent intermolecular crosslinking of the collagens (Vaccaro, F. et al., Biomacromolecules, 2001. 2(3): p. 906-11). Chelated transition metal ions, particularly Ni(II), can participate in oxidative crosslinking of biomolecules. Much of the research in this area has been done from the perspective of understanding nickel toxicity, which may be largely due to its oxidative activity when chelated by peptides, proteins, or nucleic acids (Gill, G., et al., Chem Res Toxicol, 1997. 10(3): p. 302-9; Bal, W., et al., Chem Res Toxicol, 2000. 13(7): p. 616-24). A second area of research has focused on creating synthetic catalysts that mimic metalloenzymes. For example, tyrosinase model complexes have been synthesized that are capable of regiospecific oxidation of phenol and catechol (Monzani, E., et al. Inorganic Chemistry, 1998. 37: p. 553-562) and regiospecific polymerization of phenol into poly(1,4-phenylene oxide) (Higashimura, H., et al. J. Am. Chem. Soc., 1998. 120: p. 8529-8530). A third area of research has been directed at exploiting the oxidative activity of chelated Ni(II) to create reagents for in vitro conjugation, crosslinking, or cleavage of biomolecules. A number of metal complexes have been synthesized that specifically modify DNA (Muller, J. G., et al., J Inorg Biochem, 1994. 54(3): p. 199-206; Burrows, C. J., et al., Acta Chem Scand, 1996. 50(4): p. 337-44; Hickerson, R. P., et al., J Mol Biol, 1998. 279(3): p. 577-87; Stemmler, A. J. et al.: JACS, 1999. 121(29): p. 6956-6957). With regard to protein modification, others have found that Ni(II) complexed by the tripeptide NH2-Gly-Gly-His (GGH) in the presence of the relatively strong oxidant monoperoxyphthalic acid (MMPP) crosslinked proteins known to associate in solution (Brown, K. C., et al., Biochemistry, 1995. 34(14): p. 4733-9). Subsequently, GGH genetically appended to the dimeric protein, ecotin, mediated intermolecular crosslinking between tyrosine residues in the presence of MMPP and Ni(II) (Brown, K. C., et al., Biochemistry, 1998. 37(13): p. 4397-406). Crosslinking between wild-type ecotin, in which tyrosine residues at the dimer interface are separated by 20 Å, was relatively inefficient (15%). By placing tyrosine residues within 5 Å of one another at the dimer interface, crosslinking efficiency was increased to 60%. This demonstrated a major advantage of protein crosslinking mediated by peptide metal complexes, that a redox active Ni(II) chelator and target tyrosine residues can be genetically positioned within a protein, creating the potential for site specific protein modification through oxidative conjugation or crosslinking. A recent report, however, revealed that this chemistry is much more complex than just dityrosine formation. A number of reactions occur in the strong oxidizing environment, and crosslinking between the terminal GG residues and tyrosine is one of the major reactions (Person, M. D., et al., Protein Sci, 2001. 10(8): p. 1549-62). The His6 tag (SEQ ID NO. 1) commonly used for purification of recombinant proteins by immobilized metal affinity chromatography (IMAC) has also been shown to be redox active in the presence of nickel(II) and peracid oxidants. HIS-tagged glutathione S-transferase (H6GST (SEQ ID NO. 2)), a dimer in solution, was covalently crosslinked in the presence of Ni(II) and MMPP (Fancy, D. A., et al., Chem Biol, 1996. 3(7): p. 551-9). Proteins that do not naturally associate with H6GST were not crosslinked, demonstrating that His6-mediated crosslinking does not proceed through a highly diffusible reactant and crosslinking is localized to the vicinity of the His6 tag. Going further, the same research group demonstrated that, in the presence of MMPP and Ni(II), H6GST mediated the formation of dityrosine from free tyrosine, that the mutagenic removal of tyrosine residues from H6GST decreased crosslinking efficiency, and that chemical addition of tyrosine residues using the Bolton-Hunter reagent increased crosslinking efficiency (Fancy, D. A., et al., Biochem Biophys Res Commun, 1998. 247(2): p. 420-26). The primary interest of this research appears to be the architectural analysis of multi-protein complexes. A large and successful industry has grown up around the development of reagents for the post-translational chemical modification of proteins. Despite the ingenious variety of reagents and methods available, there is a continuing need for new protein technologies that grows in proportion to the increasing importance of proteins in several major industries, including pharmaceutics, clinical diagnostics, chemicals, energy, agriculture, environmental protection, food, and textiles processing. New and better tools for labeling, conjugating, crosslinking, and immobilizing proteins would be valuable in all of these industries. The expanding industrial use of proteins, driven by new protein technologies, may have profound effects on human health, ranging from more cost effective pharmaceuticals to decreased environmental and the consequent human health impact from the production of chemicals and energy. In particular, methods are desired for crosslinking proteins, polymers, and/or other moieties, including those that are not naturally associated, illustratively in a manner that is predictable. Accordingly, a method of crosslinking proteins (such as enzymes), polymers (including biopolymers such as protein, polysaccharide, poly-nucleic acid, lipid, and synthetic polymers such as polyethylene glycol, (“PEG”), polypropylene glycol, polyesters, and polymeric surfaces (such as pluronics)), and/or other moieties (such as fluorescent compounds, small molecules illustratively having a molecular weight from 50 g/mol to 800 g/mol, and small molecules having a degree of polymerization from 1 to about 10), by contact with an oxidant after associating the two species to be linked in a coordination complex with a metal ion or ions is provided. Such a method is useful in a variety of applications, including the labeling of proteins, PEGylating proteins, coupling proteins and polymers, and affixing proteins to surfaces. In some embodiments, the method comprises a method of crosslinking a first and a second protein comprising the steps of attaching a metal-binding peptide, illustratively a HY-tag, to the first protein using methods known in the art; attaching a metal-binding peptide to the second protein using methods known in the art; forming a coordination complex between the first protein, the second protein, and a metal ion; and crosslinking the first and second proteins by exposing the coordination complex to an oxidant. In illustrative embodiments of the instant invention, the metal ion is selected from the group consisting of nickel, copper, zinc, and cobalt, gadolinium, iron, osmium, palladium, rhodium, ruthenium, samarium, selenium, silver, strontium, tantalum, thulium, tin, tungsten, vanadium, yttrium, and zinc. In others, the metal ion may be a first row transition metal ion. The methods of this invention may be used for crosslinking any combination of proteins, polymers, and small molecules. An oxidizing agent is a chemical reagent that is an oxidizer, or which promotes the oxidation of a desired reagent. In some embodiments of the invention, MMPP is used to promote the oxidation of tyrosine residues. Other oxidants have been found suitable as well, including peroxides, other peracids, oxidizing enzymes such as tyrosinase, oxygen, and other weaker oxidants, wherein a “weaker oxidant” is weaker than MMPP. In some embodiments, however, a stronger oxidant may be used. Illustratively, the oxidizing agent may be generated from an electrode surface. In one embodiment, the electrode surface is coated with a synthetic or natural polymer. Na2SO3 may also be used. While not itself an oxidant, Na2SO3 auto-oxidizes in the presence of complexed NiH to persulfate (SO5). In another embodiment, the oxidizing agent may be activated by a metalloenzyme, including but not limited to a peroxidase, a tyrosinase, a laccase, and a catechol oxidase. One suitable metalloenzyme is horseradish peroxidase. In some embodiments, the ligand used to create the coordination complex is a metal-binding peptide or metal chelating tag, such as an HY-tag. In illustrative embodiments of the instant invention, the HY-tag is chosen from a group of sequences that comprise about four to ten histidine residues and a number of tyrosine residues. The sequences largely differ from each other in the placement of the tyrosines. As used herein, the term HIS-tags refers to HIS-tags generally, while HIS-TYR tags or HY-tags refer to HIS-tags that include tyrosines therein. Either may be referred to as his6-tags when the number of histidine residues is specified. Also, it is understood that while HY-tags are used in illustrative embodiments, other chelating constructs comprised of amino acids and/or other natural or synthetic monomers may be used, illustratively including tyrosine, dihydroxyphenylalanine, or other phenolic groups. It is understood that phenolic groups includes compounds having one or more aromatic benzene rings having one or more hydroxyl groups (—OH). In addition, phenolic derivatives, including oxidized forms of phenolic groups, may be used. Phenolic groups and phenolic derivatives may contain further substituents on the benzene ring in addition to the hydroxyl group(s). Some of the embodiments of the invention may comprise methods for labeling proteins, as when a fluorescent label (illustratively fluorescein, rhodamine, CY-3, and CY-5), enzyme, or other molecule is attached. Other such molecules could include biotin, digoxigenin, polyethylene glycol, pluronics, and other suitable labels. In some embodiments, the invention comprises a method of conjugating a protein with a synthetic polymer comprising the steps of attaching a HY-tag to a selected protein; attaching a HY-tag or other metal-chelating group containing or in close proximity to a phenolic functional group to a selected polymer; forming a coordination complex between the protein, the polymer, and a metal ion; and crosslinking the protein and polymer by exposing the coordination complex to an oxidant. In various of these embodiments, the polymer is a synthetic polymer. In some, the polymer is polyethylene glycol. In others, the polymer is chosen from the group of polyacrylates, polymer surfaces such as pluronics, carbohydrates such as dextran, and lipids. In still other embodiments, HY-tags, which may be the same or different, are used to link two polymers. Other embodiments of the instant invention comprise methods of immobilizing a protein or other moiety on a polymer surface under conditions that preserve protein structure and activity, comprising the steps of modifying a polymeric surface such that the polymeric surface comprises a synthetic chelator; attaching a HY-tag to a protein; forming a coordination complex between the polymeric surface, the protein, and a metal ion; and immobilizing the protein to the polymeric surface by exposing the coordination complex to an oxidant, thus causing the crosslinking of the polymer and the protein. In some embodiments, the polymer surface is further comprised of a synthetic polymer. In others, the polymer is polyethylene glycol. In still others, the polymer is a pluronic. Similarly, the moiety may already be immobilized on a solid surface and the method may be used to link a second moiety to the surface. Examples of solid surfaces include tissues, polymers, metals, ceramics, composites, biopolymers, bioceramics (such as bones and teeth), and colloidal particles. Colloidal particles illustratively include materials gold, silver, silica, semiconductors, fluorescent semiconductors, polystyrene, polymeric micelles, dendrimers, liposomes, and viruses, and may be of any size, illustratively of from 1 nm to 100 μM. The polymer may be coated onto or otherwise bound to the solid surface. It is also understood that the methods of this invention may be used to link two different surfaces together, wherein each of the two moieties is immobilized on its respective surface. Illustratively, this may be useful when each of the surfaces is a tissue, and the crosslinking may function as a surgical glue. While targets catalyzed by the mildest possible oxidant, illustratively O2, are desired for use with proteins that are particularly sensitive to oxidation, it is understood that stronger oxidants may be used in some instances, and that the metal complex may be selected accordingly. Also, while tyrosines are used to crosslink through dityrosine formation, other phenolic residues may be used and crosslinking may occur through a substituted bis-phenol adduct. Various features and embodiments of the instant invention are useful for a variety of common research and medical applications. One of these is use in the formation of hydrogels. The ability to provide predictable crosslinking of the proteins in such gels could allow the formation of new types of gels with unique properties and characteristics. This application could also be used to encapsulate cells, proteins, and DNA for preservation and use. A related application would be use of the invention as a surgical glue. Such a glue could be composed of specifically-chosen proteins selected for ability to prevent or avoid an immune response, promote growth and regeneration of surrounding tissue, degrade over time, or exhibit any other possible characteristic. Additionally, the glue could be applied in a liquid form to the wound, and then the glue could be cured and the wound sanitized simultaneously by the application of hydrogen peroxide as an oxidant/sterilant. Many other uses are possible. These and other objects, features, and advantages of the present invention will become more fully apparent from the following description and appended claims, or maybe learned by the practice of the invention as set forth hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A-D are a schematic representation of attachment of a HY-tagged protein to a substrate followed by oxidative formation of a dityrosine crosslink between the protein and the substrate; FIG. 1A shows all of the component parts, FIG. 1B shows chelation of the metal by both the HY-tagged protein and the substrate, FIG. 1C represents oxidation of the tyrosine, and FIG. 1D shows the dityrosine crosslink. FIG. 2 shows phenol oxidation to two bis-phenolic species. FIG. 3A shows sedimentation equilibrium data for H6GY-titin I28 (SEQ ID NO. 6) protein without Ni+2. The lower panels show experimental data points for 3 different loading concentrations of each protein with the corresponding calculated curve fit (solid line). The H6GY-titin I28 protein is fit to a monomer model, MW=12.3±1 kDa. The upper panels show the residuals for these fits, all are small and random indicating a good fit. FIG. 3B shows sedimentation equilibrium data for H6GY-titin I28 (SEQ ID NO. 6) protein with a ten fold molar excess of Ni+2. The lower panels show experimental data points for 3 different loading concentrations of each protein with the corresponding calculated curve fit (solid line). The H6GY-titin I28 protein with a ten fold molar excess of Ni+2 is fit to a monomer-dimer equilibrium KD of approximately 200 μM. The upper panels show the residuals for these fits, all are small and random indicating a good fit. FIG. 4 is a gel showing the results of crosslinking of I28 domains with various HY-tags; lane 1: YH6-I28 (SEQ ID NO. 3), lane 2: YGH6-I28 (SEQ ID NO. 4), lane 3: YGYGH6-I28 (SEQ ID NO. 5), lane 4: H6GY-I28 (SEQ ID NO. 6), lane 5: H6GYGY-I28 (SEQ ID NO. 7), lane 6: YGH6GY-I28 (SEQ ID NO. 8); lane 7: H3GYG H3-I28 (SEQ ID NO. 9), lane 8: no tyr control. FIG. 5 shows fluorescence emission spectra of HY-tagged I28 with and without Ni2+. FIG. 6 shows structure of solid phase binding constructs with oxidative reactions between two tyrosines. DETAILED DESCRIPTION OF THE INVENTION The presently preferred embodiments of the present invention will be best understood by reference to the following more detailed description of the embodiments of the apparatus, system, and method of the present invention. This detailed description is not intended to limit the scope of the invention, as claimed, but is merely representative of presently preferred embodiments of the invention. FIGS. 1A-D illustrate attachment of a HY-tagged protein to a substrate followed by oxidative formation of a dityrosine crosslink between the protein and the substrate. As illustrated in FIG. 1B, the conjugation site is pre-established as a complex before chemically reactive groups are created by an oxidant, illustratively a mild oxidant (FIG. 1C). The conjugation site itself catalyzes the creation of the reactive species, which localizes covalent bond formation to an intended region (FIG. 1D). As illustrated, random modifications that may damage or inactivate the target protein are limited. Further, the conjugation site on the protein may be genetically encoded in the form of a metal chelating peptide. Such a target protein would not require purification to be modified; it can be modified within a complex mixture of proteins. One advantage for protein array applications is that recombinant proteins may be selectively captured onto a solid support from a crude lysate of cells expressing the protein, and this can be done without purification and post-translational chemical modification. The radical homo-coupling of peptidyl tyrosine to form dityrosine is an irreversible process that leads to intermolecular crosslinks. The reaction proceeds at physiological pH through the formation of tyroxyl radicals by abstraction of a hydrogen atom from the hydroxyl group of tyrosine by a variety of oxidants (Eickhoff, H., et al., Tetrahedron, 2001. 57(2): p. 353-364; Dhirigra, O. P., Intramolecular Oxidative Coupling of Aromatic Substrates, in Oxidation in ORGANIC CHEMISTRY, W. S. Trahanovsky, Editor. 1982, Academic Press: New York). Dityrosine is formed by recombination of two of these tyroxyl radicals (FIG. 2) (Pennathur, S., et al., J. Biol. Chemistry, 1999. 274(49): p. 34621-34628; Jacob, J. S., et al., J. Biol. Chemistry, 1996. 271(33): p. 19950-19956; Spikes, J. D., et al., Photochemistry and Photobiology, 1999. 69: p. 84s-84s; Goldstein, S., et al., J. Biol. Chemistry, 2000. 275(5): p. 3031-3036; Souza, J. M., et al., J. Biol. Chemistry, 2000. 275(24): p. 18344-18349). As shown in FIG. 2, in the absence of a base, tyrosine undergoes a one-electron oxidation to give the cation radical. This species rapidly deprotonates to the neutral phenoxyl radical, which then reacts with another phenoxyl to form dityrosine. Several reaction pathways exist, however two predominant isomers of dityrosine have been identified, 3,3′-dityrosine (dityrosine) and 3-[4′-(2-carboxy-2-aminoethyl)phenoxy]tyrosine or (isodityrosine). Because of the instability of the radical species involved, the structure of reaction intermediates and mechanisms of chemical transformations remain hypothetical and are often deduced from the structure of the identified products of the oxidation. The generation of the tyroxyl radical occurs at +1.2 V versus SCE. At this potential, many oxidizing agents are thermodynamically capable of generating the tyroxyl radical. Metal catalysts for this reaction are known and comprise FeCl3, potassium hexacyanoferrate(III) under aqueous conditions, Ag2O, NiO2, Ce+4. In addition, electrochemical oxidations have been reported (Eickhoff, H., et al., Tetrahedron, 2001. 57(2): p. 353-364; Dhirigra, O. P., Intramolecular Oxidative Coupling of Aromatic Substrates, in Oxidation in Organic Chemistry, W. S. Trahanovsky, Editor. 1982, Academic Press: New York). Nickel(II) mediated association of proteins through his-tags has been reported (Horn, L. G., et al., Biotechniques, 1998. 25(1): p. 20-22). Thus, as an initial approach to investigating chelated metal-mediated protein crosslinking, tyrosine residues were genetically placed within and around his6 tags on a model protein, a monomeric titin I28 Ig domain (Chen, L., et al., Bioconjug Chem, 2000. 11(5): p. 734-40). In the presence of Ni(II) and MMPP, HIS-tagged I28 domains with tyr residues between the HIS-tag and titin domain were efficiently crosslinked (Example 1). Those with tyr residues outside of the HIS-tags and the no tyr control did not crosslink. EXAMPLES Example 1 Chelator Synthesis Two I28 proteins—proteins from an Ig domain of the muscle protein titin—were crosslinked though HIS-tags containing tyrosine residues. Tyrosine residues were placed within and around his6-tags on a model protein, a monomeric titin I28 Ig domain, as shown in Table I, below. In the presence of NO) and MMPP, HIS-tagged I28 domains with tyr residues between the his-tag and titin domain were efficiently crosslinked (FIG. 3, lanes 4, 5). Those with tyr residues outside of the HIS-tags (lanes 1-3, 6, 7) and the no tyr control (lane 8) did not crosslink. A convenient method to detect and monitor dityrosine formation is to measure its characteristic fluorescence at 410 nm (Aeschbach, R., et al., Biochim Biophys Acta, 1976. 439(2): p. 292-301; Dalle-Donne, I., et al., American Biotechnology Laboratory, 2001. 19(13): p. 34-36). This detection method was used to detect dityrosine formation using the HIS-tagged-I28 constructs discussed above, but using Ni(II) and sodium sulfite. The reactions took place within minutes in water, at near neutral pH, and under conditions that are biocompatible. That the HY-I28 proteins were crosslinked by dityrosine in the presence of this mild oxidant is confirmed by analyzing fluorescence emission spectra after treatment with Ni(H) and sodium sulfite (FIG. 4). Consistent with the electrophoresis results, only H6GY-I28 (SEQ ID NO. 6) and H6GYGY-I28 (SEQ ID NO. 7) fluoresced significantly at 410 nm (Table I). In the absence of Ni(II) or oxidant, no dityrosine was formed. Likewise, the control protein with no tyrosine in the his6-tag did not fluoresce when treated with Ni(II) and sodium sulfite. Thus, with properly constructed HY-tags, crosslinking can occur in the presence of a mild oxidant. TABLE I normalized dityrosine fluorescence (410nm) of His-tyr-tagged 128 proteins. Conditions HIS-tag Ni(II)/Na2SO3 Na2SO3 only YH6-I28 (SEQ ID NO. 3) 0.03 0 YGH6-I28 (SEQ ID NO. 4) 0.01 0 YGYGH6-I28 (SEQ ID NO. 5) 0.04 0 H6GY-I28 (SEQ ID NO. 6) 0.43 0.17 H6GYGY-I28 (SEQ ID NO. 7) 1 0.13 YGH6GY-I28 (SEQ ID NO. 8) 0.29 0.01 H3GYGH3-I28 (SEQ ID NO. 9) 0.04 0.01 Control 0.02 0 (no tyr) Example 2 Two Ligand System As a further example, a second chelator may be formed that is capable of forming a complex with a Ni++HY-tag that can be conveniently coupled to synthetic polymers. An oligopeptide illustratively containing tyrosine and histidine, such as those described above, may be used as this second ligand. The peptide chelator is easily coupled to fluorescent labels. Illustratively, an inexpensive synthetic ligand may be designed by modifying the synthesis of the nitrilotriacetic acid chelator used previously (Ho et al., Langmuir, 1998. 14:3889-3894; Wang et al., Nature, 1999. 397:417-420). One approach for this is to substitute imidazole or phenolic groups for the carboxylic acid groups on NTA. It is expected that these functionalities will react with the oxidized tyrosine in the HY-tag of the protein. Example 3 Surface Immobilization Protein arrays are widely expected to have a dramatic impact on human health care. The proteome is much more complex than the genome because of alternative splicing and post-translational modifications and therefore contains more useful information about disease states. The ability to “profile” directly the amount and chemical state of hundreds or thousands of proteins simultaneously in blood or specific tissue samples, and to correlate protein profiles with a specific disease state would have a profound effect on clinical diagnosis. As basic biomedical research tools, protein arrays would be invaluable for mapping the protein-to-protein connections of the human proteome, for high-throughput protein functional analysis like ligand binding, for identifying new protein drug targets, for identifying disease markers, for drug screening, and more. To test coupling of proteins to a synthetic support, nitrilotriacetic (NTA) acid was synthesized with a proximal tyrosine residue on PEGylated polystyrene beads (FIG. 5). The H6YGYG-I28 (SEQ ID NO. 7) protein was immobilized on the surface of the beads by Ni(II) or Cu(II) chelation through the NTA group. Some samples were oxidized with H2O2. The amount of protein bound to the beads was determined for each condition. To determine if the protein crosslinked covalently to the beads, bead bound protein was measured after washing the beads with EDTA, a chelating agent that disrupts Ni(II)-NTA-his-tag bonds. Without metal ion, I28 did not bind to the beads (Table II). In the presence of Ni(II) or Cu(II) protein was bound to the beads, with about 3× more protein bound with Ni(II) than Cu(II). EDTA stripped the protein off the beads with both metals, as expected. On the other hand, Cu(II) samples oxidized with H2O2 had bead bound protein that was not stripped by EDTA in about the same amount as the unoxidized and unstripped samples. Although preliminary, the results suggest that covalent bonds were formed between the I28 his-tyr-tags and the tyr-NTA groups on the bead surface. TABLE II relative H6YGYG-I28 bound to tyr-NTA beads. Sample no EDTA EDTA No metal 0 — Ni(II) 1.0 ± 0.38 0 Cu(II) 0.33 ± 0.04 0.03 Cu(II)/H202 — 0.32 ± 0.06 H202 — 0 Together with the literature precedents, the HY-tagged I28 crosslinking and the surface immobilization results demonstrate that, in principle, a metal complex between two chelators will catalyze crosslinking between strategically placed phenolic groups (tyrosines) in the presence of a suitable oxidant. These results are distinct in several respects from the earlier reports of his6-tag mediated crosslinking (Fancy, D. A., et al., Chem Biol, 1996. 3(7): p. 551-9). First, titin I28 domains do not naturally associate in solution. Second, the position of the tyr residues relative to the his6-tag is shown to be a major factor in crosslinking efficiency. Third, the technique has been extended to crosslinking a peptide chelator to a surface-bound synthetic chelator. It is expected that the HIS-tag, which is nearly ubiquitous on recombinant proteins, can be used generally as a convenient site for site-specific conjugation, crosslinking, and immobilization of proteins. Example 4 Protein Hydrogels Utility for protein encapsulation and protein-based hydrogels is demonstrated by coupling the synthetic chelator to a monomer. The coupled monomer may then be copolymerized with acrylamide in a manner analogous to earlier work on hybrid hydrogels crosslinked with I28 domains. Chen et al., Bioconjugate Chem., 11:734-740 (2000). Hydrogel formation is initiated through metal coordination bonds, and is then converted to covalent bonds. Covalent bond formation is demonstrated by evaluating hydrogel structure under conditions that disrupt metal coordination bonds. Double HY-tagged will polymerize. Novel protein materials will be created by crosslinking single and mixed double HY-tagged protein domains. These novel protein block copolymers may have unique properties. A possible application is use as a biocompatible, water-based surgical or dental adhesive. Such adhesives could be made up of polymer, protein/polymer, or simply protein compositions applied to a wound or tooth which could then be cured by the application of a mild oxidant as a curing agent. In some embodiments, especially those utilizing peroxides, such glues would sterilize the wound to which they are applied. Further, the protein used could be specifically designed to meet immunological tolerances and could include human proteins in part or whole. The instant invention could also be used in encapsulating proteins, cells, microbes, viruses, etc., through the formation of hydrogels containing the desired particles. Example 5 DNA Conjugates DNA Conjugates would often take the form of DNA-chips covered with thousands of differing sequences. By attaching a polynucleotide to a ligand as described herein, such will interact with HY-tagged target proteins and allow bonding. This would allow specific proteins to be addressed/targeted to specific DNAs, or even protein sequences on a surface, and then to be covalently bound there. Similarly, protein arrays such as those using PPO triblock pluronics with exposed (to the aqueous phase) PEO for preventing denaturing on surfaces could be used with the method of the instant invention. These would show additional usefulness since they allow for the specific orientation of the surface proteins. Example 6 Chelators Most chelators provide “space” for up to four coordination bonds. In one embodiment, the illustrative synthetic chelators discussed herein illustratively have capacity to form at least six of such bonds in order to form the complex needed and to cause covalent bond formation from the coordination bond in response to exposure to a mild oxidant as described herein. Four of the sites are used by the chelator, thus leaving two to form coordination bonds with the HY-tags. Illustratively, the chelators contain or are in close proximity to a phenolic functional group. Other functional groups for oxidative crosslinking may be used. All patents and other publications cited herein are expressly incorporated by reference. Although the invention has been described in detail with reference to certain preferred embodiments, variations and modifications exist within the scope and spirit of the invention as described and defined in the following claims.

<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>Complex networks of highly crosslinked biopolymers are common materials in living tissues. Familiar examples of these are the networks of collagen fibers that form the matrices of skin, bones, and connective tissues. The crosslinking found in these materials gives them their tensile strength, elasticity, and other valuable characteristics. In nature, the crosslinking, which is so critical to the function of these tissues, is accomplished by enzymatic oxidation of specific amino acid side chains of the protein materials involved, thus creating reactive intermediates which spontaneously form crosslinks. In the case of collagen and elastin, the s-amino group of specific lysine residues are oxidatively deaminated by lysyl oxidase into reactive aldehyde groups that spontaneously condense with neighboring peptidyl aldehydes or s-amino groups (Kagan, H. M. et al., J Cell Biochem, 2003. 88(4): p. 660-72). Another widely occurring mechanism of biomolecule crosslinking is oxidative coupling through phenols. Examples are the formation of lignin, which is a major structural component of plant cell walls, the formation of melanin pigments, the curing of tree sap into hard lacquers, the formation of peptidic natural products that exhibit high biological activity, such as vancomycin (Jung, G., Letters in Peptide Science, 2001. 8(3-5): p. 259-265; Malnar, I. et al. Tetrahedron Letters, 2000. 41(12): p. 1907-1911; Nishiyama, S., et al., Tetrahedron Letters, 1994. 35(45): p. 8397-8400) and bouvardin (Boger, D. L., et al. JACS, 1994. 116(19): p. 8544-56), through the formation of dityrosine protein crosslinks. Dityrosine protein linkages have been found in many structural proteins including elastin (LaBella, F., et al., Biochem Biophys Res Commun., 1967. 26(6): p. 748-53; Malanik, V. et al., Connect Tissue Res, 1979. 6(4): p. 235-40), silk (Raven, D. J., C. Earland, et al., Biochim Diophys Acta, 1971. 251(1): p. 96-99), plant cell wall extensin (Fry, S. C., Biochem J, 1982. 204(2): p. 449-55; Brady, J. D., et al. Biochem J, 1996. 315(Pt 1): p. 323-7), and in hardened fertilization membranes of insect and sea urchin eggs (Foerder, C. A. et al., PNAS ( USA ), 1977. 74(10): p. 4214-8). These oxidative phenolic coupling processes are catalyzed by a large number of structurally and mechanistically distinct metalloenzymes, including peroxidases, tyrosinases, and laccases. Peroxidases crosslink tyrosines by extracting a single electron from the phenol side chain to create a radical that then reacts with a vicinal phenol side chain to form dityrosine or isodityrosine (Michon, T., et al., Biochemistry, 1997. 36(28): p. 8504-13; Eickhoff, H., et al., Tetrahedron, 2001. 57(2): p. 353-364). Tyrosinases may crosslink tyrosine residues in two steps: first, the phenol side chain is hydroxylated forming 3,4-dihydroxyphenyl-L-alanine (DOPA); second, DOPA is further oxidized to form reactive o-quinones that spontaneously crosslink (Sanchez-Ferrer, A., et al., Biochim Biophys Acta, 1995. 1247(1): p. 1-11; Espin, J. C., et al., Eur J Biochem, 2000.267(5): p. 1270-9). These natural oxidative protein crosslinking mechanisms are mediated by transition metal-peptidyl coordination complexes. The redox active metal complexes come in many forms. Lysyl oxidase contains a single copper (II) atom and an organic co-factor formed by the intermolecular crosslinking of a lysine &amine and a tyroxyl quinone (Kagan, H. M. et al., J Cell Biochem, 2003. 88(4): p. 660-72). Tyrosinases (Sanchez-Ferrer, A., et al., Biochim Biophys Acta, 1995. 1247(1): p. 1-11) and laccases (Thurston, C. F., Microbiology, 1994. 140: p. 19-26) are multi-copper enzymes that transfer electrons to molecular oxygen. Peroxidases that crosslink tyrosines are iron-heme proteins that transfer single electrons from phenols to H 2 O 2 (Michon, T., et al., Biochemistry, 1997. 36(28): p. 8504-13; Oudgenoeg, C., et al., J. Agric. Food Chem., 2001.49(5): p. 2503-10). Nature has found many distinct metal-mediated pathways for extracting electrons to crosslink phenolic compounds. Another particularly intriguing example of crosslinking through tyrosine derivatives occurs in mussel byssal threads, which are specialized ligaments that bond the animals to an external substrate. The byssal threads contain several proteins and are heavily diDOPA crosslinked (Rzepecki, L. M., et al., Mol Mar Bid Biotechmol, 1991. 1(1): p. 78-88; McDowell, L. M., et al., J Biol Chem, 1999. 274(29): p. 20293-5). The thread proteins include three unusual collagens with blocky primary structures; a central collagen block is flanked by either elastin-like blocks (pre-ColP) (Coyne, K. J., et al., Science, 1997. 277(5333) p. 1830-2), silk-like blocks (pre-ColD) (Qin, X X., et al., J Biol Chem, 1997. 272(51): p. 32623-7), or amorphous glycine-rich blocks (pre-ColNG) (Qin, X X. et al., PNAS ( USA ), 1998. 95(18): p. 10517-22). All three have histidine- and DOPA-rich domains at the amino- and carboxyl-termini. The histidine blocks likely chelate the several metal ions found associated with byssal threads. Chelate complexes are thought to participate in non-covalent intermolecular crosslinking of the collagens (Vaccaro, F. et al., Biomacromolecules, 2001. 2(3): p. 906-11). Chelated transition metal ions, particularly Ni(II), can participate in oxidative crosslinking of biomolecules. Much of the research in this area has been done from the perspective of understanding nickel toxicity, which may be largely due to its oxidative activity when chelated by peptides, proteins, or nucleic acids (Gill, G., et al., Chem Res Toxicol, 1997. 10(3): p. 302-9; Bal, W., et al., Chem Res Toxicol, 2000. 13(7): p. 616-24). A second area of research has focused on creating synthetic catalysts that mimic metalloenzymes. For example, tyrosinase model complexes have been synthesized that are capable of regiospecific oxidation of phenol and catechol (Monzani, E., et al. Inorganic Chemistry, 1998. 37: p. 553-562) and regiospecific polymerization of phenol into poly(1,4-phenylene oxide) (Higashimura, H., et al. J. Am. Chem. Soc., 1998. 120: p. 8529-8530). A third area of research has been directed at exploiting the oxidative activity of chelated Ni(II) to create reagents for in vitro conjugation, crosslinking, or cleavage of biomolecules. A number of metal complexes have been synthesized that specifically modify DNA (Muller, J. G., et al., J Inorg Biochem, 1994. 54(3): p. 199-206; Burrows, C. J., et al., Acta Chem Scand, 1996. 50(4): p. 337-44; Hickerson, R. P., et al., J Mol Biol, 1998. 279(3): p. 577-87; Stemmler, A. J. et al.: JACS, 1999. 121(29): p. 6956-6957). With regard to protein modification, others have found that Ni(II) complexed by the tripeptide NH 2 -Gly-Gly-His (GGH) in the presence of the relatively strong oxidant monoperoxyphthalic acid (MMPP) crosslinked proteins known to associate in solution (Brown, K. C., et al., Biochemistry, 1995. 34(14): p. 4733-9). Subsequently, GGH genetically appended to the dimeric protein, ecotin, mediated intermolecular crosslinking between tyrosine residues in the presence of MMPP and Ni(II) (Brown, K. C., et al., Biochemistry, 1998. 37(13): p. 4397-406). Crosslinking between wild-type ecotin, in which tyrosine residues at the dimer interface are separated by 20 Å, was relatively inefficient (15%). By placing tyrosine residues within 5 Å of one another at the dimer interface, crosslinking efficiency was increased to 60%. This demonstrated a major advantage of protein crosslinking mediated by peptide metal complexes, that a redox active Ni(II) chelator and target tyrosine residues can be genetically positioned within a protein, creating the potential for site specific protein modification through oxidative conjugation or crosslinking. A recent report, however, revealed that this chemistry is much more complex than just dityrosine formation. A number of reactions occur in the strong oxidizing environment, and crosslinking between the terminal GG residues and tyrosine is one of the major reactions (Person, M. D., et al., Protein Sci, 2001. 10(8): p. 1549-62). The His 6 tag (SEQ ID NO. 1) commonly used for purification of recombinant proteins by immobilized metal affinity chromatography (IMAC) has also been shown to be redox active in the presence of nickel(II) and peracid oxidants. HIS-tagged glutathione S-transferase (H 6 GST (SEQ ID NO. 2)), a dimer in solution, was covalently crosslinked in the presence of Ni(II) and MMPP (Fancy, D. A., et al., Chem Biol, 1996. 3(7): p. 551-9). Proteins that do not naturally associate with H 6 GST were not crosslinked, demonstrating that His 6 -mediated crosslinking does not proceed through a highly diffusible reactant and crosslinking is localized to the vicinity of the His 6 tag. Going further, the same research group demonstrated that, in the presence of MMPP and Ni(II), H 6 GST mediated the formation of dityrosine from free tyrosine, that the mutagenic removal of tyrosine residues from H 6 GST decreased crosslinking efficiency, and that chemical addition of tyrosine residues using the Bolton-Hunter reagent increased crosslinking efficiency (Fancy, D. A., et al., Biochem Biophys Res Commun, 1998. 247(2): p. 420-26). The primary interest of this research appears to be the architectural analysis of multi-protein complexes. A large and successful industry has grown up around the development of reagents for the post-translational chemical modification of proteins. Despite the ingenious variety of reagents and methods available, there is a continuing need for new protein technologies that grows in proportion to the increasing importance of proteins in several major industries, including pharmaceutics, clinical diagnostics, chemicals, energy, agriculture, environmental protection, food, and textiles processing. New and better tools for labeling, conjugating, crosslinking, and immobilizing proteins would be valuable in all of these industries. The expanding industrial use of proteins, driven by new protein technologies, may have profound effects on human health, ranging from more cost effective pharmaceuticals to decreased environmental and the consequent human health impact from the production of chemicals and energy. In particular, methods are desired for crosslinking proteins, polymers, and/or other moieties, including those that are not naturally associated, illustratively in a manner that is predictable. Accordingly, a method of crosslinking proteins (such as enzymes), polymers (including biopolymers such as protein, polysaccharide, poly-nucleic acid, lipid, and synthetic polymers such as polyethylene glycol, (“PEG”), polypropylene glycol, polyesters, and polymeric surfaces (such as pluronics)), and/or other moieties (such as fluorescent compounds, small molecules illustratively having a molecular weight from 50 g/mol to 800 g/mol, and small molecules having a degree of polymerization from 1 to about 10), by contact with an oxidant after associating the two species to be linked in a coordination complex with a metal ion or ions is provided. Such a method is useful in a variety of applications, including the labeling of proteins, PEGylating proteins, coupling proteins and polymers, and affixing proteins to surfaces. In some embodiments, the method comprises a method of crosslinking a first and a second protein comprising the steps of attaching a metal-binding peptide, illustratively a HY-tag, to the first protein using methods known in the art; attaching a metal-binding peptide to the second protein using methods known in the art; forming a coordination complex between the first protein, the second protein, and a metal ion; and crosslinking the first and second proteins by exposing the coordination complex to an oxidant. In illustrative embodiments of the instant invention, the metal ion is selected from the group consisting of nickel, copper, zinc, and cobalt, gadolinium, iron, osmium, palladium, rhodium, ruthenium, samarium, selenium, silver, strontium, tantalum, thulium, tin, tungsten, vanadium, yttrium, and zinc. In others, the metal ion may be a first row transition metal ion. The methods of this invention may be used for crosslinking any combination of proteins, polymers, and small molecules. An oxidizing agent is a chemical reagent that is an oxidizer, or which promotes the oxidation of a desired reagent. In some embodiments of the invention, MMPP is used to promote the oxidation of tyrosine residues. Other oxidants have been found suitable as well, including peroxides, other peracids, oxidizing enzymes such as tyrosinase, oxygen, and other weaker oxidants, wherein a “weaker oxidant” is weaker than MMPP. In some embodiments, however, a stronger oxidant may be used. Illustratively, the oxidizing agent may be generated from an electrode surface. In one embodiment, the electrode surface is coated with a synthetic or natural polymer. Na 2 SO 3 may also be used. While not itself an oxidant, Na 2 SO 3 auto-oxidizes in the presence of complexed NiH to persulfate (SO 5 ). In another embodiment, the oxidizing agent may be activated by a metalloenzyme, including but not limited to a peroxidase, a tyrosinase, a laccase, and a catechol oxidase. One suitable metalloenzyme is horseradish peroxidase. In some embodiments, the ligand used to create the coordination complex is a metal-binding peptide or metal chelating tag, such as an HY-tag. In illustrative embodiments of the instant invention, the HY-tag is chosen from a group of sequences that comprise about four to ten histidine residues and a number of tyrosine residues. The sequences largely differ from each other in the placement of the tyrosines. As used herein, the term HIS-tags refers to HIS-tags generally, while HIS-TYR tags or HY-tags refer to HIS-tags that include tyrosines therein. Either may be referred to as his 6 -tags when the number of histidine residues is specified. Also, it is understood that while HY-tags are used in illustrative embodiments, other chelating constructs comprised of amino acids and/or other natural or synthetic monomers may be used, illustratively including tyrosine, dihydroxyphenylalanine, or other phenolic groups. It is understood that phenolic groups includes compounds having one or more aromatic benzene rings having one or more hydroxyl groups (—OH). In addition, phenolic derivatives, including oxidized forms of phenolic groups, may be used. Phenolic groups and phenolic derivatives may contain further substituents on the benzene ring in addition to the hydroxyl group(s). Some of the embodiments of the invention may comprise methods for labeling proteins, as when a fluorescent label (illustratively fluorescein, rhodamine, CY-3, and CY-5), enzyme, or other molecule is attached. Other such molecules could include biotin, digoxigenin, polyethylene glycol, pluronics, and other suitable labels. In some embodiments, the invention comprises a method of conjugating a protein with a synthetic polymer comprising the steps of attaching a HY-tag to a selected protein; attaching a HY-tag or other metal-chelating group containing or in close proximity to a phenolic functional group to a selected polymer; forming a coordination complex between the protein, the polymer, and a metal ion; and crosslinking the protein and polymer by exposing the coordination complex to an oxidant. In various of these embodiments, the polymer is a synthetic polymer. In some, the polymer is polyethylene glycol. In others, the polymer is chosen from the group of polyacrylates, polymer surfaces such as pluronics, carbohydrates such as dextran, and lipids. In still other embodiments, HY-tags, which may be the same or different, are used to link two polymers. Other embodiments of the instant invention comprise methods of immobilizing a protein or other moiety on a polymer surface under conditions that preserve protein structure and activity, comprising the steps of modifying a polymeric surface such that the polymeric surface comprises a synthetic chelator; attaching a HY-tag to a protein; forming a coordination complex between the polymeric surface, the protein, and a metal ion; and immobilizing the protein to the polymeric surface by exposing the coordination complex to an oxidant, thus causing the crosslinking of the polymer and the protein. In some embodiments, the polymer surface is further comprised of a synthetic polymer. In others, the polymer is polyethylene glycol. In still others, the polymer is a pluronic. Similarly, the moiety may already be immobilized on a solid surface and the method may be used to link a second moiety to the surface. Examples of solid surfaces include tissues, polymers, metals, ceramics, composites, biopolymers, bioceramics (such as bones and teeth), and colloidal particles. Colloidal particles illustratively include materials gold, silver, silica, semiconductors, fluorescent semiconductors, polystyrene, polymeric micelles, dendrimers, liposomes, and viruses, and may be of any size, illustratively of from 1 nm to 100 μM. The polymer may be coated onto or otherwise bound to the solid surface. It is also understood that the methods of this invention may be used to link two different surfaces together, wherein each of the two moieties is immobilized on its respective surface. Illustratively, this may be useful when each of the surfaces is a tissue, and the crosslinking may function as a surgical glue. While targets catalyzed by the mildest possible oxidant, illustratively O 2 , are desired for use with proteins that are particularly sensitive to oxidation, it is understood that stronger oxidants may be used in some instances, and that the metal complex may be selected accordingly. Also, while tyrosines are used to crosslink through dityrosine formation, other phenolic residues may be used and crosslinking may occur through a substituted bis-phenol adduct. Various features and embodiments of the instant invention are useful for a variety of common research and medical applications. One of these is use in the formation of hydrogels. The ability to provide predictable crosslinking of the proteins in such gels could allow the formation of new types of gels with unique properties and characteristics. This application could also be used to encapsulate cells, proteins, and DNA for preservation and use. A related application would be use of the invention as a surgical glue. Such a glue could be composed of specifically-chosen proteins selected for ability to prevent or avoid an immune response, promote growth and regeneration of surrounding tissue, degrade over time, or exhibit any other possible characteristic. Additionally, the glue could be applied in a liquid form to the wound, and then the glue could be cured and the wound sanitized simultaneously by the application of hydrogen peroxide as an oxidant/sterilant. Many other uses are possible. These and other objects, features, and advantages of the present invention will become more fully apparent from the following description and appended claims, or maybe learned by the practice of the invention as set forth hereinafter.

<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>Complex networks of highly crosslinked biopolymers are common materials in living tissues. Familiar examples of these are the networks of collagen fibers that form the matrices of skin, bones, and connective tissues. The crosslinking found in these materials gives them their tensile strength, elasticity, and other valuable characteristics. In nature, the crosslinking, which is so critical to the function of these tissues, is accomplished by enzymatic oxidation of specific amino acid side chains of the protein materials involved, thus creating reactive intermediates which spontaneously form crosslinks. In the case of collagen and elastin, the s-amino group of specific lysine residues are oxidatively deaminated by lysyl oxidase into reactive aldehyde groups that spontaneously condense with neighboring peptidyl aldehydes or s-amino groups (Kagan, H. M. et al., J Cell Biochem, 2003. 88(4): p. 660-72). Another widely occurring mechanism of biomolecule crosslinking is oxidative coupling through phenols. Examples are the formation of lignin, which is a major structural component of plant cell walls, the formation of melanin pigments, the curing of tree sap into hard lacquers, the formation of peptidic natural products that exhibit high biological activity, such as vancomycin (Jung, G., Letters in Peptide Science, 2001. 8(3-5): p. 259-265; Malnar, I. et al. Tetrahedron Letters, 2000. 41(12): p. 1907-1911; Nishiyama, S., et al., Tetrahedron Letters, 1994. 35(45): p. 8397-8400) and bouvardin (Boger, D. L., et al. JACS, 1994. 116(19): p. 8544-56), through the formation of dityrosine protein crosslinks. Dityrosine protein linkages have been found in many structural proteins including elastin (LaBella, F., et al., Biochem Biophys Res Commun., 1967. 26(6): p. 748-53; Malanik, V. et al., Connect Tissue Res, 1979. 6(4): p. 235-40), silk (Raven, D. J., C. Earland, et al., Biochim Diophys Acta, 1971. 251(1): p. 96-99), plant cell wall extensin (Fry, S. C., Biochem J, 1982. 204(2): p. 449-55; Brady, J. D., et al. Biochem J, 1996. 315(Pt 1): p. 323-7), and in hardened fertilization membranes of insect and sea urchin eggs (Foerder, C. A. et al., PNAS ( USA ), 1977. 74(10): p. 4214-8). These oxidative phenolic coupling processes are catalyzed by a large number of structurally and mechanistically distinct metalloenzymes, including peroxidases, tyrosinases, and laccases. Peroxidases crosslink tyrosines by extracting a single electron from the phenol side chain to create a radical that then reacts with a vicinal phenol side chain to form dityrosine or isodityrosine (Michon, T., et al., Biochemistry, 1997. 36(28): p. 8504-13; Eickhoff, H., et al., Tetrahedron, 2001. 57(2): p. 353-364). Tyrosinases may crosslink tyrosine residues in two steps: first, the phenol side chain is hydroxylated forming 3,4-dihydroxyphenyl-L-alanine (DOPA); second, DOPA is further oxidized to form reactive o-quinones that spontaneously crosslink (Sanchez-Ferrer, A., et al., Biochim Biophys Acta, 1995. 1247(1): p. 1-11; Espin, J. C., et al., Eur J Biochem, 2000.267(5): p. 1270-9). These natural oxidative protein crosslinking mechanisms are mediated by transition metal-peptidyl coordination complexes. The redox active metal complexes come in many forms. Lysyl oxidase contains a single copper (II) atom and an organic co-factor formed by the intermolecular crosslinking of a lysine &amine and a tyroxyl quinone (Kagan, H. M. et al., J Cell Biochem, 2003. 88(4): p. 660-72). Tyrosinases (Sanchez-Ferrer, A., et al., Biochim Biophys Acta, 1995. 1247(1): p. 1-11) and laccases (Thurston, C. F., Microbiology, 1994. 140: p. 19-26) are multi-copper enzymes that transfer electrons to molecular oxygen. Peroxidases that crosslink tyrosines are iron-heme proteins that transfer single electrons from phenols to H 2 O 2 (Michon, T., et al., Biochemistry, 1997. 36(28): p. 8504-13; Oudgenoeg, C., et al., J. Agric. Food Chem., 2001.49(5): p. 2503-10). Nature has found many distinct metal-mediated pathways for extracting electrons to crosslink phenolic compounds. Another particularly intriguing example of crosslinking through tyrosine derivatives occurs in mussel byssal threads, which are specialized ligaments that bond the animals to an external substrate. The byssal threads contain several proteins and are heavily diDOPA crosslinked (Rzepecki, L. M., et al., Mol Mar Bid Biotechmol, 1991. 1(1): p. 78-88; McDowell, L. M., et al., J Biol Chem, 1999. 274(29): p. 20293-5). The thread proteins include three unusual collagens with blocky primary structures; a central collagen block is flanked by either elastin-like blocks (pre-ColP) (Coyne, K. J., et al., Science, 1997. 277(5333) p. 1830-2), silk-like blocks (pre-ColD) (Qin, X X., et al., J Biol Chem, 1997. 272(51): p. 32623-7), or amorphous glycine-rich blocks (pre-ColNG) (Qin, X X. et al., PNAS ( USA ), 1998. 95(18): p. 10517-22). All three have histidine- and DOPA-rich domains at the amino- and carboxyl-termini. The histidine blocks likely chelate the several metal ions found associated with byssal threads. Chelate complexes are thought to participate in non-covalent intermolecular crosslinking of the collagens (Vaccaro, F. et al., Biomacromolecules, 2001. 2(3): p. 906-11). Chelated transition metal ions, particularly Ni(II), can participate in oxidative crosslinking of biomolecules. Much of the research in this area has been done from the perspective of understanding nickel toxicity, which may be largely due to its oxidative activity when chelated by peptides, proteins, or nucleic acids (Gill, G., et al., Chem Res Toxicol, 1997. 10(3): p. 302-9; Bal, W., et al., Chem Res Toxicol, 2000. 13(7): p. 616-24). A second area of research has focused on creating synthetic catalysts that mimic metalloenzymes. For example, tyrosinase model complexes have been synthesized that are capable of regiospecific oxidation of phenol and catechol (Monzani, E., et al. Inorganic Chemistry, 1998. 37: p. 553-562) and regiospecific polymerization of phenol into poly(1,4-phenylene oxide) (Higashimura, H., et al. J. Am. Chem. Soc., 1998. 120: p. 8529-8530). A third area of research has been directed at exploiting the oxidative activity of chelated Ni(II) to create reagents for in vitro conjugation, crosslinking, or cleavage of biomolecules. A number of metal complexes have been synthesized that specifically modify DNA (Muller, J. G., et al., J Inorg Biochem, 1994. 54(3): p. 199-206; Burrows, C. J., et al., Acta Chem Scand, 1996. 50(4): p. 337-44; Hickerson, R. P., et al., J Mol Biol, 1998. 279(3): p. 577-87; Stemmler, A. J. et al.: JACS, 1999. 121(29): p. 6956-6957). With regard to protein modification, others have found that Ni(II) complexed by the tripeptide NH 2 -Gly-Gly-His (GGH) in the presence of the relatively strong oxidant monoperoxyphthalic acid (MMPP) crosslinked proteins known to associate in solution (Brown, K. C., et al., Biochemistry, 1995. 34(14): p. 4733-9). Subsequently, GGH genetically appended to the dimeric protein, ecotin, mediated intermolecular crosslinking between tyrosine residues in the presence of MMPP and Ni(II) (Brown, K. C., et al., Biochemistry, 1998. 37(13): p. 4397-406). Crosslinking between wild-type ecotin, in which tyrosine residues at the dimer interface are separated by 20 Å, was relatively inefficient (15%). By placing tyrosine residues within 5 Å of one another at the dimer interface, crosslinking efficiency was increased to 60%. This demonstrated a major advantage of protein crosslinking mediated by peptide metal complexes, that a redox active Ni(II) chelator and target tyrosine residues can be genetically positioned within a protein, creating the potential for site specific protein modification through oxidative conjugation or crosslinking. A recent report, however, revealed that this chemistry is much more complex than just dityrosine formation. A number of reactions occur in the strong oxidizing environment, and crosslinking between the terminal GG residues and tyrosine is one of the major reactions (Person, M. D., et al., Protein Sci, 2001. 10(8): p. 1549-62). The His 6 tag (SEQ ID NO. 1) commonly used for purification of recombinant proteins by immobilized metal affinity chromatography (IMAC) has also been shown to be redox active in the presence of nickel(II) and peracid oxidants. HIS-tagged glutathione S-transferase (H 6 GST (SEQ ID NO. 2)), a dimer in solution, was covalently crosslinked in the presence of Ni(II) and MMPP (Fancy, D. A., et al., Chem Biol, 1996. 3(7): p. 551-9). Proteins that do not naturally associate with H 6 GST were not crosslinked, demonstrating that His 6 -mediated crosslinking does not proceed through a highly diffusible reactant and crosslinking is localized to the vicinity of the His 6 tag. Going further, the same research group demonstrated that, in the presence of MMPP and Ni(II), H 6 GST mediated the formation of dityrosine from free tyrosine, that the mutagenic removal of tyrosine residues from H 6 GST decreased crosslinking efficiency, and that chemical addition of tyrosine residues using the Bolton-Hunter reagent increased crosslinking efficiency (Fancy, D. A., et al., Biochem Biophys Res Commun, 1998. 247(2): p. 420-26). The primary interest of this research appears to be the architectural analysis of multi-protein complexes. A large and successful industry has grown up around the development of reagents for the post-translational chemical modification of proteins. Despite the ingenious variety of reagents and methods available, there is a continuing need for new protein technologies that grows in proportion to the increasing importance of proteins in several major industries, including pharmaceutics, clinical diagnostics, chemicals, energy, agriculture, environmental protection, food, and textiles processing. New and better tools for labeling, conjugating, crosslinking, and immobilizing proteins would be valuable in all of these industries. The expanding industrial use of proteins, driven by new protein technologies, may have profound effects on human health, ranging from more cost effective pharmaceuticals to decreased environmental and the consequent human health impact from the production of chemicals and energy. In particular, methods are desired for crosslinking proteins, polymers, and/or other moieties, including those that are not naturally associated, illustratively in a manner that is predictable. Accordingly, a method of crosslinking proteins (such as enzymes), polymers (including biopolymers such as protein, polysaccharide, poly-nucleic acid, lipid, and synthetic polymers such as polyethylene glycol, (“PEG”), polypropylene glycol, polyesters, and polymeric surfaces (such as pluronics)), and/or other moieties (such as fluorescent compounds, small molecules illustratively having a molecular weight from 50 g/mol to 800 g/mol, and small molecules having a degree of polymerization from 1 to about 10), by contact with an oxidant after associating the two species to be linked in a coordination complex with a metal ion or ions is provided. Such a method is useful in a variety of applications, including the labeling of proteins, PEGylating proteins, coupling proteins and polymers, and affixing proteins to surfaces. In some embodiments, the method comprises a method of crosslinking a first and a second protein comprising the steps of attaching a metal-binding peptide, illustratively a HY-tag, to the first protein using methods known in the art; attaching a metal-binding peptide to the second protein using methods known in the art; forming a coordination complex between the first protein, the second protein, and a metal ion; and crosslinking the first and second proteins by exposing the coordination complex to an oxidant. In illustrative embodiments of the instant invention, the metal ion is selected from the group consisting of nickel, copper, zinc, and cobalt, gadolinium, iron, osmium, palladium, rhodium, ruthenium, samarium, selenium, silver, strontium, tantalum, thulium, tin, tungsten, vanadium, yttrium, and zinc. In others, the metal ion may be a first row transition metal ion. The methods of this invention may be used for crosslinking any combination of proteins, polymers, and small molecules. An oxidizing agent is a chemical reagent that is an oxidizer, or which promotes the oxidation of a desired reagent. In some embodiments of the invention, MMPP is used to promote the oxidation of tyrosine residues. Other oxidants have been found suitable as well, including peroxides, other peracids, oxidizing enzymes such as tyrosinase, oxygen, and other weaker oxidants, wherein a “weaker oxidant” is weaker than MMPP. In some embodiments, however, a stronger oxidant may be used. Illustratively, the oxidizing agent may be generated from an electrode surface. In one embodiment, the electrode surface is coated with a synthetic or natural polymer. Na 2 SO 3 may also be used. While not itself an oxidant, Na 2 SO 3 auto-oxidizes in the presence of complexed NiH to persulfate (SO 5 ). In another embodiment, the oxidizing agent may be activated by a metalloenzyme, including but not limited to a peroxidase, a tyrosinase, a laccase, and a catechol oxidase. One suitable metalloenzyme is horseradish peroxidase. In some embodiments, the ligand used to create the coordination complex is a metal-binding peptide or metal chelating tag, such as an HY-tag. In illustrative embodiments of the instant invention, the HY-tag is chosen from a group of sequences that comprise about four to ten histidine residues and a number of tyrosine residues. The sequences largely differ from each other in the placement of the tyrosines. As used herein, the term HIS-tags refers to HIS-tags generally, while HIS-TYR tags or HY-tags refer to HIS-tags that include tyrosines therein. Either may be referred to as his 6 -tags when the number of histidine residues is specified. Also, it is understood that while HY-tags are used in illustrative embodiments, other chelating constructs comprised of amino acids and/or other natural or synthetic monomers may be used, illustratively including tyrosine, dihydroxyphenylalanine, or other phenolic groups. It is understood that phenolic groups includes compounds having one or more aromatic benzene rings having one or more hydroxyl groups (—OH). In addition, phenolic derivatives, including oxidized forms of phenolic groups, may be used. Phenolic groups and phenolic derivatives may contain further substituents on the benzene ring in addition to the hydroxyl group(s). Some of the embodiments of the invention may comprise methods for labeling proteins, as when a fluorescent label (illustratively fluorescein, rhodamine, CY-3, and CY-5), enzyme, or other molecule is attached. Other such molecules could include biotin, digoxigenin, polyethylene glycol, pluronics, and other suitable labels. In some embodiments, the invention comprises a method of conjugating a protein with a synthetic polymer comprising the steps of attaching a HY-tag to a selected protein; attaching a HY-tag or other metal-chelating group containing or in close proximity to a phenolic functional group to a selected polymer; forming a coordination complex between the protein, the polymer, and a metal ion; and crosslinking the protein and polymer by exposing the coordination complex to an oxidant. In various of these embodiments, the polymer is a synthetic polymer. In some, the polymer is polyethylene glycol. In others, the polymer is chosen from the group of polyacrylates, polymer surfaces such as pluronics, carbohydrates such as dextran, and lipids. In still other embodiments, HY-tags, which may be the same or different, are used to link two polymers. Other embodiments of the instant invention comprise methods of immobilizing a protein or other moiety on a polymer surface under conditions that preserve protein structure and activity, comprising the steps of modifying a polymeric surface such that the polymeric surface comprises a synthetic chelator; attaching a HY-tag to a protein; forming a coordination complex between the polymeric surface, the protein, and a metal ion; and immobilizing the protein to the polymeric surface by exposing the coordination complex to an oxidant, thus causing the crosslinking of the polymer and the protein. In some embodiments, the polymer surface is further comprised of a synthetic polymer. In others, the polymer is polyethylene glycol. In still others, the polymer is a pluronic. Similarly, the moiety may already be immobilized on a solid surface and the method may be used to link a second moiety to the surface. Examples of solid surfaces include tissues, polymers, metals, ceramics, composites, biopolymers, bioceramics (such as bones and teeth), and colloidal particles. Colloidal particles illustratively include materials gold, silver, silica, semiconductors, fluorescent semiconductors, polystyrene, polymeric micelles, dendrimers, liposomes, and viruses, and may be of any size, illustratively of from 1 nm to 100 μM. The polymer may be coated onto or otherwise bound to the solid surface. It is also understood that the methods of this invention may be used to link two different surfaces together, wherein each of the two moieties is immobilized on its respective surface. Illustratively, this may be useful when each of the surfaces is a tissue, and the crosslinking may function as a surgical glue. While targets catalyzed by the mildest possible oxidant, illustratively O 2 , are desired for use with proteins that are particularly sensitive to oxidation, it is understood that stronger oxidants may be used in some instances, and that the metal complex may be selected accordingly. Also, while tyrosines are used to crosslink through dityrosine formation, other phenolic residues may be used and crosslinking may occur through a substituted bis-phenol adduct. Various features and embodiments of the instant invention are useful for a variety of common research and medical applications. One of these is use in the formation of hydrogels. The ability to provide predictable crosslinking of the proteins in such gels could allow the formation of new types of gels with unique properties and characteristics. This application could also be used to encapsulate cells, proteins, and DNA for preservation and use. A related application would be use of the invention as a surgical glue. Such a glue could be composed of specifically-chosen proteins selected for ability to prevent or avoid an immune response, promote growth and regeneration of surrounding tissue, degrade over time, or exhibit any other possible characteristic. Additionally, the glue could be applied in a liquid form to the wound, and then the glue could be cured and the wound sanitized simultaneously by the application of hydrogen peroxide as an oxidant/sterilant. Many other uses are possible. These and other objects, features, and advantages of the present invention will become more fully apparent from the following description and appended claims, or maybe learned by the practice of the invention as set forth hereinafter.

20061004

20160517

20101021

60403.0

C12Q170

KOSAR, AARON J

Crosslinking Within Coordination Complexes

SMALL

ACCEPTED

C12Q

ACCEPTED

Shelf unit for use in rack for communication equipment

A shelf unit for use in a rack for communication equipment comprising: a front body including a pair of side panels for containing PCBs; a back board detachably mounted to the rear ends of the side panels of the front body; and a rear body including a pair of side panels for containing PCBs. Connecting members are mounted adjacent to the rear ends of the side panels of the front body and protrude outward therefrom. A pair of connecting plates extends forward from the front ends of the respective side panels of the rear body. L-shaped slots are provided at the connecting plates, into which the respective connecting members are fitted.

1. A shelf unit for use in a rack for communication equipment, the shelf unit comprises: a front body including a pair of side panels having front and rear ends and defining a space for containing PCBs, and connecting members mounted adjacent to the rear ends of the side panels and protruding outward from the side panels; a back board, to which the PCBs are connected, detachably mounted to the rear ends of the side panels of the front body; and a rear body including a pair of side panels having front and rear ends and defining a space for containing PCBs connected to the back board, a pair of connecting plates extending forward from the front ends of the side panels and having a distance therebetween so that the connecting plates are in close contact with outer surfaces of the side panels of the front body, and slots provided at the connecting plates into which the respective connecting members are fitted. 2. The shelf unit of claim 1, wherein each of the slots has a substantially L-shaped configuration, which includes a horizontal portion extending horizontally from the front end of the connecting plate and a vertical portion extending vertically upward from the end of the horizontal portion. 3. The shelf unit of claim 1, wherein the each of the connecting members is implemented as a screw, which is fastened into the side panels of the front body by a predetermined depth.

TECHNICAL FIELD The present invention generally relates to a shelf unit for use in a rack for communication equipment, and more particularly to a shelf unit for use in a rack for communication equipment that is designed to facilitate the demounting and remounting of a back board for repairs or maintenances. BACKGROUND ART FIG. 1 is a perspective view illustrating a conventional rack for communication equipment. As shown in the drawing, a conventions rack 1 for communication equipment includes a rectangular base plate 2 and posts 4 that are mounted vertically on the base plate 2. Reinforcing plates 6 are attached to the posts 4 and bus bars 8 are fixed to the reinforcing plates 6. A plurality of through-holes 10 is provided at the reinforcing plates 6 in a vertical line. Two groups of through-holes 10 provided at the respective reinforcing plates 6 are opposed to each other. Further, a plurality of cabling bars 12 is mounted to the re-inforcing plates 6 in such a manner that both end portions of each cabling bar 12 are fitted through the two opposite through-holes 10. A plurality of shelf units for storing communication equipment are mounted in the rack 1, which will be described with reference to FIGS. 2 and 3. A shelf unit 20 comprises a pair of side panels 22 and 24. It further comprises supporting plates 26 and 28 that are mounted to the top of the front and rear end portions of the side panels 22 and 24 for supporting them. Front PCBs (printed circuit board) 40, which include a power unit and a PBA (printed board assembly) unit, are mounted in the front-half portion of the shelf unit 20. A back board 30, to which the front PCBs 40 are connected, is mounted in the central portion of the shelf unit 20. Rear PCBs 50 are mounted in the rear-half portion of the shelf unit 20 and connected to the back board 30. In order to support the front and rear PCBs 40 and 50, PCB guides 32 and 34 are mounted at the bottom of the front and rear end portions of the side panels 22 and 24. All components described above are coupled to one another by means of screws 36 and 38. A procedure of demounting the back board 30 from the conventional shelf unit 20 is explained as follows. First, the front PCBs 40 and rear PCBs 50 are removed from the back board 30. Secondly, the screws 38 for fixing the supporting plate 28 and PCB guide 34 to the side panels 22 and 24 are released to separate the supporting plate 28 and PCB guide 34 from the side panels 22 and 24. Finally, the screws 36 for fixing the back board 30 to the shelf unit 20 are released to separate the back board 30 from the shelf unit 20. Remounting the back board 30, supporting plate 28 and PCB guide 34 to the shelf unit 20 can be achieved according to the order that is reverse to the above-mentioned demounting procedure. However, when demounting and remounting the back board from and to the shelf unit for repairs or maintenances, there is a problem in that a worker must also demount and remount other elements (e.g., the supporting plate, the PCB guide, etc.) by releasing and fastening a plurality of screws by hand. Therefore, it takes much time and labor to repair or replace the back board. Further, it is very troublesome for the worker to align the screw holes of two corresponding elements when screwing them together. DISCLOSURE OF INVENTION Technical Problem The object of the present invention is to provide a shelf unit for use in a rack for communication equipment that is designed to facilitate the demounting and remounting of a back board from and to the shelf unit for repairs or maintenances. Technical Solution To accomplish the above-mentioned object, there is provided a shelf unit for use in a rack for communication equipment, comprising: a front body, which includes (1) a pair of side panels having front and rear ends and defining a space for containing PCBs, and (2) connecting members mounted adjacent to the rear ends of the side panels and protruding outward from the side panels; a back board, to which the PCBs are connected, detachably mounted to the rear ends of the side panels of the front body; and a rear body, which includes (1) a pair of side panels having front and rear ends and defining a space for containing PCBs connected to the back board, (2) a pair of connecting plates extending forward from the front ends of the side panels and having a distance therebetween so that the connecting plates are in close contact with outer surfaces of the side panels of the front body, and (3) slots provided at the connecting plates into which the respective connecting members are fitted. Advantageous Effects According to the features of the present invention, a front body and a rear body are provided separately and assembled or disassembled simply with or from each other by means of connecting members of the front body and slots of the rear body. Thus, a worker can easily demount and remount a back board which is provided between the front body and the rear body. BRIEF DESCRIPTION OF THE DRAWINGS The above object and features of the present invention will become more apparent from the following description of the preferred embodiments given in conjunction with the accompanying drawings. FIG. 1 is a perspective view showing a conventions rack for communication equipment. FIG. 2 is a perspective view showing a conventional shelf unit for use in a rack for communication equipment. FIG. 3 is an exploded perspective view showing the shelf unit depicted in FIG. 2. FIG. 4 is a perspective view showing a shelf unit for use in a rack for communication equipment in accordance with a preferred embodiment of the present invention. FIG. 5 is an exploded perspective view showing the shelf unit depicted in FIG. 4. FIG. 6 is an enlarged view showing a connecting member and a connecting plate of the shelf unit. FIG. 7 is an enlarged view showing a coupling state of the connecting member and the connecting plate of the shelf unit. BEST MODE FOR CARRYING OUT THE INVENTION The embodiment of the present invention will be readily understood as generally described and illustrated in the Figures provided herein and the accompanying text according to the above-identified technical scope of the present invention. FIG. 4 is a perspective view showing a shelf unit in accordance with a preferred embodiment of the present invention. FIG. 5 is an exploded perspective view showing the shelf unit depicted in FIG. 4. As shown in the drawings, a shelf unit 100 according to the present invention comprises (1) a front body 110 in which front PCBs 150 are mounted, (2) a back board 140 which are fixed to the rear end of the front body 110 by means of screws, and (3) a rear body 120 detachably combined with the front body 110, in which the rear PCBs 160 are mounted. The front and rear PCBs 150 and 160 are connected to the back board 140. The front body 110 includes (1) a pair of side panels 112 and 114 defining a space for containing the front PCBs 150, (2) a supporting plate 116 mounted at the top of the front end portion of the side panels 112 and 114 for supporting them, (3) a PCB guide 118 mounted at the bottom of the side panels 112 and 114 for guiding the front PCBs 150, and (4) connecting members 119 mounted adjacent to the rear end portions of the side panels 112 and 114. Each connecting member 119 protrudes outward from the side panels 112 and 114 by a predetermined height. Preferably, the connecting member 119 is implemented as a screw, which is fastened into the side panels 112 and 114 of the front body 110 by a certain depth. The rear body 120 includes (1) a pair of side panels 122 and 124 defining a space for containing rear PCBs 160, (2) a supporting plate 126 mounted at the top of the rear end portion of the side panels 122 and 124 for supporting then, (3) a PCB guide 128 mounted at the bottom of the side panels 122 and 124 for guiding the rear PCBs 160, and (4) a pair of connecting plates 129 extending from the front ends of the respective side panels 122 and 124 toward the front body 110. The pair of connecting plates 129 has such a distance therebetween that the connecting plates 129 are in dose contact with the outer surfaces of the side panels 112 and 114 of the front body 110. Also, the connecting plates 129 are provided with L-shaped slots 130 into which the connecting members 119 formed at the side panels 112 and 114 of the front body 110 are fitted. This is so that the connecting plates 129 become hung by the connecting members 119. As shown in FIG. 6, each L-shaped slot 130 has a horizontal portion 132 extending horizontally from the front end of the connecting plate 129 and a vertical portion 134 extending vertically upward from the end of the horizontal portion 132. When assembling the shelf unit 100 of the present invention, the front and rear bodies 110 and 120, to which the supporting plates 116 and 126 and the PCB guides 118 and 128 are mounted, are provided preferentially. Then, as shown in FIGS. 5 and 6, the back board 140 is mounted to the rear end portion of the front body 110 in an erected state by means of screws. Then, the rear body 120 is moved toward the front body 110 while the connecting plates 129 closely contact the side panels 112 and 114 of the front body 110 until the connecting members 119 protruding outward from the side panels 112 and 114 of the front body 110 enter into horizontal portions 132 of the L-shaped slots 130. In a state where the respective connecting members 119 of the front body 110 enter the ends of the horizontal portions 132 of the respective L-shaped slots 130 of the rear body 120, if the removing force applied to the rear body 120 is removed, then the rear body 120 becomes subjected to a downward force due to its own weight, in which the connecting members 119 proceed into vertical portions 134 of the L-shaped slots 130. As a result, the rear body 120 is combined with the front body 110 in such a manner that the connecting plates 129 of the rear body 120 are hung by the connecting members 119 of the front body 110, as shown in FIG. 7. Accordingly, the front and rear bodies 110 and 120 can be easily disassembled simply by pulling the connecting plates 129 of the rear body 120 out of the connecting members 119 of the front body 110. This facilitates the procedures of demounting and remounting the back board 140 from and to the shelf unit 100 when there needs to be a repair or replacement. While the present invention has been shown and described with respect to a particular embodiment of a shelf unit for use in a rack for communication equipment, it will be apparent to those skilled in the art that many changes and modifications may be made without departing from the scope of the invention as defined in the appended claims and those equivalent thereto. INDUSTRIAL APPLICABILITY As described above in detail, there is provided a shelf unit for use in a rack for communication equipment that includes a front body and a rear body which are provided separately and assembled or disassembled simply with or from each other by means of connecting members of the front body and L-shaped slots of the rear body. Thus, a worker can easily demount and remount a back board which is provided between the front body and the rear body. Accordingly, the time and labor required to repair or replace the back board can be significantly mitigated.

<SOH> BACKGROUND ART <EOH>FIG. 1 is a perspective view illustrating a conventional rack for communication equipment. As shown in the drawing, a conventions rack 1 for communication equipment includes a rectangular base plate 2 and posts 4 that are mounted vertically on the base plate 2 . Reinforcing plates 6 are attached to the posts 4 and bus bars 8 are fixed to the reinforcing plates 6 . A plurality of through-holes 10 is provided at the reinforcing plates 6 in a vertical line. Two groups of through-holes 10 provided at the respective reinforcing plates 6 are opposed to each other. Further, a plurality of cabling bars 12 is mounted to the re-inforcing plates 6 in such a manner that both end portions of each cabling bar 12 are fitted through the two opposite through-holes 10 . A plurality of shelf units for storing communication equipment are mounted in the rack 1 , which will be described with reference to FIGS. 2 and 3 . A shelf unit 20 comprises a pair of side panels 22 and 24 . It further comprises supporting plates 26 and 28 that are mounted to the top of the front and rear end portions of the side panels 22 and 24 for supporting them. Front PCBs (printed circuit board) 40 , which include a power unit and a PBA (printed board assembly) unit, are mounted in the front-half portion of the shelf unit 20 . A back board 30 , to which the front PCBs 40 are connected, is mounted in the central portion of the shelf unit 20 . Rear PCBs 50 are mounted in the rear-half portion of the shelf unit 20 and connected to the back board 30 . In order to support the front and rear PCBs 40 and 50 , PCB guides 32 and 34 are mounted at the bottom of the front and rear end portions of the side panels 22 and 24 . All components described above are coupled to one another by means of screws 36 and 38 . A procedure of demounting the back board 30 from the conventional shelf unit 20 is explained as follows. First, the front PCBs 40 and rear PCBs 50 are removed from the back board 30 . Secondly, the screws 38 for fixing the supporting plate 28 and PCB guide 34 to the side panels 22 and 24 are released to separate the supporting plate 28 and PCB guide 34 from the side panels 22 and 24 . Finally, the screws 36 for fixing the back board 30 to the shelf unit 20 are released to separate the back board 30 from the shelf unit 20 . Remounting the back board 30 , supporting plate 28 and PCB guide 34 to the shelf unit 20 can be achieved according to the order that is reverse to the above-mentioned demounting procedure. However, when demounting and remounting the back board from and to the shelf unit for repairs or maintenances, there is a problem in that a worker must also demount and remount other elements (e.g., the supporting plate, the PCB guide, etc.) by releasing and fastening a plurality of screws by hand. Therefore, it takes much time and labor to repair or replace the back board. Further, it is very troublesome for the worker to align the screw holes of two corresponding elements when screwing them together.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The above object and features of the present invention will become more apparent from the following description of the preferred embodiments given in conjunction with the accompanying drawings. FIG. 1 is a perspective view showing a conventions rack for communication equipment. FIG. 2 is a perspective view showing a conventional shelf unit for use in a rack for communication equipment. FIG. 3 is an exploded perspective view showing the shelf unit depicted in FIG. 2 . FIG. 4 is a perspective view showing a shelf unit for use in a rack for communication equipment in accordance with a preferred embodiment of the present invention. FIG. 5 is an exploded perspective view showing the shelf unit depicted in FIG. 4 . FIG. 6 is an enlarged view showing a connecting member and a connecting plate of the shelf unit. FIG. 7 is an enlarged view showing a coupling state of the connecting member and the connecting plate of the shelf unit. detailed-description description="Detailed Description" end="lead"?

20061107

20110222

20070222

79329.0

A47F700

PUROL, SARAH L

SHELF UNIT FOR USE IN RACK FOR COMMUNICATION EQUIPMENT

UNDISCOUNTED

ACCEPTED

A47F

ACCEPTED

Leakage Preventing Structure of Dish Washer

A leakage preventing structure of a dishwasher is provided. The structure includes a wash motor with a motor shaft disposed at its center, a sump housing that the motor shaft passes through, and a scaling portion that seals the space between the wash motor and the sump housing. The sealing portion is an aircap that controls the water level of washing water introduced into the aircap by means of air pressure of air inside the aircap, or a sealing member coupled to the motor shaft of the wash motor.

1. A leakage preventing structure of a dishwasher, comprising: a wash motor having a motor shaft disposed at a center thereof; a sump housing having the motor shaft inserted therethrough; and a sealing portion for sealing a space between the wash motor and the sump housing. 2. The structure according to claim 1, wherein the sealing portion seals a space between the motor shaft and the sump housing. 3. The structure according to claim 1, wherein the sealing portion is an aircap for controlling a water level of washing water introduced into the aircap by means of air pressure inside the aircap. 4. The structure according to claim 1, wherein the sealing portion is a sealing member coupled to the motor shaft of the wash motor. 5. The structure according to claim 1, wherein the sump housing includes a sealing case formed thereon for allowing the motor shaft to be inserted therethrough. 6. The structure according to claim 5, wherein the sealing case has sealing oil filled therein. 7. A leakage preventing structure of a dishwasher, comprising: a motor shaft through-hole disposed at a central bottom portion of a sump housing, the sump housing including a sealing case having a diameter larger than that of the motor shaft through-hole and having a predetermined height; an aircap installed inside the sump housing and covering a top of the sealing case; and a wash motor installed beneath the sump housing. 8. The structure according to claim 7, wherein the aircap includes a motor shaft through-sleeve for inserting a motor shaft of the wash motor therethrough, an aircap upper plate having a predetermined diameter and formed at a bottom of the motor shaft through-sleeve, and at least one aircap wall having a pre-determined diameter and height and formed to extend perpendicularly down from a bottom of the aircap upper plate. 9. The structure according to claim 7, wherein the aircap has air disposed therein for regulating a maximum water level of washing water introduced into the aircap. 10. The structure according to claim 9, wherein the maximum water level of washing water introduced into the aircap is maintained to be equal to or less than the height of the sealing case. 11. The structure according to claim 7, wherein the sealing case includes a sealing cover resting therein, the sealing cover being filled with sealing oil. 12. A leakage preventing structure of a dishwasher, comprising: a leakage preventing aircap including a motor shaft through-sleeve having a pre-determined diameter and height, an aircap upper plate protruding a pre-determined distance radially from a bottom of the motor shaft through-sleeve, an aircap outer wall extending from a bottom of the aircap upper plate, and at least one aircap inner wall formed within the aircap outer wall; and a sump housing on which the aircap is installed. 13. The structure according to claim 12, wherein the aircap inner and outer walls form a space therebetween in which air is disposed. 14. The structure according to claim 12, wherein air contained in the aircap limits a water level of washing water introduced into the aircap. 15. The structure according to claim 14, wherein the water level of washing water introduced into the aircap is restricted to be equal to or less than a height of a sealing case. 16. A leakage preventing structure of a dishwasher, comprising: a wash motor; a sealing member coupled to a shaft of the wash motor; and a sump housing forming a washing water reservoir, and including a sealing case at a bottom thereof for inserting the sealing member therein. 17. The structure according to claim 16, wherein the sealing member is installed outside the sump housing. 18. The structure according to claim 16, wherein the sealing case having a pre-determined height and diameter is formed at a central bottom portion of the sump housing, and the sealing case has a motor shaft through-hole having a pre-determined diameter and is formed at a top of the sealing case for inserting the motor shaft of the wash motor therethrough. 19. The structure according to claim 16, wherein the sealing member is made of a rubber material having a predetermined elasticity. 20. The structure according to claim 16, wherein the sealing member is coupled to the motor shaft of the wash motor before the wash motor is installed below the sump housing.

TECHNICAL FIELD The present invention relates to a dishwasher, and more particularly, to a leakage preventing structure of a dishwasher, which can prevent washing water stored in a sump from leaking out through a through-hole for a motor shaft. BACKGROUND ART A dishwasher is one of home appliances that can remove food particles from dishes using high-pressure washing water sprayed from nozzles. To be specific, a dishwasher includes a tub forming an interior space in which dishes to be washed are placed, a sump mounted under the tub to store washing water, a wash pump attached to one side of the sump to pump the washing water contained in the sump to spraying nozzles, a wash motor for driving the wash pump, a drain pump for draining dirty washing water after the washing has been completed, and a drain motor for driving the drain pump. The wash pump is installed inside the sump and the wash motor is installed below the sump, so that the wash motor and the wash pump are perpendicularly coplanar. Specifically, the shaft of the wash motor in the above configuration passes through into the sump and is coupled directly to the pump. An impeller inside the pump rotates according to the rotation of the motor shaft, thereby pumping washing water. Here, when the motor shaft is inserted through the bottom of the sump, washing water runs down the outer surface of motor shaft during its rotation and leaks out from the sump. While the motor shaft rotates, friction created between the shaft and the sump wears and reduces the effectiveness of the sealing function between the motor shaft and the sump. When a gap is created in the motor shaft through-hole between the motor shaft and the sump, washing water can leak through the gap. Also, when the fixture of a sealing member to the sump precludes the installation of the motor, the surface of the sealing member can be damaged in the installation process and washing water can leak out. DISCLOSURE OF INVENTION Technical Problem An object of the present invention is to provide a leakage preventing structure of a dishwasher capable of preventing washing water stored in the sump from leaking out along an outer surface of a motor shaft. Another object of the present invention is to provide a leakage preventing structure of a dishwasher with an improved seal assembly method and process that can prevent incurring damage to the sealing member during its assembly. Technical Solution To achieve these objects and other advantages and in accordance with the purpose of the invention, as embodied and broadly described herein, a leakage preventing structure of a dishwasher according to the present invention includes: a wash motor with a motor shaft at its center; a sump housing allowing insertion therethrough of the motor shaft; and a sealing portion for sealing the gap between the wash motor and the sump housing. The sealing portion may be an aircap for controlling the water level of washing water that enters the aircap, via air pressure therein, or a sealing member coupled to the wash motor shaft. ADVANTAGEOUS EFFECTS The leakage preventing structure of a dishwasher according to the present invention prevents washing water from leaking out along an outside of a motor shaft. More specifically, a sealing cover installed in a sealing case of the motor shaft and a sealing oil primarily prevents a washing water from leaking out, and an aircap covering the sealing cover secondarily prevents washing water from leaking out toward the sealing cover. Additionally, after a sealing member for preventing washing water leakage is coupled to the motor shaft, the motor is installed on the sump, so that no damage is incurred to the sealing member during installation. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a schematic sectional view of a dishwasher with a leakage preventing structure according to the present invention; FIG. 2 is an exploded perspective view of a sump having a leakage preventing structure according to a first embodiment of the present invention; FIG. 3 is a vertical, sectional view of a sump having the leakage preventing structure according to the first embodiment of the present invention; FIG. 4 is a cut-away perspective view of the leakage preventing structure according to the first embodiment of the present invention; FIG. 5 is an enlarged sectional view showing an aircap that is partially immersed in washing water according to the first embodiment of the present invention; FIG. 6 is a perspective view of a wash motor according to a second embodiment of the present invention; and FIG. 7 is a sectional view of the wash motor of FIG. 6 coupled to a sump housing. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, preferred embodiments of a leakage preventing structure of a dishwasher according to the present invention will be described in detail with reference to the accompanying drawings. While the present invention has been described and illustrated herein with reference to the preferred embodiments thereof, it will be apparent to those skilled in the art that various modifications and variations can be made therein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of the appended claims and their equivalents. FIG. 1 is a schematic sectional view of a dishwasher with a leakage preventing structure according to the present invention. Referring to FIG. 1, the dishwasher 100 having the leakage preventing structure of the present invention includes a tub 110 forming the outer shape of the dishwasher 100 and having a dish washing chamber on its inside, a door 111 formed on the front of the tub 110 to open and close the dish washing chamber, and a sump 200 formed at the central bottom portion of the tub 110 for holding washing water. Moreover, the dishwasher 100 includes a water guide 140 for guiding washing water pumped by a wash pump, a lower nozzle 160 disposed on top of the sump 200 and formed at the bottom of the dish washing chamber for spraying washing water upward, an upper nozzle 150 attached to the upper portion of the water guide 140 and formed to extend perpendicularly from the water guide 140 to the center of the dish washing chamber, and a top nozzle 155 formed on the ceiling portion of the tub 110 for spraying washing water perpendicularly downward. In order to wash dishes through the upper nozzle 150, an upper rack 120 is installed above the upper nozzle 150. In order to wash dishes through the lower nozzle 160, a lower rack 130 is installed above the lower nozzle 160. The upper rack 120 is supported by rails (not shown) on the inner sides of the tub 110 and slides forward and backward. An operation of the dishwasher 100 according to the present invention will be described below. First, a user opens the door 111 of the dishwasher 100, and pulls the upper rack 120 and/or the lower rack 130 out from the dish washing chamber. Next, the user places dishes on the upper and/or lower racks 120 and/or 130, closes the door 111. When the user presses the power button. the dish washing cycle begins. When power is supplied to the dishwasher 100 and a wash cycle begins, washing water enters the sump 200. When the sump 200 is filled with washing water, the wash motor 330 operates. When an impeller inside a wash pump (not shown) connected to the shaft of the wash motor spins, washing water is pumped to the lower nozzle 160 and the water guide 140. The washing water pumped to the water guide 140 moves to the top and upper nozzles 155 and 150 from where it is sprayed into the dish washing chamber. The dishes stacked on the upper and lower racks 120 and 130 are washed by the sprayed washing water. Here, the top nozzle 155 sprays washing water downward and the upper nozzle 150 sprays washing water upward to wash dishes stacked on the upper rack 120. The lower nozzle 160 sprays washing water upward to wash dishes stacked on the lower rack 130. Nozzle openings may be formed on the lower portion of the upper nozzle 150 to spray washing water downward as well as upward, in order to simultaneously wash the upper portions of dishes stacked on the lower rack 130. When the wash cycle is completed, a drain pump (not shown) pumps the dirty washing water in the sump 200 out from the dishwasher 100. When the dirty washing water is expelled to the outside, clean washing water enters the sump 200 via an intake opening, and is then sprayed in the same manner through the nozzles 150, 155 and 160 as in the wash cycle. Hence, the clean washing water sprays and rinses the dishes. After the rinse cycle, a dry cycle is carried out. In this manner, the dish washing process is completed. FIG. 2 is an exploded perspective view of a sump having a leakage preventing structure according to a first embodiment of the present invention. Referring to FIG. 2, the sump 200 of the dishwasher with the leakage preventing structure according to the present invention includes a-sump housing 290 for storing water drawn through a washing water supply pipe, a wash motor 330 installed below the sump-housing 290, and a disposer 280 connected to the motor shaft 331 protruding from the center of the wash motor 330, for rotating and miniaturizing food particles. The sump 200 further includes a pump case 256 installed at the top of the disposer 280 for pumping washing water stored inside the sump housing 290, and an impeller 250 inside the pump case 256 for pumping washing water. The impeller 250 has the motor shaft 331 inserted in a central portion thereof, and rotates to pump washing water according to the rotation of the motor shaft 331. Furthermore, a mesh filter 270 is installed between the disposer 280 and the pump case 256 and filters food particles, which have been miniaturized by the disposer 280 but are still too large, from entering the pump case 256. A soil chamber 230 covers the top of the pump case 256 and forms a pumping channel that guides the flow of washing water pumped in the pump case 256. In addition, a filter 220 rests on top of the soil chamber 230 and has a spray nozzle connecting port at an edge of its central portion. The spray nozzle connecting port is connected to the spray nozzles so that washing water pumped along the pumping channel formed by the soil chamber 230 is guided to each spray nozzle. Also, a distribution valve 260 is installed on a side of the soil chamber 230 in order to selectively guide the washing water pumped along the pumping channel to each spray nozzle. More specifically, a washing water through-hole 221 and a mesh filter 227 are formed at an edge of the filter 220 for filtering food particles washed from dishes in a preliminary filtering stage. An insert hole 223 is formed at the center of the filter 220 for installing a lower nozzle arm holder 210 thereon, to be coupled to the lower nozzle. Also, a water guide insertion sleeve 226 is formed at a predetermined height and diameter on an edge of the filter 220 for inserting the lower end of the water guide 140 therein. The water guide 140 is a D-shaped pipe for guiding washing water pumped by the wash pump 256 from the bottom of the tub to the upper nozzle toward the top of the tub. A distribution valve housing 235 is formed on a portion of the soil chamber 230 to receive the distribution valve 260. A lower nozzle feed 236 is formed on the top of the soil chamber 230. The lower nozzle feed 236 is bent from the distribution valve housing 235. Also, a water guide feed 237 is formed to guide washing water from the distribution valve housing 235 towards the water guide insertion sleeve 226. At the periphery of the soil chamber 230, a drain channel 241 is formed to have a predetermined width and depth and constructed in accordance with the soil chamber 230 structure. A turbidity sensor receptacle 232 for receiving a turbidity sensor is formed on one side of the drain channel 241, and a drain hole 242 connected to the drain pump and the lower end of the sump is formed at the bottom of the other side. Here, the turbidity sensor is a sensor installed on one side of the sump for sensing impurities in washing water during a dish washing cycle. Further, a turbidity sensor guide channel 233 guides washing water pumped in the pump case 256 to the turbidity sensor inserted in the turbidity sensor receptacle 232. The washing water that descends through the washing water through-hole 221 on the filter 220 is collected in the sump housing 290. The washing water that descends onto the mesh filter 227 has its particle contaminants filtered by the mesh filter 227, then proceeds along the drain channel 241 disposed below the mesh filter 227, and is collected by the sump housing 290. At a central portion of the pump case 256 is an impeller insertion recess 257 for installing an impeller 250 therein. A pumping channel 258 is formed by the outer circumference of the impeller insertion recess 257 and the outer portion of the pump case 256. The pumping channel 258 has a predetermined depth determined by the outer wall of the pump case 256. Washing water that enters the pump case 256 moves along the pumping channel 258 towards the distribution valve 260. The sump housing 290 includes a water supply port 291 formed on a lower side thereof, a drain pump case 296 recessively formed roughly opposite to the water supply port 291, and a heater receptacle 292 recessed a predetermined depth at the center of the sump housing 290. More specifically, at the center of the heater receptacle 292 a motor shaft through-hole 293 is formed for a motor shaft to pass therethrough, and at one side of the sump housing 290 a heater insertion slot 298 is formed for a heater 320 to be inserted therethrough. A cylindrical sealing case 400, which has a diameter larger than the motor shaft through-hole 293 and a predetermined height, is formed above the motor shaft through-hole 293. Inside the sealing case 400, a sealing cover (which will be described later) is inserted around the motor shaft 331 to prevent leakage in a preliminary stage. Furthermore, an aircap 500 is inserted on the outer surface of the motor shaft 331 between the lower end of the pump case 256 and the upper end of the sealing case 400 so as to prevent leakage in a secondary stage. A detailed description of the aircap 500 will be made later. The drain pump case 296 is connected to the soil chamber drain groove 297, and the drain motor 300 is installed on the drain pump case 296. The drain impeller 310, which spins inside the drain pump case 296 to pump washing water out through a drain hose, is attached to the front of the drain motor 300. The sump housing 290 has a distribution valve mount 295 formed on a surface outside of the heater receptacle 292, with a turbidity sensor mount 294 formed a pre-determined distance apart from the distribution valve mount 295. To briefly describe the flow of washing water in the above-described sump structure according to the present invention, the washing water stored in the lower portion of the sump is first suctioned through the rotation of the wash motor 330 towards the impeller 250 installed in the pump case 256. Next, the washing water pumped by the rotation of the impeller 250 flows through the mesh filter 270 and is filtered in a preliminary stage. Subsequently, the washing water flows along the pumping channel 258 formed by the pump case 256 and the soil chamber 230, and respectively flows to the upper and lower nozzles (not shown). Here, the washing water is divided by the distribution valve 260, and respectively flows to the lower and upper nozzles through the lower nozzle feed 236 and water guide feed 237. More specifically, the distribution valve 260 opens the washing water passage to only one of the upper and lower nozzles 150 and 160 at a given time. After the given time elapses, the passage to the other nozzle is opened, so that washing water is evenly sprayed from the upper and lower nozzles. A portion of the washing water that flows through the passages passes the turbidity sensor (not shown) and flows along the drain channel 241 formed on the outer portion of the soil chamber 230 to collect at the bottom of the sump. During the draining process, the washing water moves through the drain pump case 296 and is drained through the rotating drain impeller 310 when the drain motor 300 operates. FIG. 3 is a vertical sectional view of a sump having the leakage preventing structure according to the first embodiment of the present invention, and FIG. 4 is a cut-away perspective view of the leakage preventing structure according to the first embodiment of the present invention. Referring to FIG. 3, the leakage preventing structure according to the present invention that is the aircap 500 is inserted, as previously described, around the motor shaft between the bottom of the pump case 256 and the sealing cover 410. The aircap 500 may be installed at the bottom of the disposer 280. Furthermore, the aircap 500 may have a diameter large enough to accommodate the outside of the sealing case 400 therein. The sealing case 400 is a cylinder having a predetermined diameter and height, and has the motor shaft through-hole 293 disposed at its center for inserting the motor shaft 331 therethrough. A sealing cover 410 is placed inside the sealing case 400. Sealing oil 420 is filled in the space created by the sealing case 400 and the sealing cover 410. Specifically, in order to maintain a sealed state in the space between the sealing cover 410 and the outer surface of the motor shaft 331, a plurality of sealing lips 411 are formed. Accordingly, the sealing lips 411 are pressed firmly against the outside of the motor shaft 331, to prevent washing water from leaking into the sealing case 400. Because sealing oil 420 seals the space formed by the sealing cover 410 and the sealing case 400, if washing water and the sealing oil 420 should meet, they do not mix. Furthermore, the sealing oil 420 also acts as a lubricant for the motor shaft 331. Referring to FIG. 4, the leakage preventing structure according to the present invention, that is, the aircap 500 includes a circular aircap upper plate 520 having a predetermined radial width, and a motor shaft through-sleeve 510 extending upward from the center of the aircap upper plate 520 and having a predetermined diameter and height for accommodating insertion of the motor shaft 331 therethrough. From the bottom of the outer circumference of the aircap upper plate 520 is a cylindrical aircap outer wall 530 that extends a predetermined distance downward, and an aircap inner wall 540 having a diameter smaller than the outer wall 530 is also formed at the bottom of the aircap upper plate 520. An outer chamber 560 formed between the aircap inner and outer walls 540 and 530 and an inner chamber 560 enclosed by the aircap inner wall 540 contain a predetermined amount of air. Accordingly, the air pressure inside the inner and outer chambers 560 and 550 prevents the water level of washing water from rising beyond a certain point within the chambers. In other words, the water level of the washing water storage portion in the sump is different from that in the two chambers 550 and 560. Here, the number of inner walls 540 of the aircap is not limited to the number in an embodiment of the present invention, and multiple chambers may be created by forming multiple inner walls. FIG. 5 is an enlarged sectional view showing an aircap that is partially immersed in washing water according to the first embodiment of the present invention. Referring to FIG. 5, the aircap 500 according to the present invention is installed on top of the sealing case 400 and covers the sealing case 400. The sealing case 400 is completely covered by the inside of the inner wall 540 of the aircap 500. The ends of the aircap's outer and inner walls 530 and 540 are spaced slightly apart from the floor of the sump housing 290. Washing water is allowed to flow through this slight gap. When washing water enters into the sump housing 290, washing water slowly enters the chambers 550 and 560, where its water level gradually rises. As previously described, the air present inside the chambers 550 and 560 becomes pressurized as the water level of the washing water rises. The water level rises until the pressure of the washing water becomes equal to that of the air. The maximum water level (M) allowed in the chambers 550 and 560 may be set to be lower than the height of sealing case 400. By setting the water level (H) of the washing water that enters the aircap 500 to be less than the height of the sealing case 400, washing water is prevented from leaking between the sealing case 400 and the sealing cover 410. Mode for the Invention FIG. 6 is a perspective view of a wash motor according to a second embodiment of the present invention, and FIG. 7 is a sectional view of the wash motor of FIG. 6 coupled to a sump housing. Referring to FIGS. 6 and 7, the wash motor 330 having the leakage preventing structure of the present invention includes a motor housing 332 for protecting a stationary member and a rotating member, a bearing portion 334 protruding a pre-determined distance upward from the center of the motor housing 332 and having a bearing within, a motor shaft 331 running through the top of the bearing portion to extend substantially therebeyond, and a sealing member 600 coupled to the motor shaft 331 to rest on top of the bearing portion 334. The sealing member 600 is tightly adhered to the inside of the sealing case 400, so that washing water cannot leak between the sealing case 400 and the sealing member 600. The sealing member 600 may be made of a rubber material having a predetermined elasticity. After the sealing member 600 is coupled to the motor shaft 331, it is inserted into the sealing case 400 formed at the bottom of the sump housing 290. The above method for inserting the sealing member 600 before the motor is installed is much less likely to damage the surface of the sealing member than a method where the sealing member is first installed inside the bottom of the sump housing 290, after which the motor shaft is inserted through the sealing member. As shown in FIG. 7, the sealing member 600 is installed on the outer bottom portion of the sump housing 290, instead of inside the sump housing 290, thereby facilitating replacement of the sealing member 600. In other words, when the sealing member 600 becomes substantially worn, the wash motor 600 is disassembled from the sump housing 290. Then the worn sealing member 600 is pulled off the motor shaft 331, and replaced with a new one. INDUSTRIAL APPLICABILITY The leakage preventing structure of a dishwasher according to the present invention prevents leakage in the dishwasher sump and therefore has a high industrial applicability.

<SOH> BACKGROUND ART <EOH>A dishwasher is one of home appliances that can remove food particles from dishes using high-pressure washing water sprayed from nozzles. To be specific, a dishwasher includes a tub forming an interior space in which dishes to be washed are placed, a sump mounted under the tub to store washing water, a wash pump attached to one side of the sump to pump the washing water contained in the sump to spraying nozzles, a wash motor for driving the wash pump, a drain pump for draining dirty washing water after the washing has been completed, and a drain motor for driving the drain pump. The wash pump is installed inside the sump and the wash motor is installed below the sump, so that the wash motor and the wash pump are perpendicularly coplanar. Specifically, the shaft of the wash motor in the above configuration passes through into the sump and is coupled directly to the pump. An impeller inside the pump rotates according to the rotation of the motor shaft, thereby pumping washing water. Here, when the motor shaft is inserted through the bottom of the sump, washing water runs down the outer surface of motor shaft during its rotation and leaks out from the sump. While the motor shaft rotates, friction created between the shaft and the sump wears and reduces the effectiveness of the sealing function between the motor shaft and the sump. When a gap is created in the motor shaft through-hole between the motor shaft and the sump, washing water can leak through the gap. Also, when the fixture of a sealing member to the sump precludes the installation of the motor, the surface of the sealing member can be damaged in the installation process and washing water can leak out.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a schematic sectional view of a dishwasher with a leakage preventing structure according to the present invention; FIG. 2 is an exploded perspective view of a sump having a leakage preventing structure according to a first embodiment of the present invention; FIG. 3 is a vertical, sectional view of a sump having the leakage preventing structure according to the first embodiment of the present invention; FIG. 4 is a cut-away perspective view of the leakage preventing structure according to the first embodiment of the present invention; FIG. 5 is an enlarged sectional view showing an aircap that is partially immersed in washing water according to the first embodiment of the present invention; FIG. 6 is a perspective view of a wash motor according to a second embodiment of the present invention; and FIG. 7 is a sectional view of the wash motor of FIG. 6 coupled to a sump housing. detailed-description description="Detailed Description" end="lead"?

20060214

20100810

20080710

58087.0

A47L1542

HECKERT, JASON MARK

LEAKAGE PREVENTING STRUCTURE OF DISH WASHER

UNDISCOUNTED

ACCEPTED

A47L

ACCEPTED

Respiratory apparatus

Respiratory apparatus comprising a ventilation mask (10) and means for supplying breathable gasses, under pressure, thereto and means for exhausting gases therefrom, is wherein the pressuring means is provided substantially at the inlet of the mask (10), thereby substantially reducing the length of the air supply hose to a ventilation mask (10), so that problems associated with high pressures and large volumes of dead space can be alleviated.

1. Respiratory apparatus comprising a ventilation mask and means for supplying breathable gasses, under pressure, thereto and means for exhausting gases therefrom, characterised in that the pressuring means is provided substantially at the inlet of the mask. 2. Respiratory apparatus comprising a means for conducting breathable gasses directly to the trachea of a patient, via a tracheotomy or via a tube through the mouth to the trachea, and a means suitable for supplying the breathable gasses, under pressure, thereto and means for exhausting gases therefrom, characterised in that the pressuring means is so located as to impart pressure to said gasses immediately adjacent the site of the tracheotomy or the patient's mouth. 3. Apparatus according to claim 1, further comprising a means for conducting breathable gasses directly to the trachea, via a tracheotomy or via a tube through the mouth to the trachea. 4. Apparatus according to claim 1, wherein a motor for the pressuring means is co-located therewith. 5. Apparatus according to claim 1, where the power supply is portable. 6. Apparatus according to claim 5, where the power supply is in the form of batteries. 7. Apparatus according to claim 1 wherein the pressuring means is a centrifugal impeller blower. 8. Apparatus according to claim 1, wherein both the inlet and exhaust ports of the pressuring means are communicable with the mask, in use. 9. Apparatus according to claim 8, wherein the inlet and the outlet ports of a centrifugal fan are provided in the same face of the pump 10. Apparatus according to claim 1, further incorporating a valve to regulate air, or gas, pressure in the apparatus. 11. Apparatus according to claim 10, wherein the valve regulates air, or gas, pressure in a mask. 12. Apparatus according to claim 11, wherein the valve comprises two body portions separated by a rotatable valve plate the first body portion interacting with the ventilation mask and defining a mask access chamber connecting both to the interior of the mask and the valve plate, and an exhaust chamber having an outlet to the atmosphere and connecting with the valve plate, but not the ventilation mask; the valve plate locating over the first valve body portion and having openings to provide communication between chambers of the first valve body portion and the second valve body portion; the second valve body portion comprising at least two chambers, one of which is enclosed and corresponds to the pressurised air, or gas, and the other serving as a conduit for exhaust air, both chambers being located so as to communicate with the chamber in the first body portion communicating with the mask, as determined by positioning of the valve plate. 13. Apparatus according to claim 12, wherein the valve has three possible settings to provide the patient with positive pressure, negative pressure or atmospheric pressure, and wherein the second body portion of the valve comprises at least three chambers, an optional null chamber, or land, being provided opposite the atmospheric chamber, and wherein the atmospheric chamber exhausts directly to the atmosphere. 14. Apparatus according to claim 10, wherein the inspiratory to expiratory time ratio is under the control of the apparatus. 15. Apparatus according to claim 10, wherein the apparatus has the ability to operate at high frequency, up to 1000/minute cpm, or greater. 16. Apparatus according to claim 1 which is a respirator or ventilator. 17. Apparatus according to claim 1, wherein the pressure generated by the apparatus is from a maximum of 25 cmH2O during the inspiratory phase and from a maximum of −5 cmH2O, to below, at or above ambient pressure during the expiratory phase. 18. Apparatus according to claim 17, wherein the pressure generated by the apparatus is 5-12 cm H2O above ambient pressure. 19. Apparatus according to claim 1, wherein the apparatus controls the breathing rate of the patient. 20. Apparatus according to claim 2, wherein the means for conducting breathable gasses directly to the trachea is an endotracheal tube with, optionally, a standard connection from the endotracheal tube to the means suitable for supplying the breathable gasses. 21. Apparatus according to claim 2, wherein the means for conducting breathable gasses directly to the trachea is a connecting means for linking the apparatus in a substantially air-tight manner to an existing endotracheal tube. 22. Apparatus according to claim 2, wherein the endotracheal tube is connected to the rest of the device through a tracheotomy. 23. Apparatus according to claim 2, wherein apparatus is an invasive respirator. 24. Apparatus according to claim 2, wherein the pressure generated by the apparatus is from a maximum of 40 cmH2O during the inspiratory phase and from a maximum of −15 cmH2O, to below, at or above ambient pressure during the expiratory phase. 25. Apparatus according to claim 1, wherein the apparatus comprises a filter. 26. Apparatus according to claim 1, wherein the apparatus comprises a means for reversibly securing the apparatus to the face or neck of the patient. 27. Apparatus according to claim 1, wherein the apparatus comprises a supply or feed of oxygen or breathable gasses. 28. Apparatus according to claim 1, wherein the apparatus comprises a means for reversibly securing the apparatus to the face or neck of the patient, thereby allowing the apparatus to be held in place and/or used in a substantially hands-free manner. 29. Apparatus according to claim 1, wherein the additional dead space added by the apparatus is 25-50 ml, or less. 30. Apparatus according to claim 29, wherein the additional dead space is 5-10 ml, or less. 31. Apparatus according to claim 1, wherein the apparatus is biphasic. 32. A method of ventilating a patient, comprising equipping the patient with apparatus of claim 1, and activating the pressuring means. 33. A method of ventilating a patient in need thereof, comprising the use of an apparatus of claim 1. 34. A valve as defined in claim 11. 35. Apparatus according to claim 2, wherein a motor for the pressuring means is co-located therewith. 36. Apparatus according to claim 2, where the power supply is portable. 37. A method of ventilating a patient, comprising equipping the patient with the apparatus of claim 2, and activating the pressuring means. 38. A method of ventilating a patient in need thereof, comprising the use of the apparatus of claim 2.

The present invention relates to respiratory, or ventilation, apparatus comprising a face mask and means for supplying pressurised air thereto, as well as to valves useful in such devices. Non-invasive, mask-type ventilators, which include a face mask, pressurised air supply and valve, are known. These ventilators suffer from various disadvantages, primary amongst which is inflation of the abdomen via the oesophagus. As the stomach becomes inflated, this pushes up the diaphragm which, in turn, reduces lung volume and, concomitantly, tidal volume (Vt). In addition, the ventilators of the prior art are not only cumbersome, but substantially restrict movement of the patient, as the pressurised air supply involves a length of tubing running from the mask to a fixed source of air or other suitable, breathable gas supply. The mask and tubing arrangement also tends to be heavy and somewhat inflexible, thereby putting further strain on the patient. The substantial length of the tubing also tends to add somewhat substantially to the dead space. In this context, the dead space is that volume of air involved in the overall tidal flow which never comes into contact with gas exchange surfaces, in particular, the alveoli. When a patient is breathing normally, the dead space mainly comprises the trachea, nose and pharynx which, together, form about 150 ml of a total 600 ml tidal volume. Using a mask of the prior art, the air supply tube may have a 10 mm internal radius and a length of 1800 mm, which provides an extra dead space, in addition to the 150 ml naturally occurring, of about 558 ml, thereby virtually doubling the tidal volume, as well as at least doubling the pressure required to effect satisfactory ventilation. It is such pressures which lead to problems with gas build up in the stomach. One solution to the problem is to increase tidal flow and to create leaks in the mask to allow exhaust air, rich in carbon dioxide, to escape to help reduce the dead space problem. Another option is to provide a valve in the tubing to allow exhaled air to escape at an earlier stage. Both of these options still require substantial pressure to achieve satisfactory ventilation. To achieve exhaust of CO2 in current masks, continuous positive flow and, therefore, pressure is required, even during exhalation of the patient. The pressure required to achieve this flow is around 8 cm H2O or greater. This forms the basic expiratory pressure which the patient faces at exhalation and which needs to be overcome in order for the patient to exhale. This pressure increases the work of breathing and distends lung volume, potentially beyond the need of the patient, while at least the same amplitude (the difference between peak inspiratory and trough expiratory pressures) is required to achieve adequate tidal volume, so that 0-10 cm H2O for a normal patient becomes 8-18 cm H2O (or more) for a patient using a face mask. The effects may be even more deleterious, as tidal volume of 0-10 cm H2O is greater than 8-18 cm H2O due to the lung pressure-volume curve. One type of mask ventilator providing positive pressure ventilation, and which is non-invasive, is disclosed at page 609 of “Respiratory Care Equipment”, 2nd edition, 1999. A valve therein relies on natural exhalation, so that it is activated by expiration to cut off or reduce the supply of positive pressure, thereby enabling the patient to breathe out. In this type of ventilator, only one phase of the respiratory cycle, the inspiratory phase, is assisted and therefore active. This has the disadvantage that it is not possible to increase the respiratory rate above 4-30 cycles per minute, as there is no option to do anything other than rely on the natural expiration of the patient. As passive recoil generally requires a minimum of one second, this means that such ventilators cannot work at more than 30 cpm. There is an exhaust valve in the power unit, so that dead space is still a problem, and there is a single pressure chamber through which air from the blower passes, either to the patient during inhalation, or through an exhaust, during exhalation in order to reduce or cut off supply. Swiss Patent no. CH685678 discloses an inhaler comprising a base-shaped container in which pressurised oxygen is stored. French Patent Application no. FR2446115 discloses a resuscitator, which fits over the mouth of the patient to supply air from a bulb, further comprising a tongue depressor. Pressure, created by an hand-operated airbag or bulb, forces air into the mouth of the patient. U.S. Pat. No. 3,216,413 discloses a hand-operated concentric bellows-type resuscitator apparatus for artificial respiration without a hose, wherein one bellows is situated within a second bellows, and there is an arrangement of valves to enable assisted inhalation and exhalation of air from the patient's lungs at the appropriate pressures. U.S. Pat. No. 3,939,830 discloses a manually operated resuscitator or dechoker for removing an obstruction from the throat of a patient. In and out strokes of a piston are used to inflate and deflate the lungs of the patient. U.S. Pat. application No. 2003/0111074 discloses a positive pressure hood comprising a power operated blower which forces air through a filter in order to generate a positive pressure within the hood. A one-way purge valve exists for the exhaust of exhaled gases. The apparatus is only suitable for maintaining a clean air supply, for instance in a laboratory or other contaminated environment, inside the hood and, therefore, is not suitable for respirating a patient European Patent Application no. 0 352 938 discloses a powered respirator comprising a motor driven fan unit which draws air through an upstream filter unit, or alternatively, forces air through a downstream filter unit, for delivery to a face piece. The fan is triggered by a pressure sensor, which detects inhalation or exhalation by the patient leading to a corresponding assistance by the fan. Therefore, this device requires the patient to be breathing in the first place and cannot, therefore, be considered a respirator. The object of the device disclosed in European Patent Application no. 0 352 938 is to save battery life by only triggering the fan when inspiration is required. Thi is achieved by matching fan output to the inhalation of the user. Furthermore, the apparatus comprises significant dead space of its own, as can be seen in FIG. 1, with the associated problems this entails, as discussed above. Surprisingly, it has now been found that, by substantially reducing the length of the air supply hose, problems associated with high pressures can be alleviated. Thus, in a first aspect, there is provided respiratory apparatus comprising a ventilation mask and means for supplying breathable gasses, under pressure, thereto and means for exhausting gases therefrom, characterised in that the pressuring means is provided substantially at the inlet of the mask. By supplying the pressurising effect at the inlet of the mask, rather than at a distance through a tube, the creation of a substantial amount of dead space is avoided, and substantially lower pressures and flow are effective to achieve ventilation, given that less CO2 needs to be flushed out, as there is little or no tube. Indeed, it is now possible to use sufficiently low pressures that portable, battery operated devices can be employed-and worn-by-patients, thereby allowing substantially unfettered movement, where the patient is capable. In order to provide the required pressure at the mask interface, a suitable fan pump may be provided. The fan may be driven directly by a power supply and motor co-located therewith. Alternatively, the power supply, for example in the form of batteries, may be provided elsewhere, such as in a pocket. It is also feasible for the motor to be provided at a distance, and linked by a suitable gear link or train to the fan. In general, it is preferred that a lightweight, motorised air pump be provided, mounted directly on the mask, with a remote power supply connected, for example, by suitable cables, or other means. Suitable pumps are centrifugal impeller blowers, of the type illustrated at www.rietschle.co.uk/principles/radial.asp, suitably miniaturised, or otherwise adapted, to provide a preferred maximum flow of 50 L/min. This contrasts with the 180 L/min used in the art, and reflects the benefits of the present invention, as well as enabling a portable power source to be used. It is preferred that the maximum inspiratory pressure output be in the region of 25 cmH2O, with a range of 5-12 cmH2O being preferably employed, in use. Again, this compares extremely favourably with the standard 15-20 cmH2O and up to 30-35 cmH2O used in standard mask ventilators. The pressures used in the present invention are considerably more effective than those used in the art, as dead space and tidal volume problems are minimised, and there is much better response at lower pressures, as seen in pressure volume curve. It is preferred that the pumps used in the present invention have a voltage requirement of no more than 24V, preferably no more than 15V, with a range of 6-12V being preferred, although any pump or impeller capable of providing the requisite flow may be used. The air supplied for breathing by the patient may simply be atmospheric air, in which case there is not generally any requirement for a supply, other than an atmospheric supply. However, where any other form of breathable gas is required or desired, then this may be supplied in any suitable fashion to the pump or, if only required in less than 100% quantities, independently of the pump. The exhaust means may comprise a simple valve in the mask which is not generally activated by the pressure generated by the pump, alone, but is only activated by exhalation of the patient. Whilst this embodiment provides many advantages over the prior art, it is generally preferred to enhance the respiratory apparatus of the invention by further incorporation of a valve to regulate air, or gas, pressure supplied to the mask. It is also preferred to employ both the inlet and exhaust ports of the pump when providing ventilation in association with such a valve. Particularly suitable pumps for use in this connection are lightweight, centrifugal pumps, such as illustrated above, which draw air in at, or near, the rotational axis of the fan and generate an increased air pressure at the perimeter of the rotor, or impeller, which can be expressed via a suitable port. In an advantageous embodiment, both the inlet and the outlet ports of a centrifugal fan are provided in the same face of the pump. This has the advantage of facilitating interaction with the valve. It is a particular advantage of this aspect of the present invention that it is possible to fully control the I/E Ratio (the inspiratory to expiratory time ratio), as there is no dependency on passive recoil of the lungs, so that both phases of the respiratory cycle may be fully controlled and active, allowing the I/E Ratio to be varied to practically any desired level. Suitable valves of the present invention may comprise two body portions separated by a rotatable valve plate. A first body portion interacts with the ventilation mask, and may be secured thereto by any appropriate means, either fixedly or removably. Where the body portion is removable, attachment may be by any suitable means, such as interference fit, push fit or snap fit, for example. The first body portion preferably defines a mask access chamber connecting both to the interior of the mask and the valve plate, and an exhaust chamber having an outlet to the atmosphere and connecting with the valve plate, but not the ventilation mask. Communication between the two chambers is generally prevented by the valve plate. The valve plate locates over the first valve body and has openings to provide communication between the chambers of the first value body and the second valve body portions. Movement of the plate, such as by rotation, serves to define how the chambers of each valve body portion communicate with the other. For ease, the openings in the valve plate are generally sectorial and identical in size, and it is preferred that the valve plate works in a back-forwards, or contra-rotatory, motion, in this case allowing complete control of the I/E ratio to be achieved through control of the time spent in the different sections of the valve. As such, it is also generally preferred that the valve section or, at least that part containing the valve plate, is circular, although it will be appreciated that the housing and walls surrounding the valve may be any appropriate configuration, as desired, and may have any appropriate configuration suitable to manual manipulation, for example. It is preferred that the valve plate be mounted on a spindle or other actuatable means suitable to effect movement to locate the apertures in the plate in conjunction with the appropriate chambers in the valve body portions. The spindle may be actuatable by a second motor means, for example. This second motor is preferably controlled and may be responsive to the patient (in a triggered or synchronised mode) or external settings (in a controlled mode). When responsive to the patient, exhalation may trigger the plate to move to allow or encourage exhalation. Similarly with inhalation, as both phases of the respiratory cycle may be fully and actively controlled. Suitable detector elements located in the mask can provide a signal to an effector associated with the motor. Alternatively, the pump may be controlled independently of the patient's breathing, and set to a certain required pressure, for example. With the valves of the invention, the speed and number of cycles can be determined and this can readily exceed 1000/minute cpm or even higher. The second valve body portion comprises at least two chambers, one of which is enclosed and corresponds to the pressurised air, or gas. The other chamber serves as a conduit for exhaust air. Both chambers are located to communicate with the chamber in the first body portion communicating with the mask, depending on the positioning of the valve plate. Where it is desired that the patient should simply exhale, and not be subject to any pressure, either positive or negative, then the exhaust chamber in the second valve body portion may be open to the atmosphere. This chamber, or a further chamber, may be connected to the inlet of the pump, in order to subject the patient to negative pressure to encourage exhalation, in which case it will be appreciated that the chamber will connect only with the inlet of the pump on the one hand and the connecting chamber of the first body portion on the other hand, when the valve plate is in the correct configuration. In a preferred embodiment, a valve of the invention has three possible settings, providing the patient with positive pressure, negative pressure or simply atmospheric pressure. In this embodiment, the second body portion of the valve will comprise at least three chambers. A fourth, null chamber, or simple land, may be provided opposite the atmospheric chamber, for example. Where a null chamber is provided, this may be open, if desired. It will be appreciated that, when the outlet of the pump is connected to the connecting chamber in the first body portion of the valve, then the inlet of the pump will be connected to the chamber in the first body portion of the valve which connects and, therefore, is exhausted to the atmosphere. Likewise, when the inlet is connected to the connecting chamber, then the outlet will be connected and exhausted to the atmosphere. The above pump embodiments are particularly preferred, and form a separate aspect of the invention and, in particular, for use with respiratory apparatus of the present invention, or any other respiratory apparatus. The ventilation mask is not critical to the present invention. Conventional masks may be used or adapted, and it is generally preferred that they provide a substantially gas-tight linkage with the airways of the patient. The present invention may also be applied to an apparatus where the mask portion is replaced by an endotracheal tube or means for connecting to such a tube. Thus, in a further aspect, the present invention also provides a respiratory apparatus comprising a means for conducting breathable gasses directly to the trachea, via a tracheotomy or via a tube through the mouth to the trachea, and a means suitable for supplying the breathable gasses, under pressure, thereto and means for exhausting gases therefrom, characterised in that the pressuring means is provided substantially at the site of the tracheotomy or the patient's mouth. The means for conducting breathable gasses directly to the trachea is preferably an endotracheal tube with, optionally, a standard connection from the endotracheal tube to the means suitable for supplying the breathable gasses. Alternatively, the means for conducting breathable gasses directly to the trachea is preferably a connecting means for linking the apparatus in a substantially air-tight manner to an existing endotracheal tube. The endotracheal tube may be connected to the rest of the device through the patient's mouth and tracheal opening, or, more preferably, through a hole or incision in the patient's throat, for instance a tracheotomy. In this instance, the pressuring means is provided substantially at the inlet of the tracheotomy. Thus, this aspect of the present invention is preferably suitable for use in conventional invasive positive pressure ventilation (PPV), for instance on a patient with a tracheotomy. Thus, the apparatus is, preferably, an invasive respirator. The apparatus may also be suitably adapted as described in the present application with respect to the mask aspect of the invention. In particular, the apparatus may comprise a valve, preferably as described herein. The apparatus can, preferably, operate as either a positive pressure ventilator or a high frequency oscillator. There are several advantages to using this aspect of the invention, for instance as an invasive respirator. A direct connection can be made from the apparatus to the endotracheal tube, thus minimising the tubing required. The advantage this gives is again a reduction in dead space during ventilation (although there is already less dead space in PPV than in mask ventilators) and, therefore, lower pressures are required to adequately ventilate patients. Again, this helps avoid the negative side effects of high pressures. Furthermore, as the apparatus can be directly connected to the trachea, this can result in a significant decrease in the dead space associated with the patient's trachea and mouth, for instance as much as 50%. The endotracheal tube may also form part of the mask according to the present invention, such that the respiratory apparatus comprises both a mask and an endotracheal tube. The apparatus is easy to clean and sterilize, as it has few parts and little or not rubbing, thus reducing the risk of infection for the patient. Furthermore, the apparatus is small, lightweight and this, with the option of being battery operated, allows the invention to be used as a mobile respirator that also takes up far less space when used in the intensive care. Monitoring can be done as in conventional ventilators by sending the information in a wireless manner, such as Bluetooth or infrared, for instance. Most mobile transport ventilators are either fairly large battery operated devices requiring substantial amounts of battery power or most commonly (due to this reason) smaller pneumatic devices that require compressed air for them to work. (See chapter 17 Branson et al “Transport Ventilators” p527-565, Respiratory Care equipment). Pressures suitable for generation by the apparatus of the present invention are generally low by comparison with the prior art, and suitable pressures have been found, for the mask, to be typically be 5-12 cmH2O above ambient pressure and, as a maximum, 25cmH2O during the inspiratory phase and from a maximum of −5cmH2O, to below, at or above ambient pressure during the expiratory phase. In the case of the endotracheal apparatus the pressures generated can be higher and are typically from a maximum of 40 cmH2O during the inspiratory phase and from a maximum of −15 cmH2O, to below, at or above ambient pressure during the expiratory phase. These pressures are for guidelines only, and it will be appreciated that higher pressures, as well as lower pressures, may be employed, but these require greater input of power, and may be associated with the problems of the prior art. The present invention further provides a method of ventilating a patient, comprising equipping the patient with the apparatus, particularly the mask, as defined above, and activating the pump. Preferably, the apparatus comprises a supply of oxygen or breathable gasses, for instance in a pressurised vessel or tank, or via a connection to a source of said gasses. Preferably, an oxygen supplement is fed through a connection to the apparatus, preferably to the valve, in order to increase FiO2 (Fraction of Inspired Oxygen) to above room air level. Any condition treatable by conventional ventilation apparatus or masks may be treated in accordance with the present invention, and may cover patients with sleep apnoea and lung diseases to those on life support, as may be directed by a skilled physician. Therefore, also provided is a method of ventilating a patient in need thereof, comprising the use of an apparatus according to the present invention. Preferably, the apparatus is a respirator or ventilator. It is also preferred that the apparatus according to present invention controls the breathing rate of the patient, rather the apparatus being triggered by the breathing of the patient. Preferably, therefore, according to this embodiment of the present invention, inspiration and expiration are not triggered by the patient of his or her breathing, but are controlled by a suitable control device, such a s life support machine, for instance. Accordingly, the present invention may be used on a patient that is not breathing on his or her own. In a further embodiment of the present invention, the apparatus may also comprise a filter for removing contaminants, for instance, from the inspired and/or expired air. Preferably, the apparatus comprises means for reversibly securing the apparatus to the face or neck of the patient, as appropriate, thereby allowing the apparatus to be held in place and/or used in a substantially hands-free manner, without the patient having to hold it in place. For instance, where the apparatus is a mask, it is preferred that the means for reversibly securing the apparatus comprises at least one or a plurality of straps or ties, suitable for the purpose, that may be passed around the patient's head. The straps or ties are preferably elastic. Where the apparatus comprises an endotracheal tube, it is preferred that the straps or ties are suitable for passage around the patient's neck, for instance. -The apparatus may also comprise a series of flanges which may be used to secure the apparatus to the patient by means of bandages. Preferably, the additional dead space added by the apparatus to that naturally occurring in the patient, is kept to an absolute minimum, preferably 200 ml or less, more preferably 100 ml or less, preferably 50 ml or less, preferably 200 ml or less, preferably 25-50 ml, preferably 10-20 ml, preferably 10-15 ml, preferably 5-10 ml more preferably 10 ml and most preferably 5 ml or less. The apparatus is also preferably biphasic such that it not only forces air into the patient's lungs, but also actively expels the air from the lungs, rather than simply allowing the lungs to deflate naturally of their own accord, as is the case in many of the prior art devices. Both phases may be triggered by the patients breathing, or may be under the control of the apparatus, under the control of an onboard processor, or under the control of a further control means, such as a life-support machine, for instance. This has the advantage of providing the user or doctor with a greater degree of control with respect to the inspiration/expiration rate. The invention will now be further illustrated with reference to the accompanying drawings, in which: FIG. 1 illustrates a mask and valve of the present invention where the valve has three pressure settings; FIG. 2 illustrates a valve of the present invention having two pressure settings; FIG. 3 illustrates a valve for use with the present invention; and FIG. 4 illustrates an alternative embodiment of the valve of FIG. 1. In FIG. 1, there is shown face mask (10) having processes (20) for the attachment of straps, or the like, to secure the mask (10) over the mouth and nose of the patient (not shown). Valve (30) is shown in three sections (40, 50, 60) and is locatable in aperture (25) of mask (10) via flange (65) of first body portion (40). Connecting chamber (70) provides an unobstructed passageway between the inside of mask (10) and valve plate (50). Chamber (75) is sealed by land (80), and does not provide gaseous communication with the inside of mask (10). Exhaust slot (85) provides communication with the external atmosphere. Valve plate (50) is provided with spindle (90), which locates in corresponding recess (95) in first valve body portion (40). Spindle (90) is suitably equipped with external drive means (not shown) to effect rotation. Apertures (100, 105) control communication between first valve body portion (40) and second valve body portion (60). The periphery of the valve plate (50) locates on internal flange (110) in valve body portion (40), thereby providing a gas-tight seal, or substantially gas-tight seal. It will be appreciated that with the general volume of air flow, it is not necessarily important that the seal be especially gas-tight, provided that any gas getting past the seal does not substantially interfere with the desired ventilation effect. Second valve body portion (60) is equipped with four chambers (120, 130, 140, 150) equipped with slots (123, 126, 133, 136, 145, 155). Impeller end plate (160) is shown, with negative pressure port or inlet (165) and positive pressure port, or outlet (170). The rest of the impeller is not shown. Positive port (170) corresponds with chamber (120) of second valve body portion (60), while negative port (165) corresponds with chamber (130). When aperture (100) is located over aperture (133), then aperture (105) will be located over aperture (123). In this configuration, negative port (165) communicates via aperture (133) and aperture (100) with communicating chamber (70) to reduce the pressure in mask (10). At the same time, positive pressure port (170) acts via apertures (123, 105) to exhaust via slot (85) in dead end chamber (75). Rotating the valve plate (50) to engage aperture (100) with aperture (136) places aperture (105) in conjunction with aperture (126), so that the reverse effect is achieved. Namely, negative port (165) communicates via apertures (136) and (100) with null chamber (75) to draw in air through slot (85) while positive pressure port (170) communicates via apertures (126) and (105) with communicating chamber (70) to raise the pressure in the mask (10). It will be appreciated that the same effect will be achieved if aperture (105) corresponds to aperture (136) rather than aperture (126), and that the one configuration of the two possible is described for purposes of simplicity. Similar considerations apply to any other configuration where a plurality of equivalent possibilities exists. In a third configuration, apertures (105) and (100) interact with apertures (145) and (155), respectively. In this configuration, as with all other configurations of this embodiment, neither chamber (150) nor open chamber (140) corresponds to any port on the impeller. Thus, in this configuration, the effect is to provide a direct atmospheric link to the mask via connecting chamber (70) and apertures (100) and (145), the lack of wall in chamber (140) providing immediate access to the atmosphere. In FIG. 2, valve (30′) is shown, consisting of first valve body portion (40′), valve plate (50′) and second valve body portion (60′). In this embodiment, the numerals have the same meanings as in FIG. 1. An alternative version of the first valve body portion (40′) is shown, in which the chamber (75) is not hollowed in any fashion, thereby simply providing an aperture (85) communicating with the atmosphere, in the chamber. In second valve body portion (60′), chambers (140) and (150) are not present, so that only positive pressure chamber (120) and negative pressure chamber (130) are provided. In this configuration, negative pressure is provided to the ventilation mask when aperture (100) corresponds with aperture (133) and aperture (105) corresponds with aperture (123). Positive pressure is provided when aperture (100) corresponds with aperture (126) and aperture (105) of the valve plate (50′) corresponds with aperture (136). In FIG. 3 valve (30″) is for use with a blower where only the positive pressure outlet engages with chamber (120) of valve bodyportion (60″). Chamber (130) is open to the atmosphere. There is no slot (85) in valve body portion (40′). Instead, chamber (72) connects directly to opening (123) in valve body portion (60′) when opening (105) in valve face plate (50′) is appropriately located. When opening (105) corresponds with opening (133), then positive pressure is fed into the mask via chamber (70), while chamber (72) is closed by valve face plate (50′). Valve face plate (50″) may also occupy a central position where slot (105) corresponds to neither opening (123) nor opening (133), so that air may neither pass in nor out of the mask in this configuration. This may be appropriate between inhalation and exhalation, for example. As with FIGS. 1 and 2, recessed portion (180) locates within and abuts against lip (185) on valve body section (40′). FIG. 4 depicts a valve embodiment similar to that of FIG. 1, and functions in a similar manner. In this embodiment, valve body portion (40′″) is lacking land portion (72) such that, when any of openings (136), (155) and (123) is exposed by either of openings (100) and (105), then direct contact with the ambient atmosphere is made. Chamber (70) in body portion (40′″) takes the form of a lumen in male member (75) which docks with female member (78) in the mask (10). Openings (126), (145) and (133) communicate with lumen (70) when exposed thereto by either of openings (100) and (105) via chamber (72) recessed beneath flange (110), providing positive, negative or atmospheric pressure, as desired. It will be appreciated that variations are possible in the embodiments of the above Figures and that it is possible to vary the amount of pressure in the mask by varying the degree to which any particular aperture is open. For example, it may be desirable to continue to provide a lesser positive pressure during exhalation rather than atmospheric or negative pressure. Where desired, this may be effected either by lowering pressure in the blower, or preferably by controlling pressure through the I/E Ratio, thereby maintaining an overall positive pressure in the mask, even where the disc is allowing atmospheric or negative pressure into the mask. Although it is possible to vary the speed of the impeller, it is generally preferred to keep this at a constant rate, except when the ventilation device is switched off, in order to conserve energy and provide the most rapid possible reaction time.

20060621

20110920

20070315

94629.0

A62B1802

DOUGLAS, STEVEN O

RESPIRATORY APPARATUS

SMALL

ACCEPTED

A62B

ACCEPTED

Curing composition with improved heat resistance

The present invention provides a curable composition including: an organic polymer (A) which has on average 1.1 to 50 groups per one molecule thereof each represented by the general formula (1) and has one or more silicon-containing functional groups capable of cross-linking by forming siloxane bonds: —NR1—C(═O)— (1) wherein R1 is a hydrogen atom, or a substituted or unsubstituted monovalent organic group; and a metal carboxylate and/or a carboxylic acid (B), the curable composition giving a cured article excellent in curability and also excellent in heat resistance although a non-organotin catalyst is used.

1. A curable composition comprising: an organic polymer (A) which has on average 1.1 to 50 groups per one molecule thereof each represented by the general formula (1) and has one or more silicon-containing functional groups capable of cross-linking by forming siloxane bonds: —NR1—C(═O)— (1) wherein R1 is a hydrogen atom, or a substituted or unsubstituted monovalent organic group; and a metal carboxylate and/or a carboxylic acid (B). 2. The curable composition according to claim 1, in which the carbon atom adjacent to the carbonyl group of the metal carboxylate and/or of the carboxylic acid (B) is a tertiary or quaternary carbon atom. 3. The curable composition according to claim 1, in which the carbon atom adjacent to the carbonyl group of the metal carboxylate and/or of the carboxylic acid (B) is a quaternary carbon atom. 4. The curable composition according to claim 1, in which the component (B) is a carboxylic acid. 5. The curable composition according to claim 1, comprising the component (B) in an amount of 0.01 to 20 parts by weight in relation to 100 parts by weight of the component (A). 6. The curable composition according to claim 1, further comprising an amine compound as a component (C). 7. The curable composition according to claim 6, comprising the component (C) in an amount of 0.01 to 20 parts by weight in relation to 100 parts by weight of the component (A). 8. The curable composition according to claim 2, in which the component (B) is a carboxylic acid. 9. The curable composition according to claim 3, in which the component (B) is a carboxylic acid. 10. The curable composition according to claim 2, comprising the component (B) in an amount of 0.01 to 20 parts by weight in relation to 100 parts by weight of the component (A). 11. The curable composition according to claim 3, comprising the component (B) in an amount of 0.01 to 20 parts by weight in relation to 100 parts by weight of the component (A). 12. The curable composition according to claim 4, comprising the component (B) in an amount of 0.01 to 20 parts by weight in relation to 100 parts by weight of the component (A). 13. The curable composition according to claim 2, further comprising an amine compound as a component (C). 14. The curable composition according to claim 3, further comprising an amine compound as a component (C). 15. The curable composition according to claim 4, further comprising an amine compound as a component (C). 16. The curable composition according to claim 5, further comprising an amine compound as a component (C).

TECHNICAL FIELD The present invention relates to a curable composition including an organic polymer having silicon-containing functional groups (hereinafter also referred to as “reactive silicon groups”) capable of cross-linking by forming siloxane bonds. BACKGROUND ART There have hitherto been known organic polymers with the molecular chain terminals thereof capped with reactive silicon groups by taking advantage of the high reactivity between the isocyanate group and various types of active hydrogen groups, and accordingly, properties of urethane resins have been improved. These organic polymers have already been produced industrially, and used in wide applications as sealants and adhesives. Curable compositions including these organic polymer are cured with silanol condensation catalysts, and organotin catalysts such as dibutyltin dilaurylate are widely used. However, cured articles obtained from the curable compositions each including any of the organic polymers and an organotin catalyst are poor in heat resistance, leading to a problem that physical properties of the cured articles are largely degraded by heating. Additionally, organotin catalysts having carbon-tin bonds have recently been pointed out to be toxic. Techniques for improving the heat resistance by structural alteration of the organic polymers are disclosed in Japanese Patent Laid-Open Nos. 10-53637 and 2001-31947, U.S. Pat. No. 6,197,912, Japanese Patent Laid-Open No. 2002-155145, and the like. However, even the use of these techniques sometimes has not resulted in sufficient heat resistance. On the other hand, curable compositions in which carboxylic acids or metal carboxylates are used as the curing catalysts for polyoxyalkylene polymers having reactive silicon groups are disclosed in Japanese Patent Laid-Open No. 55-9669, Japanese Patent No. 3062626, Japanese Patent Laid-Open Nos. 6-322251, 2000-345054 and 5-117519, and the like. However, there have not hitherto been disclosed specific examples in which carboxylic acids or metal carboxylates are used as the curing catalysts for organic polymers having bonding groups produced by the reaction between isocyanate groups and active hydrogen groups and having reactive silicon groups. DISCLOSURE OF THE INVENTION In view of the above described existing circumstances, the present invention takes as its object the provision of a curable composition capable of giving a cured article excellent in heat resistance and curability although a non-organotin catalyst is used. The present inventors made intensive investigations in an attempt to solve the problems mentioned above and consequently found that the problem of the heat resistance of an organic polymer derived from a group (hereinafter, also referred to as an amide segment) produced by the reaction between an isocyanate group and an active hydrogen group can be improved by using a particular curing catalyst. On the basis of this finding, the present invention has been achieved. More specifically, the present invention relates to a curable composition including: an organic polymer (A) which has on average 1.1 to 50 groups per one molecule thereof each represented by the general formula (1) and has one or more silicon-containing functional groups capable of cross-linking by forming siloxane bonds: —NR1—C(═O)— (1) wherein R1 is a hydrogen atom, or a substituted or unsubstituted monovalent organic group; and a metal carboxylate and/or a carboxylic acid (B). A preferred embodiment relates to the above described curable composition, in which the carbon atom adjacent to the carbonyl group of the metal carboxylate and/or of the carboxylic acid (B) is a tertiary or quaternary carbon atom. Another preferred embodiment relates to the above described curable composition, in which the carbon atom adjacent to the carbonyl group of the metal carboxylate and/or of the carboxylic acid (B) is a quaternary carbon atom. Still another preferred embodiment relates to any one of the above described curable compositions, in which the component (B) is a carboxylic acid. Yet another preferred embodiment relates to any one of the above described curable compositions, including the component (B) in an amount of 0.01 to 20 parts by weight in relation to 100 parts by weight of the component (A). Still yet another preferred embodiment relates to any one of the above described curable compositions, further including an amine compound as a component (C). Further another preferred embodiment relates to the above described curable compositions, including the component (B) in an amount of 0.01 to 20 parts by weight and the component (C) in an amount of 0.01 to 20 parts by weight, in relation to 100 parts by weight of the component (A). The curable composition of the present invention is excellent in heat resistance and curability although a non-organotin catalyst is used therein. BEST MODE FOR CARRYING OUT THE INVENTION In the following, the present invention will be described in detail. A reactive silicon group-containing organic polymer (A) to be used in the present invention has on average 1.1 to 50 groups (amide segments) per one molecule thereof each represented by the general formula (1): —NR1—C(═O)— (1) wherein R1 is the same as described above. The number of the amide segments on average per one molecule is preferably 1.2 to 25, more preferably 1.5 to 10, and particularly preferably 2 to 5. When smaller than 1.1, the curing rate tends to become slow, sometimes the number of the reactive silicon group introduced into the organic polymer is small, and sometimes satisfactory rubber elasticity is hardly attained. On the other hand, when larger than 50, sometimes the organic polymer is high in viscosity to give a composition poor in workability. As the amide segment, groups produced by the reactions of an isocyanate group with various types of active hydrogen-containing groups are preferable because they provide a marked improvement effect of the heat resistance in the present invention. Specific examples of the amide segment may include: a urethane group, produced by a reaction between an isocyanate group and a hydroxy group, represented by a general formula (2), —NH—C(═O)—O— (2); a urea group, produced by a reaction between an isocyanate group and an amino group, represented by a general formula (3), —NH—C(═O)—NR— (3), wherein R2 represents a hydrogen atom, or a substituted or unsubstituted monovalent organic group; and a thiourethane group, produced by a reaction between an isocyanate group and a mercapto group, represented by a general formula (4), —NH—C(═O)—S— (4). In the present invention, those groups produced by the further reactions between the active hydrogen in these urethane, urea and thiourethane groups with an isocyanate group are also included in the groups represented by the general formula (1). The reactive silicon group contained in the organic polymer (A) has a hydroxy or hydrolyzable groups bonded to a silicone atoms, and is a group capable of cross-linking by forming siloxane bonds on the basis of a reaction to be accelerated by a silanol condensation catalyst. Examples of the reactive silicon group may include the group represented by the general formula (5): —(SiR32-bXbO)n—SiR43-aXa (5) wherein R3 and R4 each are independently an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or a triorganosiloxy group represented by (R′)3SiO—, and when there are two or more R3s and/or R4s, they may be the same or different from each other; here, R′ represents a monovalent hydrocarbon group having 1 to 20 carbon atoms, and 3 R's may be the same or different from each other; X represents a hydroxy group or a hydrolyzable group, and when there are two or more Xs, they may be the same or different from each other; a represents 0, 1, 2 or 3; b represents 0, 1 or 2; b's in n (SiR32-bXbO) groups may be the same or different from each other; n represents an integer of 0 to 19; and the relation a+Σb≧1 is to be satisfied. No particular constraint is imposed on the hydrolyzable group as long as it is a hydrolyzable group well known in the art. Specific examples of the hydrolyzable group may include, for example, a hydrogen atom, a halogen atom, an alkoxy group, an acyloxy group, a ketoximate group, an amino group, an amide group, an acid amide group, an aminooxy group, a mercapto group and an alkenyloxy group. Among these, a hydrogen atom, an alkoxy group, an acyloxy group, a ketoximate group, an amino group, an amide group, an aminooxy group, a mercapto group and an alkenyloxy group are preferable, and an alkoxy group is particularly preferable from the viewpoints of moderate hydrolyzability and easiness in handling. One to three hydrolyzable and/or hydroxy groups are able to be bonded to one silicon atom, and (a+Σb) preferably falls within a range from 1 to 5. When two or more hydrolyzable and/or hydroxy groups are bonded in a reactive silicon group, they may be the same or different. In particular, the reactive silicon group represented by the general formula (6) is preferable because of easy availability: —SiR43-cXc (6) wherein R4 and X are the same as described above, and c represents an integer of 1 to 3. Specific examples of R3 and R4 in the general formulas (5) and (6) may include, for example, alkyl groups such as a methyl group and an ethyl group; cycloalkyl groups such as a cyclohexyl group; aryl groups such as a phenyl group; aralkyl groups such as a benzyl group; and triorganosiloxy groups represented by (R′)3SiO— wherein R′ is a methyl group, a phenyl group or the like. Among these, a methyl group is particularly preferable. More specific examples of the reactive silicon group may include: a trimethoxysilyl group, a triethoxysilyl group, a triisopropoxysilyl group, a dimethoxymethylsilyl group, a diethoxymethylsilyl group and a diisopropoxymethylsilyl group. From the viewpoint of high activity and obtainable satisfactory curability, a trimethoxysilyl group, a triethoxysilyl group and a dimethoxymethylsilyl group are more preferable, and a trimethoxysilyl group is particularly preferable. Alternatively, from the viewpoint of storage stability, a dimethoxymethylsilyl group is particularly preferable. Those reactive silicon groups each having 3 hydrolyzable groups bonded to the silicon atom such as a trimethoxysilyl group, a triethoxysilyl group and a triisopropoxysilyl group are particularly preferable from the viewpoints of the recovery properties, durability and creep resistance of the curable composition to be obtained. Additionally, a diethoxymethylsilyl group and a triethoxysilyl group are particularly preferable because the alcohol produced by the hydrolysis reaction of the reactive silicon groups is ethanol which is high in safety. The reactive silicon groups may be located at the terminals or in the interior, or both at the terminals and in the interior of the molecular chain of the organic polymer (A). In particular, the reactive silicon groups located at the molecular terminals are preferable on the grounds that the effective network chain length in the organic polymer component contained in the finally formed cured article is large, and hence it is easier to obtain a rubber-like cured article having a high strength and a high elongation property, and also on other grounds. The number of the reactive silicon groups per one molecule of the component (A) is on average preferably 1 to 5, more preferably 1.1 to 4, and particularly preferably 1.2 to 3. When the number of the reactive silicon groups per one molecule is less than 1, sometimes the curability is insufficient and a satisfactory rubber elasticity behavior tends to be hardly attained, while when larger than 5, sometimes the elongation of the cured article is small. No particular constraint is imposed on the organic polymer (A) and the organic polymer (A) may be a polymer obtained by any production method as long as the organic polymer (A) has on average 1.1 to 50 groups per one molecule represented by the general formula (1), —NR1—C(═O)— (1) wherein R1 is the same as described above, and has one or more reactive silicon groups. As an example of the industrial methods for easily producing the organic polymer (A), here can be cited a method [production method (a)] in which an excessive amount of a polyisocyanate compound (E) is reacted with an organic polymer (D) having active hydrogen-containing groups at the terminals thereof to convert the organic polymer (D) into a polymer having isocyanate groups at the terminals of the polyurethane main chain thereof, and thereafter, or at the same time, the whole isocyanate groups or a part of the isocyanate groups are reacted with the W group of a silicon compound (F) represented by formula (7) to produce the organic polymer (A): W—R5—SiR43-cXc (7) wherein R4, X and c are the same as described above; R5 is a divalent organic group, and is more preferably a substituted or unsubstituted divalent hydrocarbon group having 1 to 20 carbon atoms; W is an active hydrogen-containing group selected from the group consisting of a hydroxy group, a carboxyl group, a mercapto group and an amino group (primary or secondary). Examples of the production methods, well known in the art, of organic polymers related to the production method (a) may include Japanese Patent Publication No. 46-12154 (U.S. Pat. No. 3,632,557); Japanese Patent Laid-Open Nos. 58-109529 (U.S. Pat. No. 4,374,237), 62-13430 (U.S. Pat. No. 4,645,816), 8-53528 (EP0676403) and 10-204144 (EP0831108); National Publication of International Patent Application No. 2003-508561 (U.S. Pat. No. 6,197,912); Japanese Patent Laid-Open Nos. 6-211879 (U.S. Pat. No. 5,364,955), 10-53637 (U.S. Pat. No. 5,756,751), 11-100427, 2000-169544, 2000-169545 and 2002-212415; Japanese Patent No. 3313360; U.S. Pat. Nos. 4,067,844 and 3,711,445; and Japanese Patent Laid-Open No. 2001-323040. As another example, here can be cited a method [production method (b)] in which an hydrolyzable silicon group-containing isocyanate compound (G) represented by formula (8) is reacted with the organic polymer (D) having active hydrogen-containing groups at the terminals thereof to produce the organic polymer (A)): O═C═N—R5—SiR43-cXc (8) wherein R4, R5, X and c are the same as described above. Examples of the production methods, well known in the art, of organic polymers related to the production method (b) may include Japanese Patent Laid-Open Nos. 11-279249 (U.S. Pat. No. 5,990,257), 2000-119365 (U.S. Pat. No. 6,046,270), 58-29818 (U.S. Pat. No. 4,345,053), 3-47825 (U.S. Pat. No. 5,068,304), 11-60724, 2002-155145 and 2002-249538. The production method (a) is more preferable than the production method (b) because the former can produce the polymer (A) at a lower cost than the latter. Alternatively, the production method (b) is more preferable than the production method (a) because the former can produce the polymer (A) with a smaller number of the amide segments and a more satisfactory heat resistance than the latter. Examples of the organic polymer (D) having active hydrogen-containing groups at the terminals thereof may include oxyalkylene polymer having hydroxy groups at the terminals thereof (polyether polyol), polyacryl polyol, polyester polyol, saturated hydrocarbon polymer having hydroxy groups at the terminals thereof (polyolefin polyol), polythiol compounds and polyamine compounds. Among these, oxyalkylene polymer, polyacryl polyol and saturated hydrocarbon polymer are preferable because the obtained polymer (A) is relatively low in glass transition temperature and the obtained cured article is excellent low-temperature resistance. Among others, oxyalkylene polymer is particularly preferable because the obtained organic polymer (A) is low in viscosity, satisfactory in workability and satisfactory in deep-part curability. More preferable are polyacryl polyol and saturated hydrocarbon polymers because the cured article of the obtained organic polymer (A) is satisfactory in weather resistance and heat resistance. As the oxyalkylene polymer having hydroxy groups at the terminals thereof, oxyalkylene polymers produced by any production methods can be used; however, preferable is an oxyalkylene polymer having at least 0.7 hydroxy group per one molecular terminal thereof, at the terminals thereof, on average over all the molecules. Specific examples of such an oxyalkylene polymer may include an oxyalkylene polymer produced with a conventional alkali metal catalyst, and an oxyalkylene polymer produced by reacting an alkylene oxide with an initiator such as a polyhydroxy compound having at least 2 hydroxy groups in the presence of a double metal cyanide complex or cesium. Examples of the synthesis methods, well known in the art, of polyoxyalkylene polymer may include: a polymerization method based on a transition metal compound-porphyrin complex catalyst such as a complex prepared by reacting an organoaluminum compound with porphyrin, disclosed in Japanese Patent Laid-Open No. 61-215623; polymerization methods based on double metal cyanide complex catalysts, disclosed in Japanese Patent Publication Nos. 46-27250 and 59-15336, and U.S. Pat. Nos. 3,278,457, 3,278,458, 3,278,459, 3,427,256, 3,427,334, 3,427,335 and the like; a polymerization method using a catalyst composed of a polyphosphazene salt disclosed in Japanese Patent Laid-Open No. 10-273512, and a polymerization method using a catalyst composed of a phosphazene compound disclosed in Japanese Patent Laid-Open No. 11-060722. However, the synthesis method of polyoxyalkylene polymer is not limited to these examples. Among these polymerization methods, the polymerization methods using alkali metal catalysts or double metal cyanide complexes are preferable because the polymerization catalysts used are low in price. Among the above described polymerization methods, the polymerization methods using the double metal cyanide complexes are preferable because these methods can give oxyalkylene polymers lower in unsaturation degree, narrower in Mw/Mn, lower in viscosity, higher in acid resistance and higher in weather resistance than conventional oxyalkylene polymers produced by use of alkali metal catalysts. Additionally, the methods using the double metal cyanide complexes are preferable because these methods can produce oxyalkylene polymers higher in molecular weight than the oxyalkylene polymers produced by use of alkali metal catalysts or phosphazene compound catalysts, and can give cured articles higher in elongation. As the double metal cyanide complex, those complexes having zinc hexacyanocobaltate as the main component are preferable, and ether and/or alcohol complexes thereof are preferable. As the compositions of such complexes, essentially those compositions as described in Japanese Patent Publication No. 46-27250 can be used. As ethers, tetrahydrofuran, and glymes such as glyme and diglyme are preferable, and among these, tetrahydrofuran and glyme are preferable because these can give oxyalkylene polymers narrower in Mw/Mn and lower in unsaturation degree. As alcohols, t-butanol as described in Japanese Patent Laid-Open No. 4-145123 is preferable because it gives oxyalkylene polymers lower in unsaturation degree. The oxyalkylene polymer is essentially a polymer having the repeating units represented by the general formula (9): —R6—O— (9) wherein R6 is a divalent organic group, and a straight chain or branched alkylene group having 1 to 14 carbon atoms. In the general formula (9), R6 is preferably a straight chain or branched alkylene group having 1 to 14 carbon atoms, and more preferably 2 to 4 carbon atoms. Specific examples of the repeating units represented by the general formula (9) may include: The main chain skeleton of the polyoxyalkylene polymer may be formed of either only one type of repeating unit or two or more types of repeating units. In particular, in the case where the polymer is used for a sealant and the like, it is preferable that the main chain skeleton is formed of a polymer containing as the main component a propyleneoxide polymer because a polymer having such a main chain skeleton is amorphous and relatively low in viscosity. For the purpose of facilitating the reactions with the polyisocyanate compound (E) and the hydrolyzable silicon group-containing isocyanate compound (G), preferable is an oxyalkylene polymer in which ethylene oxide is copolymerized so as for the terminal hydroxy groups to be primary ones. Examples of the polyacryl polyol may include a polyol which has the skeleton formed of an alkyl (meth)acrylate (co)polymer and additionally has hydroxy groups in the molecule thereof. The synthesis method of this polymer is preferably the living radical polymerization method because this method can lead to narrow molecular weight distributions and low viscosities, and the atom transfer radical polymerization method is further preferable. Additionally, it is preferable to use a polymer based on the so-called SGO process which is obtained by continuous block polymerization of an alkyl acrylate monomer at a high temperature and under a high pressure, as described in Japanese Patent Laid-Open No. 2001-207157. Specific examples of such a polymer may include UH-2000 manufactured by Toagosei Co., Ltd. Examples of the polyester polyol may include, for example, polymers obtained by polycondensation of dicarboxylic acids such as maleic acid, fumaric acid, adipic acid, sebacic acid and phthalic acid with the diols; ring-opening polymers produced from ε-caprolactone, valerolactone and the like; and active hydrogen compounds each having 2 or more active hydrogen atoms such as castor oil. Examples of the saturated hydrocarbon polymers having hydroxy groups at the terminals thereof may include, for example, polyols having the skeletons including ethylene/α-olefin, polyisobutylene, hydrogenated polyisoprene or hydrogenated polybutadiene. Examples of the polythiol compound may include liquid polysulfides represented by the general formula, HS—(R—SS)l—R—SH, wherein R is —C2H4—, —C3H6—, —C2H4—O—C2H4—, —C2H4—O—CH2—O—C2H4—, —C3H6—O—C3H6—O—C3H6— or —C2H4—O—(C2H4—O)m—C2H4—; and l and m each represent an integer of 2 to 50. Specific examples of such a compound may include LP-282 and LP-55 manufactured by Toray Thiocoal Co., Ltd. Examples of the polyamine compound may include primary amino group-containing oligomers such as Jeffamine D-400, D-2000, D-4000, D-403, T-3000 and T-5000 manufactured by Mitsui Fine Chemicals, Inc., acrylonitrile-butadiene copolymer rubber having primary amino groups at both terminals thereof such as ATMN 1300X16 manufactured by Ube Industries, Ltd.; and secondary amino group-containing polymers. For the purpose of attaining a high molecular weight by the reaction with the polyisocyanate compound (E) and also for the purpose of increasing the introduction ratio of the silyl group by the reaction with the hydrolyzable silicon group-containing isocyanate group (G), the number of the active hydrogen-containing groups in the organic polymer (D) is preferably at least 1.2 or more, more preferably 1.6 or more, and particularly preferably 1.8 to 4, per one molecule on average over all the molecules. Among these, it is preferably 1.8 to 3, for the purpose of preventing gelation at the time of reaction with the polyisocyanate compound (E). An oxyalkylene polymer for which the number of hydroxy groups is 2 or more can be produced by replacing a part or the whole of the bifunctional initiators with a trifunctional or higher functional initiator; mixing the obtained bifunctional or higher functional oxyalkylene polymer with a bifunctional or lower functional oxyalkylene polymer makes it possible to obtain an oxyalkylene polymer having 1.2 to 4 hydroxy groups per one molecule on average over all the molecules. With respect to the number average molecular weight of the organic polymer (D) having active hydrogen-containing groups at the terminals thereof, the organic polymer (D) having a number average molecular weight of 1000 or more as measured by GPC relative to polystyrene standards can be used. When the number average molecular weight of the organic polymer (D) is small, the number of the amide segments introduced into the organic polymer (A) to be obtained comes to be large, the viscosity comes to be relatively high, and hence the number average molecular weight of the organic polymer (D) is preferably 2000 or more, and particularly preferably 4000 or more. As the polyisocyanate compound (E), any polyisocyanate compounds can be used. The number of the isocyanate groups contained in the polyisocyanate compound (E) is preferably 2 to 5 per one molecule on average, and more preferably 2 to 3 from the viewpoint of easy availability. Furthermore, because no gelation is caused when reacting with the organic polymer (D) having active hydrogen-containing groups at the terminals thereof, the number of the isocyanate groups concerned is most preferably 2. Specific examples of the polyisocyanate compound may include: aromatic monomers such as tolylene diisocyanate (TDI), 4,4-diphenylmethane diisocyanate (MDI), polymeric MDI, xylylene diisocyanate (XDI), naphthylene diisocyanate (NDI), tolydine diisocyanate (TODI), p-phenylene diisocyanate (PPDI), triphenylmethane triisocyanate, tris(isocyanate phenyl) thiophosphate, tetramethylxylylene diisocyanate (TMXDI); and aliphatic monomers such as hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), dicyclohexylmethane diisocyanate (hydrogenated MDI), 1,3-bis(isocyanatomethyl)cyclohexane (hydrogenated XDI), lysine diisocyanate (LDI), isopropylidene bis(4-cyclohexyl isocyanate), cyclohexyl diisocyanate (CHDI), 1,6,11-undecane triisocyanate, 1,3,6-hexamethylene triisocyanate, bicycloheptane triisocyanate, and trimethylhexamethylene diisocyanate. Dimmers, trimers, uretodione derivatives, isocyanurate derivatives, cyanurate derivatives, carbodiimide derivatives, and alohanate-, biuret- and urea-modified compounds of these compounds can also be used. More preferable among the polyisocyanate compounds (E) are those compounds in which all the isocyanate groups in the molecules thereof are not directly bonded to any of aromatic rings and carbon-carbon unsaturated bonds because cured articles using the organic polymers (A) obtained with these compounds attain satisfactory weather resistance. No particular constraint is imposed on such polyisocyanate compounds as log as such compounds do not contain any of the structures, aromatic ring carbon-N═C═O, —C═C—N═C═O and —C≡C—N═C═O. Specific examples of such compounds may include aliphatic monomers such as hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), dicyclohexylmethane diisocyanate (hydrogenated MDI), and 1,3-bis(isocyanatomethyl)cyclohexane (hydrogenated XDI); and xylylene diisocyanate (XDI). Additionally, various types of derivatives of these compounds may be included. No particular constraint is imposed on the silicon compound (F); however, specific examples thereof may include: amino group-containing silanes such as γ-aminopropyltrimethoxysilane, γ-aminopropyltriethoxysilane, γ-aminopropylmethyldimethoxysilane, N-(β-aminoethyl)-γ-aminopropyltrimethoxysilane, N-(β-aminoethyl)-γ-aminopropyltriethoxysilane, N-(β-aminoethyl)-γ-aminopropylmethyldimethoxysilane, γ-(N-phenyl)aminopropyltrimethoxysilane, N-ethylaminoisobutyltrimethoxysilane, aminomethyltrimethoxysilane, N-methylaminomethyltrimethoxysilane, N-cyclohexylaminomethyltrimethoxysilane and N-phenylaminomethyltrimethoxysilane; hydroxy group-containing silanes such as γ-hydroxypropyltrimethoxysilane and hydroxymethyltrimethoxysilane; and mercapto group-containing silanes such as γ-mercaptopropyltrimethoxysilane and mercaptomethyltrimethoxysilane. Additionally, as described in Japanese Patent Laid-Open Nos. 6-211879 (U.S. Pat. No. 5,364,955), 10-53637 (U.S. Pat. No. 5,756,751), 10-204144 (EP0831108), 2000-169544 and 2000-169545, Michael addition reaction products between various types of α,β-unsaturated carbonyl compounds and primary amino group-containing silanes, or Michael addition reaction products between various types of (meth)acryloyl group-containing silanes and primary amino group-containing compounds can also be used as the silicon compound (F). No particular constraint is imposed on the silicon group-containing isocyanate compound (G); however, specific examples thereof may include: γ-trimethoxysilylpropyl isocyanate, γ-triethoxysilylpropyl isocyanate, γ-methyldimethoxysilylpropyl isocyanate and γ-methyldiethoxysilylpropyl isocyanate. As described in Japanese Patent Laid-Open No. 2000-119365 (U.S. Pat. No. 6,046,270), silicon group-containing isocyanate compounds obtained by reacting the silicon compounds (F) with excessive amounts of the polyisocyanate compounds (E) can also be used as the component (G). Catalysts can be used for the reaction between the active hydrogen-containing groups in the organic polymer (D) and an isocyanate group and the reaction between the W group in the silicon compound (F) and an isocyanate group; however, when the storage stability of the organic polymer (A) to be obtained is degraded, these reactions are preferably carried out in the absence of these catalysts. When a catalyst is used, catalysts well known in the art may be used as long as such catalysts catalyze the reaction between a hydroxy group and an isocyanate group. The organic polymer (A) may be a straight chain or may have branches, and the number average molecular weight thereof, as measured by GPC relative to polystyrene standards, is preferably of the order of 500 to 50,000, and more preferably 1,000 to 30,000. When the number average molecular weight is less than 500, there is found an adverse trend involving the elongation properties of the cured article, while when the number average molecular weight exceeds 50000, there is found an adverse trend involving the workability because the viscosity is high. The organic polymers (A) may be used each alone or in combinations of two or more thereof. In the present invention, as the component (B), a metal carboxylate (B1) and/or a carboxylic acid (B2) is used. The component (B) functions as a so-called silanol condensation catalyst capable of forming siloxane bonds from the hydroxy groups or the hydrolyzable groups, each bonded to a silicon atom, contained in the organic polymer as the component (A). The component (B) displays a practical curability and can increase the heat resistance of the obtained cured article as compared to the other silanol condensation catalysts such as organotin catalysts although the component (B) is a non-organotin catalyst. No particular constraint is imposed on the metal carboxylates and/or the carboxylic acid to be used in the present invention, and various types of compounds can be used. As the metal carboxylate (B1), because of high catalytic activity, preferable are tin carboxylates, lead carboxylates, bismuth carboxylates, potassium carboxylates, calcium carboxylates, barium carboxylates, titanium carboxylates, zirconium carboxylates, hafnium carboxylates, vanadium carboxylates, manganese carboxylates, iron carboxylates, cobalt carboxylates, nickel carboxylates and cerium carboxylates; more preferable are tin carboxylates, lead carboxylates, bismuth carboxylates, titanium carboxylates, iron carboxylates and zirconium carboxylates; and particularly preferable are tin carboxylates and most preferable are divalent tin carboxylates. As the carboxylic acids having the acid radicals of the metal carboxylates, preferably used are compounds containing hydrocarbon based carboxylic acid radicals each having 2 to 40 carbon atoms inclusive of the carbonyl carbon atom(s); because of availability, hydrocarbon carboxylic acids having 2 to 20 carbon atoms are particularly preferably used. Specific examples may include: straight chain saturated fatty acids such as acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, 2-ethylhexanoic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, heptadecylic acid, stearic acid, nonadecanoic acid, arachic acid, behenic acid, lignoceric acid, cerotic acid, montanic acid, melissic acid and lacceric acid; monoene unsaturated fatty acids such as undecylenic acid, linderic acid, tsuzuic acid, physeteric acid, myristoleic acid, 2-hexadecenic acid, 6-hexadecenic acid, 7-hexadecenic acid, palmitoleic acid, petroselic acid, oleic acid, elaidic acid, asclepinic acid, vaccenic acid, gadoleic acid, gondoic acid, cetoleic acid, erucic acid, brassidic acid, selacholeic acid, ximenic acid, lumequeic acid, acrylic acid, methacrylic acid, angelic acid, crotonic acid, isocrotonic acid and 10-undecenoic acid; polyene unsaturated fatty acids such as linoelaidic acid, linoleic acid, 10,12-octadecadienoic acid, hiragoic acid, α-eleostearic acid, β-eleostearic acid, punicic acid, linolenic acid, 8,11,14-eicosatrienoic acid, 7,10,13-docosatrienoic acid, 4,8,11,14-hexadecatetraenoic acid, moroctic acid, stearidonic acid, arachidonic acid, 8,12,16,19-docosatetraenoic acid, 4,8,12,15,18-eicosapentaenoic acid, clupanodonic acid, nishinic acid and docosahexaenoic acid; branched fatty acids such as 1-methylbutyric acid, isobutyric acid, 2-ethylbutyric acid, isovaleric acid, tuberculostearic acid, pivalic acid and neodecanoic acid; fatty acids having a triple bond such as propiolic acid, tariric acid, stearolic acid, crepenynic acid, ximenynic acid and 7-hexadecynoic acid; alicyclic carboxylic acids such as naphthenic acid, malvalic acid, sterculic acid, hydnocarbic acid, chaulmoogric acid and gorlic acid; oxygen-containing fatty acids such as acetoacetic acid, ethoxy acetic acid, glyoxylic acid, glycolic acid, gluconic acid, sabinic acid, 2-hydroxytetradecanoic acid, ipurolic acid, 2-hydroxyhexadecanoic acid, jalapinolic acid, juniperic acid, ambrettolic acid, aleuritic acid, 2-hydroxyoctadecanoic acid, 12-hydroxyoctadecanoic acid, 18-hydroxyoctadecanoic acid, 9,10-dihydroxyoctadecanoic acid, ricinoleic acid, camlolenic acid, licanic acid, pheronic acid and cerebronic acid; and halogen-substituted monocarboxylic acids such as chloroacetic acid, 2-chloroacrylic acid and chlorobenzoic acid. Examples of fatty dicarboxylic acids may include saturated dicarboxylic acids such as adipic acid, azelaic acid, pimelic acid, superic acid, sebacic acid, ethylmalonic acid, glutaric acid, oxalic acid, malonic acid, succinic acid and oxydiacetic acid; and unsaturated dicarboxylic acids such as maleic acid, fumaric acid, acetylenedicarboxylic acid and itaconic acid. Examples of fatty polycarboxylic acids may include tricarboxylic acids such as aconitic acid, citric acid and isocitric acid. Examples of aromatic carboxylic acids may include aromatic monocarboxylic acids such as benzoic acid, 9-anthracenecarboxylic acid, atrolactic acid, anisic acid, isopropylbenzoic acid, salicylic acid and toluic acid; and aromatic polycarboxylic acids such as phthalic acid, isophthalic acid, terephthalic acid, carboxyphenylacetic acid and pyromellitic acid. Additional other examples may include amino acids such as alanine, leucine, threonine, aspartic acid, glutamic acid, arginine, cysteine, methionine, phenylalanine, tryptophane and histidine. The carboxylic acid is preferably 2-ethylhexanoic acid, octylic acid, neodecanoic acid, oleic acid, naphthenic acid or the like, because particularly these acids are easily available and low in price, and satisfactorily compatible with the component (A). When the melting point of the carboxylic acid is high (the crystallinity is high), the metal carboxylate having the acid radical of the carboxylic acid concerned has similarly a high melting point and is hardly handlable (poor in workability). Accordingly, the melting point of the carboxylic acid is preferably 65° C. or less, more preferably −50 to 50° C, and particularly preferably −40 to 35° C. Additionally, when the number of the carbon atoms in the carboxylic acid is large (the molecular weight thereof is large), the metal carboxylate having the acid radical of the carboxylic acid takes a solid form or a highly viscous liquid form to be hardly handlable (poor in workability). On the contrary, when the number of the carbon atoms in the carboxylic acid is small (the molecular weight thereof is small), sometimes tin carboxylate having the acid radical contains such components that are easily evaporated by heating, and the catalytic activity of the metal carboxylate is degraded. Particularly, under the conditions that the composition is extended thinly (under the conditions of a thin layer), sometimes the evaporation due to heating is significant, and the catalytic activity of the metal carboxylate is largely degraded. Accordingly, for the carboxylic acid, the number of the carbon atoms inclusive of the carbonyl carbon atom(s) is preferably 2 to 20, more preferably 6 to 17, and particularly preferably 8 to 12. From the viewpoint of easy handlability (workability and viscosity) of the metal carboxylate, the metal carboxylate is preferably a metal dicarboxylate or a metal monocarboxylate, and more preferably a metal monocarboxylate. Additionally, the metal carboxylate is preferably a metal carboxylate in which the carbon atom adjacent to the carbonyl group is a tertiary carbon atom (tin 2-ethylhexanoate and the like) or a metal carboxylate in which the carbon atom adjacent to the carbonyl group is a quaternary carbon atom (tin neodecanoate, tin pivalate and the like) because of rapid curing rate, and is particularly preferably a metal carboxylate in which the carbon atom adjacent to the carbonyl group is a quaternary carbon atom. The metal carboxylate in which the carbon atom adjacent to the carbonyl group is a quaternary carbon atom leads to a better adhesion as compared to other metal carboxylates. Examples of the carboxylic acid having the acid radical of the metal carboxylate in which the carbon atom adjacent to the carbonyl group is a quaternary carbon atom may include linear fatty acids represented by the general formula (10): wherein R7, R8 and R9 each are independently a substituted or unsubstituted monovalent hydrocarbon group, and may include carboxyl groups; and cyclic fatty acids having a structure represented by the general formula (11): wherein R10 is a substituted or unsubstituted monovalent hydrocarbon group, R11 is a substituted or unsubstituted divalent hydrocarbon group, and R10 and R11 each may include carboxyl groups, and having a structure represented by the general formula (12): wherein R12 is a substituted or unsubstituted trivalent hydrocarbon group, and may include carboxyl groups. Specific examples may include: linear monocarboxylic acids such as pivalic acid, 2,2-dimethylbutyric acid, 2-ethyl-2-methylbutyric acid, 2,2-diethylbutyric acid, 2,2-dimethylvaleric acid, 2-ethyl-2-methylvaleric acid, 2,2-diethylvaleric acid, 2,2-dimethylhexanoic acid, 2,2-diethylhexanoic acid, 2,2-dimethyloctanoic acid, 2-ethyl-2,5-dimethylhexanoic acid, neodecanoic acid, versatic acid, 2,2-dimethyl-3-hydroxypropionic acid; linear dicarboxylic acids such as dimetylmalonic acid, ethylmethylmalonic acid, diethylmalonic acid, 2,2-dimethylsuccinic acid, 2,2-diethylsuccinic acid and 2,2-dimethylglutaric acid; linear tricarboxylic acids such as 3-methylisocitric acid and 4,4-dimethylaconitic acid; cyclic carboxylic acids such as 1-methylcyclopentane carboxylic acid, 1,2,2-trimethyl-1,3-cyclopentane dicarboxylic acid, 1-methylcyclohexane carboxylic acid, 2-methylbicyclo[2.2.1]-5-heptene-2-carboxylic acid, 2-methyl-7-oxabicyclo[2.2.1]-5-heptene-2-carboxylic acid, 1-adamantane carboxylic acid, bicyclo[2.2.1]heptane-1-carboxylic acid and bicyclo[2.2.2]octane-1-carboxylic acid. Compounds having such structures are abundant in natural products, and such compounds can certainly be used. Particularly, metal salts of monocarboxylic acids are more preferable because these metal salts are satisfactory in the compatibility with the component (A) and easy in handling; additionally, metal salts of linear monocarboxylic acids are more preferable. Additionally, because of easy availability, metal salts of pivalic acid, neodecanoic acid, versatic acid, 2,2-dimethyloctanoic acid, 2-ethyl-2,5-dimethylhexanoic acid and the like are particularly preferable. The number of the carbon atoms in such a carboxylic acid having the acid radical of a metal carboxylate in which the carbon atom adjacent to the carbonyl group is a quaternary carbon atom is preferably 5 to 20, more preferably 6 to 17, and particularly preferably 8 to 12. When the number of the carbon atoms exceeds these ranges, the metal carboxylate tends to take a solid form, becomes hardly compatible with the component (A), and tends to hardly exhibit activity. On the other hand, when the number of the carbon atoms is small, the carboxylic acids tends to be easily evaporated and tends to display strong odor. From the viewpoints of these issues, metal slats of neodecanoic acid, versatic acid, 2,2-dimethyloctanoic acid and 2-ethyl-2,5-dimethylhexanoic acid are most preferable. The use of such metal carboxylates as the component (B1) of the present invention provides cured articles having satisfactory heat resistance, recovery properties, durability and creep resistance. Also provided are cured articles satisfactory in water-resistant adhesion, adhesion durability under conditions of high temperatures and high humidities, residual tack, dust sticking property, staining property, surface weather resistance, heat resistance and adhesion to concrete. The used amount of the component (B1) is preferably of the order of 0.01 to 20 parts by weight, and more preferably of the order of 0.5 to 10 parts by weight in relation to 100 parts by weight of the component (A). When the blended amount of the component (B1) is less than these ranges, sometimes the curing rate becomes slow, and the curing reaction tends to hardly proceed to a sufficient extent. On the other hand, when the blended amount of the component (B1) exceeds these ranges, the work life tends to be too short and the workability thereby tends to be degraded, and the storage stability also tends to be degraded. The metal carboxylates as the component (B1) may be used each alone, and additionally, may be used in combinations of two or more thereof. In the present invention, carboxylic acids can be used as the component (B2). The heat resistance of the cured article obtained by use of a carboxylic acid as a catalyst is preferably better than the heat resistance of the cured article obtained by use of a metal carboxylate (B1). The component (B2) may be used alone as a curing catalyst, but the use thereof in combination with the component (B1) displays an advantageous effect of improving the curing activity of the curable composition of the present invention. When a metal carboxylate as the component (B1) is used as a curing catalyst, sometimes the curability is degraded after storage; however, the use of the component (B2) added in combination with the component (B1) can suppress the degradation of the curability after storage. Examples of the carboxylic acid as the component (B2) may include the above described various types of carboxylic acids each having the acid radical of a metal carboxylate as the component (B1). Additionally, those carboxylic acid derivatives which can produce the above described carboxylic acids by hydrolysis, namely, the derivatives such as carboxylic acid anhydrides, esters, acyl halides, nitriles and amides, can also be used as the component (B2). The number of the carbon atoms, inclusive of the carbonyl carbon atom(s), of a carboxylic acid as the component (B2) is preferably 2 to 20, more preferably 6 to 17, and particularly preferably 8 to 12, similarly to the carboxylic acids each having the acid radical of a metal carboxylate as the component (B1). From the viewpoint of easy handlability (workability and viscosity) of the carboxylic acid, the carboxylic acid is preferably a dicarboxylic acid or a monocarboxylic acid, and more preferably a monocarboxylic acid. Additionally, the carboxylic acid is preferably a carboxylic acid in which the carbon atom adjacent to the carbonyl group is a tertiary carbon atom (2-ethylhexanoic acid and the like) or a carboxylic acid in which the carbon atom adjacent to the carbonyl group is a quaternary carbon atom (neodecanoic acid, pivalic acid and the like) because of rapid curing rate, and is particularly preferably a carboxylic acid in which the carbon atom adjacent to the carbonyl group is a quaternary carbon atom. From the viewpoints of the availability, curability and workability, as the carboxylic acids, 2-ethylhexanoic acid, neodecanoic acid, versatic acid, 2,2-dimethyloctanoic acid and 2-ethyl-2,5-dimethylhexanoic acid are particularly preferable. The use of the carboxylic acid as the component (B2) provides curable compositions giving cured articles having satisfactory heat resistance, recovery properties, durability and creep resistance. Also provided are cured articles satisfactory in water-resistant adhesion, adhesion durability under conditions of high temperatures and high humidities, residual tack, dust sticking property, staining property, surface weather resistance, heat resistance, adhesion to concrete and the like. The used amount of the component (B2) is preferably of the order of 0.01 to 20 parts by weight, and further preferably of the order of 0.5 to 10 parts by weight in relation to 100 parts by weight of the component (A). When the blended amount of the component (B2) is less than these ranges, sometimes the curing rate tends to become slow. On the other hand, when the blended amount of the component (B2) exceeds these ranges, the work life tends to be too short and the workability thereby tends to be degraded, and the viscosity also tends to be increased. The carboxylic acids as the component (B2) may be used each alone, and additionally may be used in combinations of two or more thereof. The component (B1) and the component (B2) may be used each alone or in combination. In this connection, when only with the component (B), activity is low and hence no appropriate curability is obtained, an amine compound may be added as the component (C). Specific examples of the amine compound as the component(C) may include: aliphatic primary amines such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, amylamine, hexylamine, octylamine, 2-ethylhexylamine, nonylamine, decylamine, laurylamine, pentadecylamine, cetylamine, stearylamine and cyclohexylamine; aliphatic secondary amines such as dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diamylamine, dihexylamine, dioctylamine, di(2-ethylhexyl)amine, didecylamine, dilaurylamine, dicetylamine, distearylamine, methylstearylamine, ethylstearylamine and butylstearylamine; aliphatic tertiary amines such as triamylamine, trihexylamine and trioctylamine; aliphatic unsaturated amines such as triallylamine and oleylamine; aromatic amines such as laurylaniline, stearylaniline and triphenylamine; and other amines such as benzylamine, monoethanolamine, diethanolamine, triethanolamine, 3-hydroxypropylamine, ethylenediamine, N,N-diethylethylenediamine, xylylenediamine, diethylenetriamine, triethylenetetramine, 3-methoxypropylamine, 3-lauryloxypropylamine, N-methyl-1,3-propanediamine, 3-dimethylaminopropylamine, 3-diethylaminopropylamine, 3-(1-piperazinyl)propylamine, 3-morphorinopropylamine, 2-(1-piperazinyl)ethylamine, hexamethylenediamine, triethylenediamine, guanidine, diphenylguanidine, 2,4,6-tris(dimethylaminomethyl)phenol, morpholine, N-methylmorpholine, 2-ethyl-4-methylimidazole, 1,8-diazabicyclo(5,4,0)undecene-7 (DBU) and 1,5-diazabicyclo(4,3,0)nonene-5 (DBN). However, the amine compound as the component (C) is not limited to these examples. Because the cocatalytic activity of the component (C) is largely varied depending on the structure of the component (C) itself and the compatibility thereof with the component (A), it is preferable that an appropriate compound is selected as the component (C) in conformity with the type of the component (A) to be used. When a polyoxyalkylene polymer, for example, is used as the component (A), primary amines such as octylamine and laurylamine are preferable because these amines are high in cocatalytic activity; additionally, preferable are the amine compounds each having a hydrocarbon group having at least one hetero atom. Examples of the hetero atom as referred to here may include N, O and S atoms, but the hetero atom is not limited to these examples. Examples of such amine compounds may include the amines described above under the category of other amines. Among such amines, more preferable are the amine compounds each having a hydrocarbon group having a hetero atom at the carbon atom at position 2, 3 or 4, and furthermore preferable are the amine compounds each having a hydrocarbon group having a hetero atom at the carbon atom at position 3. Examples of such amine compounds may include 3-hydroxypropylamine, 3-methoxypropylamine, 3-ethoxypropylamine, 3-lauryloxypropylamine, N-methyl-1,3-propanediamine, 3-dimethylaminopropylamine, 3-diethylaminopropylamine, 3-(1-piperazinyl)propylamine and 3-morpholinopropylamine. Among these, 3-diethylaminopropylamine and 3-morpholinopropylamine are more preferable because of high cocatalytic activity; 3-diethylaminopropylamine is particularly preferable because this compound gives curable compositions satisfactory in adhesion, storage stability and workability. Additionally, when an isobutylene polymer is used as the component (A), relatively long chain aliphatic secondary amines such as dioctylamine and distearylamine and aliphatic secondary amines such as dicyclohexylamine are preferable because of high cocatalytic activity. The blended amount of the amine compound as the component (C) is preferably of the order of 0.01 to 20 parts by weight and more preferably 0.1 to 5 parts by weight in relation to 100 parts by weight of the organic polymer as the component (A). When the blended amount of the amine compound is less than 0.01 part by weight, sometimes the curing rate becomes slow, and the curing reaction hardly proceeds to a sufficient extent. On the other hand, when the blended amount of the amine compound exceeds 20 parts by weight, sometimes the pot life tends to be too short, and sometimes the curing rate becomes slow in reverse. To the composition of the present invention, a (meth)acrylate polymer having reactive silicon groups may be added. The addition of the (meth)acrylate polymer improves the adhesion, weather resistance and chemical resistance of the composition of the present invention. No particular constraint is imposed on the (meth)acrylate monomers constituting the main chain of the above described (meth)acrylate polymer, and various types can be used. Examples of the monomers concerned may include (meth)acrylic acid based monomers such as (meth)acrylic acid, methyl(meth)acrylate, ethyl(meth)acrylate, n-propyl(meth)acrylate, isopropyl(meth)acrylate, n-butyl(meth)acrylate, isobutyl(meth)acrylate, tert-butyl(meth)acrylate, n-pentyl(meth)acrylate, n-hexyl(meth)acrylate, cyclohexyl(meth)acrylate, n-heptyl(meth)acrylate, n-octyl(meth)acrylate, 2-ethylhexyl(meth)acrylate, nonyl(meth)acrylate, decyl(meth)acrylate, dodecyl(meth)acrylate, phenyl(meth)acrylate, toluyl(meth)acrylate, benzyl(meth)acrylate, 2-methoxyethyl (meth)acrylate, 3-methoxybutyl(meth)acrylate, 2-hydroxyethyl(meth)acrylate, 2-hydroxypropyl(meth)acrylate, stearyl(meth)acrylate, glycidyl(meth)acrylate, 2-aminoethyl(meth)acrylate, γ-(methacryloyloxypropyl)trimethoxysilane, ethylene oxide adduct of (meth)acrylic acid, trifluoromethylmethyl(meth)acrylate, 2-trifluoromethylethyl(meth)acrylate, 2-perfluoroethylethyl(meth)acrylate, 2-perfluoroethyl-2-perfluorobutylethyl(meth)acrylate, 2-perfluoroethyl(meth)acrylate, perfluoromethyl(meth)acrylate, diperfluoromethylmethyl(meth)acrylate, 2-perfluoromethyl-2-perfluoroethylmethyl(meth)acrylate, 2-perfluorohexylethyl(meth)acrylate, 2-perfluorodecylethyl(meth)acrylate and 2-perfluorohexadecylethyl(meth)acrylate. The above described (meth)acrylate monomers can also be copolymerized with the following vinyl monomers. Examples of the vinyl monomers concerned may include styrene monomers such as styrene, vinyltoluene, α-methylstyrene, chlorstyrene, and styrenesulfonic acid and the salts thereof; fluorine-containing vinyl monomers such as perfluoroethylene, perfluoropropylene and vinylidene fluoride; silicon-containing vinyl monomers such as vinyltrimethoxysilane and vinyltriethoxysilane; maleic acid anhydride, maleic acid, and monoalkyl esters and dialkyl esters of maleic acid; fumaric acid, and monoalkyl esters and dialkyl esters of fumaric acid; maleimide monomers such as maleimide, methylmaleimide, ethylmaleimide, propylmaleimide, butylmaleimide, hexylmaleimide, octylmaleimide, dodecylmaleimide, stearylmaleimide, phenylmaleimide and cyclohexylmaleimide; nitrile group-containing vinyl monomers such as acrylonitrile and methacrylonitrile; amide group-containing vinyl monomers such as acrylamide and methacrylamide; vinyl esters such as vinyl acetate, vinyl propionate, vinyl pivalate, vinyl benzoate and vinyl cinnamate; alkenes such as ethylene and propylene; conjugated dienes such as butadiene and isoprene; and vinyl chloride, vinylidene chloride, allyl chloride and allylalcohol. These monomers may be used each alone or two or more of these monomers may be copolymerized. Among these, from the viewpoint of the physical properties and the like of the products, polymers formed of styrene monomers and (meth)acrylic acid monomers are preferable. More preferable are the (meth)acrylic polymers formed of acrylate monomers and methacrylate monomers, and particularly preferable are the acrylic polymers formed of acrylate monomers. Examples of the manufacturing method of a reactive silicon group-containing (meth)acrylate polymer may include, for example, a manufacturing method in which the polymer concerned is obtained by using reactive silicon group-containing monomers such as vinyltrimethoxysilane, vinyltriethoxysilane, γ-methacryloyloxypropylmethyldimethoxysilane, γ-acryloyloxypropyltrimethoxysilane and the above described individual monomers, and by applying a common free radical polymerization method with a polymerization initiator such as an azo compound or a peroxide; the free radical polymerization methods with chain transfer agents as disclosed in Japanese Patent Publication Nos. 3-14068 and 4-55444, Japanese Patent Laid-Open No. 6-211922 and the like; and the atom transfer radical polymerization method as disclosed in Japanese Patent Laid-Open No. 9-272714 and the like. However, the manufacturing method concerned is not limited particularly to these methods. The used amount of the reactive silicon group-containing (meth)acrylate polymer is preferably of the order of 1 to 500 parts by weight, and more preferably 10 to 100 parts by weight, in relation to 100 parts by weight of the organic polymer as the component (A). When the blended amount of the (meth)acrylate polymer is less than 1 part by weight, sometimes the improvement effects of the adhesion, weather resistance and chemical resistance are small, while when the blended amount of the (meth)acrylate polymer exceeds 50 parts by weight, som etimes the elongation of the obtained cured article is small. To the composition of the present invention, a silicate may be added. The silicate functions as a cross-linking agent, and has functions to improve the recovery properties, durability and creep resistance of the organic polymer as the component (A) of the present invention. The silicate further has effects to improve the adhesion, water-resistant adhesion and adhesion durability under conditions of high temperatures and high humidities. As the silicate, tetraalkoxysilane, alkylalkoxysilane, or the partially hydrolyzed condensates thereof may be used. Specific examples of the silicate may include, for example, tetraalkoxysilanes (tetraalkyl silicates) such as tetramethoxysilane, tetraethoxysilane, ethoxytrimethoxysilane, dimethoxydiethoxysilane, methoxytriethoxysilane, tetra-n-propoxysilane, tetra-i-propoxysilane, tetra-n-butoxysilane, tetra-i-butoxysilane and tetra-t-butoxysilane; and the partially hydrolyzed condensates thereof. The partially hydrolyzed condensates of the tetraalkoxysilanes are more preferable because these condensates have larger improvement effects of the recovery properties, durability and creep resistance in the present invention than the tetraalkoxysilanes. Examples of the partially hydrolyzed condensates of the tetraalkoxysilanes may include products obtained by condensation through partial hydrolysis of the tetraalkoxysilanes by adding water to the tetraalkoxysilanes according to common methods. As partially hydrolyzed condensates of organosilicate compounds, commercially available products may be used. Examples of such condensates may include Methyl Silicate 51 and Ethyl Silicate 40 (manufactured by Colcoat Co., Ltd.). The used amount of the silicate is preferably of the order of 0.01 to 20 parts by weight, and more preferably 0.1 to 5 parts by weight in relation to 100 parts by weight of the organic polymer as the component (A). When the blended amount of the silicate is less than 0.01 part by weight, sometimes the improvement effects of the recovery properties, durability and creep resistance are small, while when the blended amount of the silicate exceeds 20 parts by weight, sometimes the elongation of the obtained cured article is small. To the composition of the present invention, a filler may be added. Examples of the filler may include: reinforcing fillers such as fumed silica, precipitated silica, crystalline silica, fused silica, dolomite, anhydrous silicic acid, hydrous silicic acid and carbon black; fillers such as ground calcium carbonate, precipitated calcium carbonate, magnesium carbonate, diatomite, sintered clay, clay, talc, titanium oxide, bentonite, organic bentonite, ferric oxide, aluminum fine powder, flint powder, zinc oxide, active zinc white, shirasu balloon, glass microballoon, organic microballoons of phenolic resin and vinylidene chloride resin, and resin powders such as PVC powder and PMMA powder; and fibrous fillers such as asbestos, glass fiber and glass filament. When a filler is used, the used amount thereof is 1 to 250 parts by weight, and preferably 10 to 200 parts by weight in relation to 100 parts by weight of the organic polymer as the component (A). When it is desired to obtain a cured article high in strength by use of these fillers, preferable is a filler mainly selected from fumed silica, precipitated silica, crystalline silica, fused silica, dolomite, anhydrous silicic acid, hydrous silicic acid, carbon black, surface treated fine calcium carbonate, sintered clay, clay, active zinc white and the like; a desirable effect is obtained when such a filler is used within a range from 1 to 200 parts by weight in relation to 100 parts by weight of the reactive silicon group-containing organic polymer (A). Also, when it is desired to obtain a cured article low in tensile strength and large in elongation at break, a desirable effect is obtained by use of a filler mainly selected from titanium oxide, calcium carbonate such as ground calcium carbonate, magnesium carbonate, talc, ferric oxide, zinc oxide, shirasu balloon and the like within a range from 5 to 200 parts by weight in relation to 100 parts by weight of the reactive silicon group-containing organic polymer (A). It is to be noted that in general, calcium carbonate exhibits, with increasing specific surface area value thereof, an increasing improvement effect of the tensile strength at break, elongation at break and adhesion of the cured article. Needless to say, these fillers may be used each alone or in admixtures of two or more thereof. When calcium carbonate is used, it is desirable to use surface treated fine calcium carbonate in combination with calcium carbonate larger in particle size such as ground calcium carbonate. The particle size of surface treated fine calcium carbonate is preferably 0.5 μm or less, and the surface treatment is preferably carried out by treating with a fatty acid or a fatty acid salt. A calcium carbonate larger in particle size is preferably 1 μm or more in particle size, and can be used without being subjected to surface treatment. For the purpose of improving the workability (unstickiness and the like) of the composition and matting the surface of the cured article, organic balloons and inorganic balloons are preferably added. Such fillers can be subjected to surface treatment, and may be used each alone or in admixtures of two or more thereof. For the purpose of improving the workability (unstickiness and the like), the particle sizes of these balloons are preferably 0.1 mm or less. For the purpose of matting the surface of the cured article, the particle sizes are preferably 5 to 300 μm. On the grounds that the cured article of the composition of the present invention is satisfactory in weather resistance and the like, the composition of present invention is suitably used for joints of housing exterior wall such as sizing boards, in particular, ceramic sizing boards, for an adhesive for exterior wall tiles, for an adhesive for exterior wall tiles remaining in the joints and for the like purposes; in this connection, it is desirable that the design of the exterior wall and the design of the sealant are in harmony with each other. Particularly, posh exterior walls have come to be used by virtue of sputter coating and mixing colored aggregates. When the composition of the present invention is blended with a scale-like or granular material having a diameter of 0.1 mm or more, preferably of the order of 0.1 to 5.0 mm, the cured article comes to be in harmony with such posh exterior walls, and is excellent in chemical resistance, so that the composition concerned comes to be an excellent composition in the sense that the exterior appearance of the cured article remains unchanged over a long period of time. Use of a granular material provides a dispersed sand-like or sandstone-like surface with a rough texture, while use of a scale-like material provides an irregular surface based on the scale-like shape of the material. The preferable diameter, blended amount and materials for the scale-like or granular material are described in Japanese Patent Laid-Open No. 9-53063 as follows. The diameter is 0.1 mm or more, preferably of the order of 0.1 to 5.0 mm, and there is used a material having an appropriate size in conformity with the material quality and pattern of exterior wall. Materials having a diameter of the order of 0.2 mm to 5.0 mm and materials having a diameter of the order of 0.5 mm to 5.0 mm can also be used. In the case of a scale-like material, the thickness is set to be as thin as the order of 1/10 to ⅕ the diameter (the order of 0.01 to 1.00 mm). The scale-like or granular material is transported to the construction site as a sealant in a condition that the material is beforehand mixed in the main part of the sealant, or is mixed in the main part of the sealant at the construction site when the sealant is used. The scale-like or granular material is blended in a content of the order of 1 to 200 parts by weight in relation to 100 parts by weight of a composition such as a sealant composition and an adhesive composition. The blended amount is appropriately selected depending on the size of the scale-like or granular material, and the material quality and pattern of exterior wall. As the scale-like or granular material, natural products such as silica sand and mica, synthetic rubbers, synthetic resins and inorganic substances such as alumina are used. The material is colored in an appropriate color so as to match the material quality and pattern of exterior wall for the purpose of heightening the design quality when filled in the joints. A preferable finishing method and the like are described in Japanese Patent Laid-Open No. 9-53063. When a balloon (preferably the mean particle size thereof is 0.1 mm or more) is also used for a similar purpose, the surface is formed to have a dispersed sand-like or sandstone-like surface with a rough texture, and a reduction of weight can be achieved. The preferable diameter, blended amount and materials for the balloon are described in Japanese Patent Laid-Open No. 10-251618 as follows. The balloon is a spherical filler with a hollow interior. Examples of the material for such a balloon may include inorganic materials such as glass, shirasu and silica; and organic materials such as phenolic resin, urea resin, polystyrene and Saran™; however, the material concerned is not limited to these examples; an inorganic material and an organic material can be compounded, or can be laminated to form multiple layers. An inorganic balloon, an organic balloon, a balloon made of a compounded inorganic-organic material or the like can be used. Additionally, as a balloon to be used, either a single type of balloon or an admixture of multiple types of balloons can be used. Moreover, a balloon with the processed surface thereof or with the coated surface thereof can be used, and additionally, a balloon with the surface thereof subjected to treatment with various surface treatment agents can also be used. More specifically, there may be included examples in which an organic balloon is coated with calcium carbonate, talc, titanium oxide and the like, and an inorganic balloon is subjected to surface treatment with a silane coupling agent. For the purpose of obtaining a dispersed sand-like or sandstone-like surface with a rough texture, the particle size of the balloon is preferably 0.1 mm or more. A balloon of a particle size of the order of 0.2 mm to 5.0 mm or a balloon of a particle size of the order of 0.5 mm to 5.0 mm can also be used. Use of a balloon of a particle size of less than 0.1 mm sometimes only increases the viscosity of the composition, and yields no rough texture even when the blended amount of the balloon is large. The blended amount of the balloon can be easily determined in conformity with the desired degree of the dispersed sand-like or sandstone-like rough texture. Usually, it is desirable that a balloon of 0.1 mm or more in particle size is blended in a ratio of 5 to 25 vol % in terms of the volume concentration in the composition. When the volume concentration of the balloon is less than 5 vol %, no rough texture can be obtained, while when the volume concentration of the balloon exceeds 25 vol %, the viscosity of the sealant and that of the adhesive tend to be high to degrade the workability, and the modulus of the cured article is high, so that the basic performance of the sealant and that of the adhesive tend to be impaired. The preferable volume concentration to balance with the basic performance of the sealant is 8 to 22 vol %. When a balloon is used, there may be added an antislip agent described in Japanese Patent Laid-Open No. 2000-154368 and an amine compound to make irregular and matte the surface of the cured article described in Japanese Patent Laid-Open No. 2001-164237, in particular, a primary amine and/or a secondary amine having a melting point of 35° C. or higher. Specific examples of the balloon are described in the following publications: Japanese Patent Laid-Open Nos. 2-129262, 4-8788, 4-173867, 5-1225, 7-113073, 9-53063, 10-251618, 2000-154368 and 2001-164237, and WO97/05201. When the composition of the present invention includes the particles of the cured article derived from a sealant, the cured article can make irregularities on the surface thereof to improve the design quality. The preferable diameter, blended amount, materials and the like of the cured article particle material derived from a sealant are described in Japanese Patent Laid-Open No. 2001-115142 as follows. The diameter is preferably of the order of 0.1 mm to 1 mm, and further preferably of the order of 0.2 to 0.5 mm. The blended amount is preferably 5 to 100 wt %, and further preferably 20 to 50 wt % in the curable composition. Examples of the materials may include urethane resin, silicone, modified silicone and polysulfide rubber. No constraint is imposed on the materials as long as the materials can be used as sealants; however, modified silicone sealants are preferable. To the composition of the present invention, a plasticizer may be added. Addition of a plasticizer makes it possible to adjust the viscosity and slump property of the curable composition and the mechanical properties such as tensile strength and elongation of the cured article obtained by curing the composition. Examples of the plasticizer may include phthalates such as dibutyl phthalate, diheptyl phthalate, di(2-ethylhexyl)phthalate and butyl benzyl phthalate; nonaroamtic dibasic acid esters such as dioctyl adipate, dioctyl sebacate, dibutyl sebacate and isodecyl succinate; aliphatic esters such as butyl oleate and methyl acetylricirinoleate; phosphates such as tricresyl phosphate and tributyl phosphate; alkyl sulfates; trimellitates; chlorinated paraffins; hydrocarbon oils such as alkyldiphenyls and partially hydrogenated terphenyls; process oils; and epoxy plasticizers such as epoxidized soybean oil and benzyl epoxystearate. Additionally, a polymer plasticizer may be used. When a polymer plasticizer is used, the initial physical properties are maintained over a longer period of time than when a low molecular weight plasticizer which is a plasticizer containing no polymer component in the molecule thereof is used. Moreover, the drying property (also referred to as coating property) can be improved when an alkyd coating material is applied onto the cured article concerned. Specific examples of the polymer plasticizer may include: vinyl polymers obtained by polymerizing vinyl monomers by means of various methods; polyalkylene glycol esters such as diethylene glycol dibenzoate, triethylene glycol dibenzoate and pentaerythritol ester; polyester plasticizers. obtained from dibasic acids such as sebacic acid, adipic acid, azelaic acid and phthalic acid and dihydric alcohols such as ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol and dipropylene glycol; polyethers including polyether polyols each having a molecular weight of 500 or more, additionally 1000 or more such as polyethylene glycol, polypropylene glycol and polytetramethylene glycol, and the derivatives of these polyether polyols in which the hydroxy groups in these polyether polyols are substituted with ester groups, ether groups and the like; polystyrenes such as polystyrene and poly-α-methylstyrene; and polybutadiene, polybutene, polyisobutylene, butadiene-acrylonitrile and polychloroprene. However, the polymer plasticizer concerned is not limited to these examples. Among polymer plasticizers, those polymer plasticizers which are compatible with the organic polymer as the component (A) are preferable. In this regard, polyethers and vinyl polymers are preferable. Additionally, the use of polyethers as plasticizers improves the surface curability and deep part curability, and causes no curing retardation after storage, and hence polyethers are preferable; among polyethers, polypropylene glycol is more preferable. Additionally, from the viewpoint of the compatibility, weather resistance and heat resistance, vinyl polymers are preferable. Among the vinyl polymers, acrylic polymers and/or methacrylic polymers are preferable, and acrylic polymers such as polyalkylacrylate are further preferable. As the synthesis method of this polymer, the living radical polymerization method is preferable because this method can lead to narrow molecular weight distributions and low viscosities, and the atom transfer radical polymerization method is further preferable. Additionally, it is preferable to use a polymer based on the so-called SGO process which is obtained by continuous block polymerization of an alkyl acrylate monomer at a high temperature and under a high pressure, as described in Japanese Patent Laid-Open No. 2001-207157. The number average molecular weight of the polymer plasticizer is preferably 500 to 15000, more preferably 800 to 10000, further preferably 1000 to 8000, particularly preferably 1000 to 5000, and most preferably 1000 to 3000. When the molecular weight is too low, the plasticizer is removed with time thermally and by rainfall, and hence it is made impossible to maintain the initial physical properties over a long period of time, and the coating property with the alkyd coating cannot be improved. On the other hand, when the molecular weight is too high, the viscosity is high and the workability is degraded. No particular constraint is imposed on the molecular weight distribution of the polymer plasticizer. However, it is preferable that the molecular weight distribution is narrow; the molecular weight distribution is preferably less than 1.80, more preferably 1.70 or less, further preferably 1.60 or less, yet further preferably 1.50 or less, particularly preferably 1.40 or less and most preferably 1.30 or less. The number average molecular weight of a vinyl polymer is measured with the GPC method, and that of a polyether polymer is measured with the end group analysis method. Additionally, the molecular weight distribution (Mw/Mn) is measured with the GPC method (relative to polystyrene standards). Additionally, the polymer plasticizer either may have no reactive silicon group or may have one or more reactive silicon groups. When the polymer plasticizer has one or more reactive silicon groups, the polymer plasticizer acts as a reactive plasticizer, and can prevent the migration of the plasticizer from the cured article. When the polymer plasticizer has one or more reactive silicon groups, the average number of the reactive silicon groups per one molecule is 1 or less, and preferably 0.8 or less. When the reactive silicon group-containing plasticizer, in particular, a reactive silicon group-containing oxyalkylene polymer is used, it is necessary that the number average molecular weight thereof be lower than that of the organic polymer as the component (A). The plasticizers may be used each alone or in combinations of two or more thereof. Additionally, a low molecular weight plasticizer and a polymer plasticizer may be used in combination. It is to be noted that these plasticizers can also be blended when the organic polymer is produced. The used amount of the plasticizer is 5 to 150 parts by weight, preferably 10 to 120 parts by weight, and further preferably 20 to 100 parts by weight, in relation to 100 parts by weight of the organic polymer as the component (A). When the used amount is less than 5 parts by weight, the effect as the plasticizer is not attained, while when the used amount exceeds 150 parts by weight, the mechanical strength of the cured article is insufficient. To the composition of the present invention, a silane coupling agent, a reaction product of a silane coupling agent or a compound other than the silane coupling agent may be added as an adhesion-imparting agent. Specific examples of the silane coupling agent may include: isocyanate group-containing silanes such as γ-isocyanatepropyltrimethoxysilane, γ-isocyanatepropyltriethoxysilane, γ-isocyanatepropylmethyldiethoxysilane and γ-isocyanatepropylmethyldimethoxysilane; amino group-containing silanes such as γ-aminopropyltrimethoxysilane, γ-aminopropyltriethoxysilane, γ-aminopropyltriisopropoxysilane, γ-aminopropylmethyldimethoxysilane, γ-aminopropylmethyldiethoxysilane, γ-(2-aminoethyl)aminopropyltrimethoxysilane, γ-(2-aminoethyl)aminopropylmethyldimethoxysilane, γ-(2-aminoethyl)aminopropyltriethoxysilane, γ-(2-aminoethyl)aminopropylmethyldiethoxysilane, γ-(2-aminoethyl)aminopropyltriisopropoxysilane, γ-(6-aminohexyl)aminopropyltrimethoxysilane, 3-(N-ethylamino)-2-methylpropyltrimethoxysilane, γ-ureidopropyltrimethoxysilane, γ-ureidopropyltriethoxysilane, N-phenyl-γ-aminopropyltrimethoxysilane, N-benzyl-γ-aminopropyltrimethoxysilane, and N-vinylbenzyl-γ-aminopropyltriethoxysilane; mercapto group-containing silanes such as γ-mercaptopropyltrimethoxysilane, γ-mercaptopropyltriethoxysilane, γ-mercaptopropylmethyldimethoxysilane and γ-mercaptopropylmethyldiethoxysilane; epoxy group-containing silanes such as γ-glycidoxypropyltrimethoxysilane, γ-glycidoxypropyltriethoxysilane, γ-glycidoxypropylmethyldimethoxysilane, β-(3,4-epoxycyclohexyl)ethyltrimethoxysilane and β-(3,4-epoxycyclohexyl)ethyltriethoxysilane; carboxysilanes such as β-carboxyethyltriethoxysilane, β-carboxyethylphenylbis(2-methoxyethoxy)silane and N-β-(carboxymethyl)aminoethyl-γ-aminopropyltrimethoxysilane; vinyl-type unsaturated group-containing silanes such as vinyltrimethoxysilane, vinyltriethoxysilane, γ-methacryloyloxypropylmethyldimethoxysilane and γ-acryloyloxypropylmethyltriethoxysilane; halogen-containing silanes such as γ-chloropropyltrimethoxysilane; and isocyanurate silanes such as tris(trimethoxysilyl)isocyanurate. Additionally, the following derivatives obtained by modifying these compounds can be used as silane coupling agents: amino-modified silylpolymer, silylated aminopolymer, unsaturated aminosilane complex, phenylamino-long chain alkylsilane, aminosilylated silicone and silylated polyester. The silane coupling agents used in the present invention are usually used within a range from 0.1 to 20 parts by weight in relation to 100 parts by weight of the reactive silicon group-containing organic polymer (A). Particularly, it is preferable to use the silane coupling agents within a range from 0.5 to 10 parts by weight. The effect of the silane coupling agent added to the curable composition of the present invention is such that the silane coupling agent exhibits marked adhesion improvement effect under either non-primer conditions or primer-treatment conditions when the silane coupling agent is applied to various types of adherends, namely, inorganic substrates made of the materials such as glass, aluminum, stainless steel, zinc, copper and mortar, and organic substrates made of the materials such as polyvinyl chloride, acrylic resin, polyester, polyethylene, polypropylene and polycarbonate. When the silane coupling agent is applied under non-primer conditions, improvement effect of adhesion to various adherends is particularly remarkable. No particular constraint is imposed on the adhesion-imparting agents other than the silane coupling agents, and specific examples of such adhesion-imparting agents may include, for example, epoxy resin, phenolic resin, sulfur, alkyl titanates and aromatic polyisocyanates. These adhesion-imparting agents may be used each alone or in admixtures of two or more thereof. Addition of these adhesion-imparting agents can improve the adhesion to adherends. To the curable composition of the present invention, according to need, there may be added a physical property modifier to modify the tensile strength of the produced cured article. No particular constraint is imposed on the physical property modifier. However, examples of the physical property modifier may include, for example, alkylalkoxysilanes such as methyltrimethoxysilane, dimethyldimethoxysilane, trimethylmethoxysilane and n-propyltrimethoxysilane; alkoxysilanes having functional groups such as alkylisopropenoxysilanes including dimethyldiisopropenoxysilane, methyltriisopropenoxysilane, and γ-glycidoxypropylmethyldiisopropenoxysilane, and γ-glycidoxypropylmethyldimethoxysilane, γ-glycidoxypropyltrimethoxysilane, vinyltrimethoxysilane, vinyldimethylmethoxysilane, γ-aminopropyltrimethoxysilane, N-(β-aminoethyl)aminopropylmethyldimethoxysilane, γ-mercaptopropyltrimethoxysilane and γ-mercaptopropylmethyldimethoxysilane; silicone varnishes; and polysiloxanes. The use of the physical property modifier makes it possible to increase the hardness obtained when the composition of the present invention is cured, or to decrease the hardness in reverse to display the elongation at break. The physical property modifiers may be used each alone or in combinations of two or more thereof. It is to be noted that a compound to hydrolytically produce a compound having a monovalent silanol group in the molecule thereof has an effect to decrease the modulus of the cured article without degrading the stickiness of the surface of the cured article. Particularly, a compound to produce trimethylsilanol is preferable. Examples of the compound to hydrolytically produce a compound having a monovalent silanol group in the molecule thereof may include a compound described in Japanese Patent Laid-Open No. 5-117521. Additionally, examples of such a compound may include a compound which is a derivative of an alkyl alcohol such as hexanol, octanol or decanol, and produces a silicon compound to hydrolytically produce R3SiOH such as trimethylsilanol,a silicon compound described in Japanese Patent Laid-Open No. 11-241029, which is a derivative of a polyhydric alcohol having three or more hydroxy groups such as trimethylolpropane, glycerin, pentaerythritol or sorbitol, and hydrolytically produces R3SiOH such as trimethylsilanol. Additionally, there may be cited such a compound as described in Japanese Patent Laid-Open No. 7-258534 which is a derivative of an oxypropylene polymer and produces a silicon compound to hydrolytically produce R3SiOH such as trimethylsilanol. Moreover, there may be used an organic polymer described in Japanese Patent Laid-Open No. 6-279693 which contains a hydrolyzable silicon-containing group capable of cross-linking and a silicon-containing group capable of hydrolytically forming a monosilanol-containing compound. The physical property modifier is used within a range from 0.1 to 20 parts by weight, and preferably from 0.5 to 10 parts by weight, in relation to 100 parts by weight of the reactive silicon group-containing organic polymer (A). To the curable composition of the present invention, according to need, a thixotropic agent (antisagging agent) may be added for the purpose of preventing sagging and improving workability. No particular constraint is imposed on the antisagging agent; however, examples of the antisagging agent may include, for example, polyamide waxes; hydrogenated castor oil derivatives; and metal soaps such as calcium stearate, aluminum stearate and barium stearate. These thixotropic agents (antisagging agents) may be used each alone or in combinations of two or more thereof. The thixotropic agents is used within a range. from 0.1 to 20 parts by weight in relation to 100 parts by weight of the reactive silicon group-containing organic polymer (A). In the composition of the present invention, a compound which contains one or more epoxy groups in one molecule thereof may be used. Use of an epoxy group-containing compound can enhance the recovery properties of the cured article. Examples of the epoxy group-containing compound may include compounds such as epoxidized unsaturated oils and fats, epoxidized unsaturated fatty acid esters, alicyclic epoxy compounds and epichlorohydrin derivatives, and admixtures of these compounds. Specific examples may include epoxidized soybean oil, epoxidized flaxseed oil, di(2-ethylhexyl)-4,5-epoxycyclohexane-1,2-dicarboxylate (E-PS), epoxyoctyl stearate and epoxybutyl stearate. Among these, E-PS is particularly preferable. It is recommended that these epoxy group-containing compounds each are used within a range from 0.5 to 50 parts by weight in relation to 100 parts by weight of the reactive silicon group-containing organic polymer (A). In the composition of the present invention, a photocuring substance may be used. Use of a photocuring substance forms a coating film of the photocuring substance on the surface of the cured article to improve the stickiness and the weather resistance of the cured article. A photocuring substance means a substance which undergoes a chemical change, caused by action of light, of the molecular structure thereof in a fairly short time to result in changes of the physical properties such as curing. Among such a large number of compounds known are organic monomers, oligomers, resins and compositions containing these substances, and any commercially available substances concerned may optionally be adopted. As representative photocuring substances, unsaturated acrylic compounds, polyvinyl cinnamates and azidized resins and the like may be used. The unsaturated acrylic compounds are monomers, oligomers and admixtures of the monomers and the oligomers, the monomers and oligomers each having one or a few acrylic or methacrylic unsaturated groups; examples of the unsaturated acrylic compounds may include monomers such as propylene (or butylene, or ethylene)glycol di(meth)acrylate and neopentylglycol di(meth)acrylate, and oligoesters of 10,000 or less in molecular weight related to these monomers. Specific examples may include special acrylates (bifunctional) such as Aronix M-210, Aronix M-215, Aronix M-220, Aronix M-233, Aronix M-240 and Aronix M-245; special acrylates (trifunctional) such as Aronix M-305, Aronix-309, Aronix M-310, Aronix M-315, Aronix M-320 and Aronix M-325; and special acrylates (multifunctional) such as Aronix M-400. Those compounds each having acrylic functional groups are particularly preferable, and additionally, those compounds each having, on average, three or more acrylic functional groups in one molecule thereof are preferable (all the aforementioned Aronix compounds are the products of Toagosei Co., Ltd.). Examples of the polyvinyl cinnamates may include photosensitive resins having cinnamoyl groups as photosensitive groups, namely, those compounds obtained by esterification of polyvinyl alcohol with cinnamic acid; and additionally, a large number of derivatives of polyvinyl cinnamates. Azidized resins are known as photosensitive resins having azide groups as photosensitive groups; common examples of the azidized resins may include a rubber photosensitive solution added with a diazide compound as a photosensitive agent, and additionally, those compounds detailed in “Photosensitive Resins (Kankosei Jusi)” (published by Insatu Gakkai Shuppanbu, Mar. 17, 1972, p.93ff, p.106ff and p.117ff); and these compounds may be used each alone or in admixtures thereof, and in combination with sensitizers to be added according to need. It is to be noted that addition of sensitizers such as ketones and nitro compounds and accelerators such as amines sometimes enhances the effect. It is recommended that the photocuring substance is used within a range from 0.1 to 20 parts by weight and preferably from 0.5 to 10 parts by weight in relation to 100 parts by weight of the reactive silicon group-containing organic polymer (A); when the content of the photocuring substance is less than 0.1 part by weight, no effect to increase the weather resistance is displayed, while when the content exceeds 20 parts by weight, the cured article tends to be too hard and cracking thereby tends to occur therein. In the composition of the present invention, an oxygen-curing substance may be used. Examples of the oxygen-curing substance may include unsaturated compounds reactable with the oxygen in the air, which react with the oxygen in the air and form a cured coating film in the vicinity of the surface of the cured article to act to prevent the surface stickiness and the sticking of dust and grime to the surface of the cured article and to do the like. Specific examples of the oxygen-curing substance may include: drying oils represented by wood oil, flaxseed oil and the like and various alkyd resins obtained by modifying these compounds; acrylic polymers, epoxy resins and silicon resins all modified with drying oils; liquid polymers such as 1,2-polybutadiene and 1,4-polybutadiene obtained by polymerizing or copolymerizing diene compounds such as butadiene, chloroprene, isoprene, 1,3-pentadiene, and polymers derived from dienes each having 5 to 8 carbon atoms, liquid copolymers such as NBR, SBR and the like obtained by copolymerizing these diene compounds with a minor proportion of monomers such as acrylonitrile, styrene and the like copolymerizable with these diene compounds, and various modified substances of these compounds (maleic modified substances, boiled-oil modified substances, and the like). These substances may be used each alone or in combinations of two or more thereof. Among these substances, wood oil and liquid diene polymers are particularly preferable. Additionally, in some cases, when catalysts to accelerate the oxidation curing reaction and metal dryers are used in combination with these substances, the effect is enhanced. Examples of these catalysts and metal dryers may include metal salts such as cobalt naphthenate, lead naphthenate, zirconium naphthenate, cobalt octylate and zirconium octylate; and amine compounds. The used amount of the oxygen-curing substance is recommended such that the oxygen-curing substance is used within a range from 0.1 to 20 parts by weight and further preferably from 0.5 to 10 parts by weight in relation to 100 parts by weight of the reactive silicon group-containing organic polymer (A); when the used amount is less than 0.1 part by weight, improvement of staining property is insufficient, while when the used amount exceeds 20 parts by weight, the tensile properties and the like of the cured article tend to be impaired. It is recommended that the oxygen-curing substance is used in combination with a photocuring substance as described in Japanese Patent Laid-Open No. 3-160053. In the composition of the present invention, an antioxidant (antiaging agent) may be used. Use of an antioxidant can increase the heat resistance of the cured article. Examples of the antioxidant may include hindered phenol antioxidants, monophenol antioxidants, bisphenol antioxidants and polyphenol antioxidants, hindered phenol antioxidants being particularly preferable. Similarly, the following hindered amine photostabilizers may also be used: Tinuvin 622LD, Tinuvin 144; Chimassorb 944LD and Chimassorb 119FL (all manufactured by Ciba Specialty Chemicals K.K.); Mark LA-57, Mark LA-62, Mark LA-67, Mark LA-63 and Mark LA-68 (all manufactured by Asahi Denka Co., Ltd.); and Sanol LS-770, Sanol LS-765, Sanol LS-292, Sanol LS-2626, Sanol LS-1114 and Sanol LS-744 (all manufactured by Sankyo Lifetech Co., Ltd.). Specific examples of the antioxidants are also described in Japanese Patent Laid-Open Nos. 4-283259 and 9-194731. The used amount of the antioxidant is recommended such that the antioxidant is used within a range from 0.1 to 10 parts by weight and further preferably from 0.2 to 5 parts by weight in relation to 100 parts by weight of the reactive silicon group-containing organic polymer (A). In the composition of the present invention, a photostabilizer may be used. Use of a photostabilizer can prevent the photooxidation degradation of the cured article. Examples of the photostabilizer may include benzotriazole compounds, hindered amine compounds and benzoate compounds; hindered amine compounds are particularly preferable. The used amount of the photostabilizer is recommended such that the photostabilizer is used within a range from 0.1 to 10 parts by weight and further preferably from 0.2 to 5 parts by weight in relation to 100 parts by weight of the reactive silicon group-containing organic polymer (A). Specific examples of the photostabilizer are also described in Japanese Patent Laid-Open No. 9-194731. When the photocuring substance is used in combination in the composition of the present invention, in particular, when an unsaturated acrylic compound is used, it is preferable to use a tertiary amine-containing hindered amine photostabilizer as a hindered amine photostabilizer as described in Japanese Patent Laid-Open No. 5-70531 for the purpose of improving the storage stability of the composition. Examples of the tertiary amine-containing hindered amine photostabilizer may include Tinuvin 622LD, Tinuvin 144 and Chimassorb ll9FL (all manufactured by Ciba Specialty Chemicals K.K.); Mark LA-57, LA-62, LA-67 and LA-63 (all manufactured by Asahi Denka Co., Ltd.); and Sanol LS-765, LS-292, LS-2626, LS-1114 and LS-744 (all manufactured by Sankyo Lifetech Co., Ltd.). In the composition of the present invention, an ultraviolet absorber may be used. Use of an ultraviolet absorber can increase the surface weather resistance of the cured article. Examples of the-ultraviolet absorber may include benzophenone compounds, benzotriazole compounds, salicylate compounds, substituted tolyl compounds and metal chelate compounds; benzotriazole compounds are particularly preferable. The used amount of the ultraviolet absorber is such that the ultraviolet absorber is used within a range from 0.1 to 10 parts by weight, and further preferably from 0.2 to 5 parts by weight in relation to 100 parts by weight of the reactive silicon group-containing organic polymer (A). It is preferable that a phenol antioxidant, a hindered phenol antioxidant, a hindered amine photostabilizer and a benzotriazole ultraviolet absorber are used in combination. To the composition of the present invention, an epoxy resin may be added. The composition added with an epoxy resin is particularly preferable as an adhesive, in particular, an adhesive for exterior wall tile. Examples of the epoxy resin may include: flame retardant epoxy resins such as epichlorohydrin-bisphenol A-type epoxy resins, epichlorohydrin-bisphenol F-type epoxy resins and glycidyl ether of tetrabromobisphenol A; novolac-type epoxy resins; hydrogenated bisphenol A-type epoxy resins; epoxy resins of the type of glycidyl ether of bisphenol A propyleneoxide adduct; p-oxybenzoic acid glycidyl ether ester-type epoxy resins; m-aminophenol epoxy resins; diaminodiphenylmethane epoxy resins; urethane-modified epoxy resins; various alicyclic epoxy resins; N,N-diglycidylaniline, N,N-diglycidyl-o-toluidine, triglycidyl isocyanurate, polyalkylene glycol diglycidyl ether and glycidyl ethers of polyhydric alcohols such as glycerin; hydantoin epoxy resins; and epoxidized substances of unsaturated polymers such as petroleum resins. However the epoxy resin is not limited to these examples, and commonly used epoxy resins may be used. Epoxy resins having at least two epoxy groups in one molecule thereof are preferable because such compositions are high in reactivity when curing is made, and the cured articles can easily form three dimensional networks. Examples of further preferable epoxy resins may include bisphenol A-type epoxy resins or novolac-type epoxy resins. The ratio of the used amount of each of these epoxy resins to the used amount of the reactive silicon group-containing organic polymer (A) falls, in terms of weight ratio, in the range such that (A)/epoxy resin=100/1 to 1/100. When the ratio of (A)/epoxy resin is less than 1/100, the effect of improving the impact strength and the toughness of the cured article of the epoxy resin is hardly obtainable, while when the ratio of (A)/epoxy resin exceeds 100/1, the strength of the cured article of the polymer is insufficient. The preferable ratio of the used amounts is varied depending on the application of the curable resin composition and hence cannot be unconditionally determined; for example, when the impact resistance, flexibility, toughness, and peel strength and the like of the cured article of the epoxy resin are to be improved, it is recommended that 1 to 100 parts by weight of the component (A), further preferably 5 to 100 parts by weight of the component (A) is used in relation to 100 parts by weight of the epoxy resin. On the other hand, when the strength of the cured article of the component (A) is to be improved, it is recommended that 1 to 200 parts by weight of the epoxy resin, further preferably 5 to 100 parts by weight of the epoxy resin is used in relation to 100 parts by weight of the component (A). When the epoxy resin is added, as a matter of course, a curing agent to cure the epoxy resin can be applied together to the composition of the present invention. No particular constraint is imposed on the usable epoxy resin curing agent, and commonly used epoxy resin curing agents may be used. Specific examples of the epoxy resin curing agent may include: primary and secondary amines such as triethylenetetramine, tetraethylenepentamine, diethylaminopropylamine, N-aminoethylpiperidine, m-xylylenediamine, m-phenylenediamine, diaminodiphenylmethane, diaminodiphenylsulfone, isophoronediamine, and amine-terminated polyethers; tertiary amines such as 2,4,6-tris(dimethylaminomethyl)phenol and tripropylamine, and salts of these tertiary amines; polyamide resins; imidazoles; dicyandiamides; borontrifluoride complexes; carboxylic acid anhydrides such as phthalic anhydride, hexahydrophthalic anhydride, tetrahydrophthalic anhydride, dodecynylsuccinic anhydride, pyromellitic anhydride and chlorenic anhydride; alcohols; phenols; carboxylic acids; and diketone complexes of aluminum and zirconium. However, the epoxy resin curing agent is not limited to these examples. Additionally, the curing agents may be used each alone or in combinations of two or more thereof. When an epoxy resin curing agent is used, the used amount thereof falls within a range from 0.1 to 300 parts by weight in relation to 100 parts by weight of the epoxy resin. As an epoxy resin curing agent, a ketimine may be used. A ketimine is stable when no moisture is present, but moisture decomposes the ketimine into a primary amine and a ketone; the thus produced primary amine acts as a room-temperature-curable curing agent to cure the epoxy resin. Use of a ketimine makes it possible to obtain a one part composition. Such a ketimine can be obtained by condensation reaction between an amine compound and a carbonyl compound. For the synthesis of a ketimine, an amine compound and a carbonyl compound well known in the art can be used. For example, the following compounds may be used as such an amine compound: diamines such as ethylenediamine, propylenediamine, trimethylenediamine, tetramethylenediamine, 1,3-diaminobutane, 2,3-diaminobutane, pentamethylenediamine, 2,4-diaminopentane, hexamethylenediamine, p-phenylenediamine and p,p′-biphenylenediamine; polyamines such as 1,2,3-triaminopropane, triaminobenzene, tris(2-aminoethyl)amine and tetra(aminomethyl)methane; polyalkylenepolyamines such as diethylenetriamine, triethylenetriamine and tetraethylenepentamine; polyoxyalkylene polyamines; and aminosilanes such as γ-aminopropyltriethoxysilane, N-(β-aminoethyl)-γ-aminopropyltrimethoxysilane and N-(γ-aminoethyl)-γ-aminopropylmethyldimethoxysilane. Additionally, the following compounds can be used as such a carbonyl compound: aldehydes such as acetoaldehyde, propionaldehyde, n-butylaldehyde, isobutylaldehyde, diethylacetoaldehyde, glyoxal and benzaldehyde; cyclic ketones such as cyclopentanone, trimethylcyclopentanone, cyclohexanone and trimethylcyclohexanone; aliphatic ketones such as acetone, methyl ethyl ketone, methyl propyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, dibutyl ketone and diisobutyl ketone; and β-dicarbonyl compounds such as acetylacetone, methyl acetoacetate, ethyl acetoacetate, dimethyl malonate, diethyl malonate, methyl ethyl malonate and dibenzoylmethane. When an imino group is present in the ketimine, the imino group can be reacted with styrene oxide; glycidyl ethers such as butyl glycidyl ether and allyl glycidyl ether; glycidyl esters; and the like. These ketimines may be used each alone or in combinations of two or more thereof; these ketimines each are used within a range from 1 to 100 parts by weight in relation to 100 parts by weight of the epoxy resin, and the used amount of each of the ketimines is varied depending on the type of the epoxy resin and the type of the ketimine. In the present invention, curing catalysts other than the component (B) may be used as long as the curing catalysts attain the advantageous effects of the present invention. Examples of the curing catalysts other than the component (B) may include organotin compounds, alkoxy metal compounds, metal chelates, organic sulfonic acids (salts), acid phosphates and inorganic acids. No particular constraint is imposed on the organotin compounds, and various types of compounds may be used. Specific examples of the organotin compounds may include: dialkyltin carboxylates; dialkyltin oxides; and the compounds represented by the general formula (13): R13dSn(OQ)4-d or [R132Sn(OQ)]2O (13) wherein R13 represents a monovalent hydrocarbon group having 1 to 20 carbon atoms; Q represents a monovalent hydrocarbon group having 1 to 20 carbon atoms or an organic group having therein one or more functional groups capable of forming coordination bonds with Sn; and d represents 1, 2, or 3. Reaction products of tetravalent tin compounds such as dialkyltin oxides and dialkyltin diacetates with low-molecular-weight, hydrolyzable silicon group-containing silicon compounds such as tetraethoxysilane, methyltriethoxysilane, diphenyldimethoxysilane and phenyltrimethoxysilane may also be used. Among these, those compounds represented by the general formula (13), namely, chelate compounds such as dibutyltin bisacetylacetonate and tin alcoholates are more preferable because these compounds are high in catalytic activity. Specific examples of the dialkyltin carboxylates may include dibutyltin dilaurate, dibutyltin diacetate, dibutyltin di(2-ethylhexanoate), dibutyltin dioctate, dibutyltin dimethylmaleate, dibutyltin diethylmaleate, dibutyltin dibutylmaleate, dibutyltin diisooctylmaleate, dibutyltin tridecylmaleate, dibutyltin dibenzylmaleate, dibutyltin maleate, dioctyltin diacetate, dioctyltin distearate, dioctyltin dilaurate, dioctyltin diethylmaleate, and dioctyltin diisooctylmaleate. Additionally, alkylstannoxane carboxylates such as 1,1,3,3-tetrabutyl-1,3-dilauroyloxydistannoxane may also be used. Specific examples of the dialkyltin oxides may include dibutyltin oxide, dioctyltin oxide, and reaction products of dibutyltin oxide with various ester compounds (dioctyl phthalate, dimethyl maleate and the like). Specific examples of the chelate compounds may include the following compounds, but the chelate compounds concerned are not limited to these examples: Among these, dibutyltin bisacetylacetonate is most preferable because it is high in catalytic activity, low in cost and easily available. Specific examples of the tin alcoholates may include the following compounds, but the tin alcoholates concerned are not limited to these examples: Among these, dialkyltin dialkoxides are preferable. In particular, dibutyltin dimethoxide is more preferable because it is low in cost and easily available. Concomitant use of an organotin compound provides an effect to remarkably improve the curability in the thin layer portions. Specific examples of the alkoxy metal compounds and the metal chelates may include: titanium alkoxides such as tetrabutyl titanate, tetraisopropyl titanate, tetramethyl titanate, tetra(2-ethylhexyl)titanate and triethanolamine titanate; titanium chelates such as titanium tetraacetylacetonate, titanium ethylacetonate, titanium lactate and diisopropoxy titanium bisacetylacetonate; aluminum alkoxides such as aluminum isopropylate, 2-butoxy diisopropoxy aluminum, and tri(2-butoxy)aluminum; aluminum chelates such as aluminum trisacetylacetonate, aluminum trisethyl acetoacetate, diisopropoxyaluminum ethylacetoacetate; zirconium alkoxides such as zirconium tetraisopropylate, zirconium tetra-n-propylate and zirconium n-butylate; zirconium chelates such as zirconium tetraacetylacetonate, zirconium bisacetylacetonate and zirconium acetylacetonate-bis-ethylacetoacetate; and other various metal alkoxides such as tetramethoxy tin and tetrabutoxy hafnium. However, the alkoxy metal compounds and the metal chelates concerned are not limited to these examples. Examples of the organic sulfonic acid may include methanesulfonic acid, toluenesulfonic acid, styrenesulfonic acid and trifluoromethanesuflonic acid; and the salts of these acids may also be used. The acid phosphate means a phosphoric acid ester which contains the moiety represented by —O—P(═O)OH, and may include the acid phosphates shown below. Organic acid phosphates are preferable from the viewpoints of compatibility and curing catalyst activity. An organic acid phosphate compound is represented by (R14O)e—P(═O)(—OH)3-e wherein e represents 1 or 2; and R14 represents an organic residue. Specific examples thereof may include the following compounds; however the organic acid phosphate is not limited to these examples: (CH3O)2—P(═O)(—OH), (CH3O)—P(═O)(—OH)2, (C2H5O)2—P(═O)(—OH), (C2H5O)—P(═O)(—OH)2, (C3H7O)2—P(═O)(—OH), (C3H7O)—P(═O)(—OH)2, (C4H9O)2—P(═O)(—OH), (C4H9O)—P(═O)(—OH)2, (C8H17O)2—P(═O)(—OH), (C8H17O)—P(═O)(—OH)2, (C10H21O)2—P(═O)(—OH), (C10H21O)—P(═O)(—OH)2, (C13H27O)2—P(═O)(—OH), (C13H27O)—P(═O)(—OH)2, (C16H33O)2—P(═O)(—OH), (C16H33O)—P(═O)(—OH)2, (HO—C6H12O)2—P(═O)(—OH), (HO—C6H12O)—P(═O)(—OH)2, (HO—C8H16O)—P(═O)(—OH), (HO—C8H16O)—P(═O)(—OH)2, {(CH2OH)(CHOH)O}2—P(═O)(—OH), {(CH2OH)(CHOH)O}—P(═O)(—OH)2, {(CH2OH)(CHOH)C2H4O}2—P(═O)(—OH) and {(CH2OH)(CHOH)C2H4O{—P(═O)(—OH)2. Examples of the inorganic acid may include hydrochloric acid, sulfuric acid, phosphoric acid and boronic acid. To the curable composition of the present invention, various additives may be added according to need for the purpose of modifying the physical properties of the curable composition or the cured article. Examples of such additives may include a flame retardant, a curability modifier, a radical inhibitor, a metal deactivator, an antiozonant, a phosphorus based peroxide decomposer, a lubricant, a pigment, a foaming agent, a solvent and a mildewproofing agent. These various additives may be used each alone or in combinations of two or more thereof. Specific additive examples other than the specific examples cited in the present specification are described, for example, in Japanese Patent Publication Nos. 4-69659 and 7-108928, and Japanese Patent Laid-Open Nos. 63-254149, 64-22904, 2001-72854 and the like. The curable composition of the present invention can also be prepared as a one-part composition in which all the ingredients are blended and hermetically stored in advance and the curing of the composition is carried out by the action of the moisture in the air after application of the composition. The curable composition of the present invention can also be prepared as two-part composition in which the ingredients such as a curing catalyst, a filler, a plasticizer, water and the like are blended in advance separately as a curing component, and the curing component composed of the blended ingredients and an organic polymer composition component are mixed together immediately before application. The one-part composition is preferable from the viewpoint of workability. When the curable composition is of the one-part type, all the ingredients are blended together beforehand, so that it is preferable that the moisture-containing ingredients are used after dehydrating and drying, or the ingredients are dehydrated by reducing pressure or the like while being kneaded for blending. When the curable composition is of the two-part type, it is not necessary to blend a curing catalyst with the main part containing a reactive silicon group-containing organic polymer, and hence there is little fear of gelation even when some moisture is contained in the blended ingredients; however, when a long term storage stability is required, it is preferable to carry out dehydration and drying. As for the methods of dehydration and drying, a thermal drying method is suitable for a powdery solid substance or the like, while a reduced pressure dehydration method or a dehydration method which uses a synthetic zeolite, active alumina, silica gel or the like is suitable for a liquid substance. Additionally, there can be adopted a method in which a small amount of isocyanate compound is blended and the isocyanate group thereof is made to react with water to dehydrate. In addition to these dehydration and drying methods, addition of the following compounds further improves the storage stability: lower alcohols such as methanol and ethanol; and alkoxysilane compounds such as n-propyltrimethoxysilane, vinyltrimethoxysilane, vinylmethyldimethoxysilane, γ-mercaptopropylmethyldimethoxysilane, γ-mercaptopropylmethyldiethoxysilane and γ-glycidoxypropyltrimethoxysilane. It is preferable that the used amount of a dehydrating agent, in particular, a silicon compound capable of reacting with water such as vinyltrimethoxysilane falls within a range from 0.1 to 20 parts by weight, and preferably 0.5 to 10 parts by weight in relation to 100 parts by weight of the reactive silicon group-containing organic polymer (A). No particular constraint is imposed on the preparation method of the curable composition of the present invention; for example, there can be adopted a common method in which the above described ingredients are blended together and kneaded with a mixer, a roll, a kneader or the like at room temperature or under heating, or a common method in which the above described ingredients are dissolved and mixed by use of a small amount of an appropriate solvent. The curable composition of the present invention forms three dimensional networks, when exposed to the air, due to the action of the moisture to be cured into a solid matter having a rubber-like elasticity. EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited only to these examples. Examples 1 to 4 and Comparative Examples 1 and 2 According to the composition prescriptions given in Table 1, the following ingredients were taken and kneaded: 100 parts by weight of an organic polymer (ST-53 or ST-55, manufactured by Hanse Chemie) as the component (A) having one or more groups represented by the general formula (1) and having one or more reactive silicon groups, —NR1—C(═O)— (1) wherein R1 is the same as above, 120 parts by weight of a surface treated precipitated calcium carbonate (Hakuenka CCR, manufactured by Shiraishi Kogyo Kaisha, Ltd.), 20 parts by weight of titanium oxide (Tipaque R-820, manufactured by Ishihara Sangyo Kaisha, Ltd.), 55 parts by weight of a plasticizer (diisodecyl phthalate (DIDP)), 2 parts by weight of thixotropic agent (Disparlon 6500, manufactured by Kusumoto Chemicals, Ltd.), 1 part by weight of a photostabilizer (Sanol LS770, manufactured by Sankyo Lifetech Co., Ltd.), 1 part by weight of an ultraviolet absorber (Tinuvin 327, manufactured by Ciba Specialty Chemicals K.K.), 1 part by weight of an antioxidant (Irganox 1010, manufactured by Ciba Specialty Chemicals K.K.), 2 parts by weight of a dehydrating agent, vinyltrimethoxysilane (A-171, manufactured by GE Toshiba Silicones Co., Ltd.), and 3 parts by weight of an adhesion-imparting agent, N-β-(aminoethyl)-γ-aminopropyltrimethoxysilane (A-1120, manufactured by GE Toshiba Silicones Co., Ltd.). Thereafter, to the mixture thus obtained, a tin carboxylate as the component (B) (tin (II) neodecanoate (trade name: U-50), manufactured by Nitto Kasei Co., Ltd.) and/or a carboxylic acid (neodecanoic acid (trade name: Versatic 10), manufactured by Japan Epoxy Resin Co., Ltd.), an amine as the component (C)(laurylamine (trade name: Farmin 20D), manufactured by Kao Corp.) were added in the amounts given in Table 1 in terms of parts by weight, and the mixture thus obtained was further kneaded to yield each of the curable compositions. On the other hand, in the comparative examples, 0.1 part by weight of an organotin catalyst (dibutyltin dilaurate (trade name: Stann-BL) manufactured by Sankyo Organic Chemicals Co., Ltd.) was added in place of the components (B) and (C), and then kneading was carried out to yield curable compositions. (Curability Evaluation) For the purpose of evaluating the curability of each of the compositions, the tack-free time was measured by means of the following method. Each of the compositions given in Table 1 was extended so as to have a thickness of about 3 mm; and the elapsed time (tack-free time) until the composition no longer stained a finger when touched with the finger was measured under the conditions of 23° C. and a humidity of 50% RH. A shorter tack-free time indicates a better curability. The results obtained are shown in Table 1. (Tensile Physical Properties of the Cured Articles) Each of the compositions given in Table 1 was aged at 23° C. for 3 days and additionally at 50° C. for 4 days to yield a sheet of about 3 mm in thickness. Each of the thus obtained sheets was blanked into a No. 3 dumbbell-shaped specimen. For each of these dumbbell-shaped specimens, the tensile test was carried out under the conditions of 23° C. and a humidity of 50% RH at a tensile rate of 200 mm/min to measure the M50 (50% tensile modulus)(MPa). The results obtained are shown in Table 1. (Heat Resistance) Each of the dumbbell-shaped cured articles obtained by means of the above described method was aged in an oven at 90° C. for 14 days, and thereafter the M50 was measured in the same manner as described above. From the M50 values before and after curing at 90° C. for 14 days, the retention rates were derived. A higher M50 retention rate indicates a better heat resistance. The results obtained are shown in Table 1. As shown in Table 1 under the headings of Comparative Examples 1 and 2, the retention rates of the M50 value are low when an organotin compound (Stann-BL) was used as a curing catalyst. On the other hand, as shown under the headings of Examples 1 to 4, in each of Examples, a practical curability was obtained and the retention rate of the M50 value was high when a metal carboxylate and/or a carboxylic acid as the component (B) of the present invention was used as a curing catalyst although the metal carboxylate and/or the carboxylic acid was a non-organotin catalyst. TABLE 1 Examples Comparative examples Composition (parts by weight ) 1 2 3 4 1 2 Component (A) Silylated urethane ST-53 100 100 100 polymers ST-55 100 100 100 Fillers Hakuenka CCR 120 120 120 120 120 120 Tipaque R-820 20 20 20 20 20 20 Plasticizer DIDP 55 55 55 55 55 55 Thixotropic agent Disparlon #6500 2 2 2 2 2 2 Photostabilizer Sanol LS-770 1 1 1 1 1 1 Ultraviolet absorber Tinuvin 327 1 1 1 1 1 1 Antioxidant Irganox 1010 1 1 1 1 1 1 Dehydrating agent A-171 2 2 2 2 2 2 Adhesion-imparting agent A-1120 3 3 3 3 3 3 Component (B) Tin carboxylate Neostann U-50 3.4 3.4 Carboxylic acid Versatic 10 1.2 6 1.2 6 Component (C) Amine Farmin 20D 0.75 1 0.75 1 Organotin compound STANN BL 0.1 0.1 Tack-free time (min) 31 18 34 15 42 30 M50 value before heat curing (MPa) 0.68 0.58 0.43 0.38 0.79 0.53 Retention rate of M50 value after (%) 80 92 72 82 68 58 heat curing of 90° C. × 14 days Synthesis Example 1 By use of a polyoxypropylene triol having a molecular weight of about 3,000 as an initiator and zinc hexacyanocobaltate-glyme complex as a catalyst, polymerization of propylene oxide was carried out to yield a hydroxy group-terminated trifunctional polypropylene oxide having a number average molecular weight of about 26,000 (a molecular weight relative to polystyrene standards as measured by using an HLC-8120 GPC manufactured by Tosoh Corp. as a liquid delivery system, a column of TSK-GEL H-type manufactured by Tosoh Corp., and THF as a solvent). To 100 parts by weight of the obtained hydroxy group-terminated polypropylene oxide, 2.1 parts by weight of γ-isocyanatepropyltrimethoxysilane was added, and the mixture was allowed to react at 90° C. for 5 hours to yield a trimethoxysilyl group-terminated polyoxypropylene polymer (A-1). On the basis of the measurement by 1H-NMR (measured in CDCl3 as solvent by using a JNM-LA400 spectrometer manufactured by JEOL Ltd.), it was found that the number of the groups represented by the general formula (1) and the number of the terminal trimethoxysilyl groups each are 2.0 per one molecule on average: —NR1—C(═O)— (1) wherein R1 is the same as described above. Examples 5 to 7 and Comparative Example 3 According to the composition prescriptions given in Table 2, curable compositions were produced in the same manner as described above except that, as the component (A), the polymer (A-1) obtained in Synthesis Example 1 was used in place of the ST-53 or ST-55 manufactured by Hanse Chemie. In the same manner as described above, for each of the compositions, the curability (tack-free time) thereof, and the tensile physical properties and the heat resistance of the cured article were evaluated. The results obtained are shown in Table 2. As shown in Table 2 under the heading of Comparative Example 3, the retention rate of the M50 value was low when an organotin compound (Stann-BL) was used as a curing catalyst. On the other hand, as shown under the headings of Examples 5 to 7, in each of Examples, a practical curability was obtained and the retention rate of the M50 value was high when a metal carboxylate and/or a carboxylic acid as the component (B) of the present invention was used as a curing catalyst although the metal carboxylate and/or the carboxylic acid was a non-organotin catalyst. TABLE 2 Comparative Examples example Composition (parts by weight) 5 6 7 3 Component (A) Silylated urethane A-1 100 100 100 100 polymer Fillers Hakuenka CCR 120 120 120 120 Tipaque R-820 20 20 20 20 Plasticizer DIDP 55 55 55 55 Thixotropic agent Disparlon #6500 2 2 2 2 Photostabilizer Sanol LS-770 1 1 1 1 Ultraviolet absorber Tinuvin 327 1 1 1 1 Antioxidant Irganox 1010 1 1 1 1 Dehydrating agent A-171 2 2 2 2 Adhesion-imparting agent A-1120 3 3 3 3 Component (B) Tin carboxylate Neostann U-50 5 3.4 Carboxylic acid Versatic 10 1.2 6 Component (C) Amine Farmin 20D 0.75 0.75 1 Organotin compound STANN BL 0.1 Tack-free time (min) 20 25 15 35 M50 value before heat curing (MPa) 0.48 0.46 0.40 0.55 Retention rate of M50 value after (%) 85 87 95 72 heat curing of 90° C. × 14 days Synthesis Example 2 By use of a polyoxypropylene diol having a molecular weight of about 2,000 as an initiator and zinc hexacyanocobaltate-glyme complex as a catalyst, polymerization of propylene oxide was carried out to yield a hydroxy group-terminated bifunctional polypropylene oxide (this will be referred to as the polymer P) having a number average molecular weight of about 25,500 (a molecular weight relative to polystyrene standards as measured by using an HLC-8120 GPC manufactured by Tosoh Corp. as a liquid delivery system, a column of TSK-GEL H-type manufactured by Tosoh Corp., and THF as a solvent). To 100 parts by weight of the polymer P, 1.9 parts by weight of γ-isocyanatepropyltrimethoxysilane was added, and the mixture was allowed to react at 90° C. for 5 hours to yield a trimethoxysilyl group-terminated polyoxypropylene polymer (A-2). On the basis of the measurement by 1H-NMR (measured in CDCl3 as solvent by using a JNM-LA400 spectrometer manufactured by JEOL Ltd.), it was found that the number of the groups represented by the general formula (1) and the number of the terminal trimethoxysilyl groups each are 1.5 per one molecule on average. Synthesis Example 3 By use of a polypropylene glycol allyl ether [H2C═CHCH2O—(CH(CH3)CH2O)n—H] having a molecular weight of about 1,500 as an initiator and zinc hexacyanocobaltate-glyme complex as a catalyst, polymerization of propylene oxide was carried out to yield a bifunctional polypropylene oxide, with a hydroxy group at one end thereof and an allyl group at the other end thereof, having a number average molecular weight of about 25,500 (a molecular weight relative to polystyrene standards as measured by using an HLC-8120 GPC manufactured by Tosoh Corp. as a liquid delivery system, a column of TSK-GEL H-type manufactured by Tosoh Corp., and THF as a solvent). In the presence of 150 ppm of an isopropanol solution of platinum vinylsiloxane complex as a catalyst with a platinum content of 3 wt %, 100 parts by weight of the obtained bifunctional polypropylene oxide, with a hydroxy group at one end thereof and an allyl group at the other end thereof, was reacted with 1.0 part by weight of a silane compound represented by the following chemical formula, HSi(CH3)2OSi(CH3)2C2H4Si(OCH3)3 at 90° C. for 2 hours to yield a polyoxypropylene polymer containing 0.5 trimethoxysilyl group per one molecule on average and containing no group represented by the general formula (1). To 100 parts by weight of this polymer, 1.3 parts by weight of γ-isocyanatepropyltrimethoxysilane was added, and the mixture was allowed to react at 90° C. for 5 hours to yield a trimethoxysilyl group-terminated polyoxypropylene polymer (A-3). On the basis of the measurement by 1H-NMR (measured in CDC13 as solvent by using a JNM-LA400 spectrometer manufactured by JEOL Ltd.), it was found that the number of the groups represented by the general formula (1) was 1.0 per one molecule on average and the number of the terminal trimethoxysilyl groups was 1.5 per one molecule on average. Synthesis Example 4 A methanol solution of NaOMe was added in an amount of 1.2 equivalents in relation to the hydroxy groups of the hydroxy group-terminated bifunctional polypropylene oxide (the above described polymer P) having a number average molecular weight of 25,500, the methanol was distilled off, and allyl chloride was further added to thereby convert the terminal hydroxy groups into allyl groups. The unreacted allyl chloride was removed by volatilization under reduced pressure. To 100 parts by weight of the obtained, crude allyl group-terminated polypropylene oxide, 300 parts by weight of n-hexane and 300 parts by weight of water were added. The mixture thus obtained was stirred to mix, and then the water was removed by centrifugal separation. To the hexane solution thus obtained, 300 parts by weight of water was further added, the mixture thus obtained was stirred to mix, the water was again removed by centrifugal separation, and then the hexane was removed by volatilization under reduced pressure. Thus, an allyl group-terminated bifunctional polypropylene oxide having a number average molecular weight of about 25,500 was obtained. In the presence of 150 ppm of an isopropanol solution of platinum vinylsiloxane complex as a catalyst with a platinum content of 3 wt %, 100 parts by weight of the obtained allyl-terminated polypropylene oxide was reacted with 3.1 parts by weight of a silane compound represented by the following chemical formula, HSi(CH3)2OSi(CH3)2C2H4Si(OCH3)3 at 90° C. for 2 hours to yield a trimethoxysilyl group-terminated polyoxypropylene polymer (A-4) containing no group represented by the general formula (1). On the basis of the measurement by 1H-NMR (measured in CDCl3 as solvent by using a JNM-LA400 spectrometer manufactured by JEOL Ltd.), it was found that the number of the terminal trimethoxysilyl groups is 1.5 per one molecule on average. Examples 8 to 11 and Comparative Examples 4 to 7 According to the composition prescriptions given in Table 3, curable compositions were prepared in the same manner as described above, by using as the component (A) the polymers (A-1 to A-4) obtained in Synthesis Examples 1 to 4, and the curability (tack-free time) of each of the compositions was evaluated in the same manner as described above. The results obtained are shown in Table 3. As shown in Table 3, when there were used the polymers (A-1 and A-2) each having the 1.1 or more groups represented by the general formula (1) per one molecule on average, the curing rate was fast and a practical curability was attained: —NR1—C(═O)— (1) wherein R1 is the same as above. TABLE 3 Examples Comparative examples Composition (parts by weight) 8 9 10 11 4 5 6 7 Reactive silicon group- A-1 2.0(*) 100 100 containing polymers A-2 1.5(*) 100 100 A-3 1.0(*) 100 100 A-4 0.0(*) 100 100 Fillers Hakuenka CCR 120 120 120 120 120 120 120 120 Tipaque R-820 20 20 20 20 20 20 20 20 Plasticizer DIDP 55 55 55 55 55 55 55 55 Thixotropic agent Disparlon #6500 2 2 2 2 2 2 2 2 Photostabilizer Sanol LS-770 1 1 1 1 1 1 1 1 Ultraviolet absorber Tinuvin 327 1 1 1 1 1 1 1 1 Antioxidant Irganox 1010 1 1 1 1 1 1 1 1 Dehydrating agent A-171 2 2 2 2 2 2 2 2 Adhesion-imparting agent A-1120 3 3 3 3 3 3 3 3 Component (B) Tin carboxylate Neostann U-50 3.4 3.4 3.4 3.4 Carboxylic acid Versatic 10 2.6 2.6 2.6 2.6 Component (C) Amine Diethylaminopropylamine 1 1 1 1 1 1 1 1 Tack-free time (min) 25 27 34 37 60 65 95 100 (*)The average number of the —NR1—C(═O)— groups per one polymer molecule. INDUSTRIAL APPLICABILITY The curable composition of the present invention can be used as tackifiers; sealants for buildings, ships, vehicles and road; adhesives; mold forming materials; vibration proof materials; damping materials; soundproof materials; foaming materials; coating materials; spraying materials and the like. Additionally, the curable composition of the present invention can be used in various applications as liquid sealants or the like to be used in materials for electric and electronic components such as backside sealants for solar cells, electric insulating materials such as insulating coating materials for use in electric wire and cable, elastic adhesives, powdery coating materials, casting materials, medical rubber materials, medical adhesives, medical instrument sealants, food packaging materials, sealants for joints in exterior materials such as sizing boards, coating materials, primers, electromagnetic wave shielding conductive materials, heat conducting materials, hot melt materials, electric and electronic potting agents, films, gaskets, various molding materials, antirust and waterproof sealants for edges (cut portions) of wire glass and laminated glass, vehicle components, electric appliance components, various machinery components and the like. Moreover, the curable composition of the present invention can adhere, by itself or with the aid of a primer, to a wide variety of substrates including glass, porcelain, woods, metals and molded resin articles, and accordingly, can be used as various types of hermetically sealing compositions and adhesive compositions.

<SOH> BACKGROUND ART <EOH>There have hitherto been known organic polymers with the molecular chain terminals thereof capped with reactive silicon groups by taking advantage of the high reactivity between the isocyanate group and various types of active hydrogen groups, and accordingly, properties of urethane resins have been improved. These organic polymers have already been produced industrially, and used in wide applications as sealants and adhesives. Curable compositions including these organic polymer are cured with silanol condensation catalysts, and organotin catalysts such as dibutyltin dilaurylate are widely used. However, cured articles obtained from the curable compositions each including any of the organic polymers and an organotin catalyst are poor in heat resistance, leading to a problem that physical properties of the cured articles are largely degraded by heating. Additionally, organotin catalysts having carbon-tin bonds have recently been pointed out to be toxic. Techniques for improving the heat resistance by structural alteration of the organic polymers are disclosed in Japanese Patent Laid-Open Nos. 10-53637 and 2001-31947, U.S. Pat. No. 6,197,912, Japanese Patent Laid-Open No. 2002-155145, and the like. However, even the use of these techniques sometimes has not resulted in sufficient heat resistance. On the other hand, curable compositions in which carboxylic acids or metal carboxylates are used as the curing catalysts for polyoxyalkylene polymers having reactive silicon groups are disclosed in Japanese Patent Laid-Open No. 55-9669, Japanese Patent No. 3062626, Japanese Patent Laid-Open Nos. 6-322251, 2000-345054 and 5-117519, and the like. However, there have not hitherto been disclosed specific examples in which carboxylic acids or metal carboxylates are used as the curing catalysts for organic polymers having bonding groups produced by the reaction between isocyanate groups and active hydrogen groups and having reactive silicon groups.

20060216

20110823

20060907

74258.0

C08G7760

PENG, KUO LIANG

CURING COMPOSITION WITH IMPROVED HEAT RESISTANCE

UNDISCOUNTED

ACCEPTED

C08G

ACCEPTED

Amidines and derivatives thereof and pharmaceutical compositions containing them

Amidines and derivatives thereof of formula (I) are described. The process for their preparation and pharmaceutical compositions thereof are also described. The amidines of the invention are useful in the inhibition of chemotaxis of neutrophils induced by IL-8. The compounds of the invention are used in the treatment of psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigo, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia and reperfusion.

1. Amidines of formula (I) and pharmaceutically acceptable salts thereof, wherein Ar is selected from: 3′-benzoylphenyl, 3′-(4-chloro-benzoyl)-phenyl, 3′-(4-methyl-benzoyl)-phenyl, 3′-acetyl-phenyl, 3′-propionyl-phenyl, 3′-isobutanoyl-phenyl, 4′-trifluoromethanesulfonyloxy-phenyl, 4′-benzenesulfonyloxy-phenyl, 4′-trifluoromethanesulfonylamino-phenyl, 4′-benzenesulfonyloxy-phenyl, 4′-benzenesulfonylmethyl-phenyl, 4′-acetoxyphenyl, 4′-propionyloxy-phenyl, 4′-benzoyloxyphenyl, 4′acetylamino-phenyl, 4′propionylamino-phenyl, 4′-benzoylamino-phenyl, R is selected from H, C1-C5-alkyl, phenyl, C1-C5-phenylalkyl, C1-C5-cycloalkyl, C1-C5-alkenyl, C1-C5-alkoxy; a residue of formula —(CH2)n-NRaRb wherein n is an integer from 0 to 5 and each Ra and Rb, which may be the same or different, are C1-C6-alkyl, C1-C6-alkenyl or, alternatively, Ra and Rb, together with the nitrogen atom to which they are bound, form a heterocycle form 3 to 7 member of formula (II), wherein W represents a single bond, O, S, N—Rc, Rc being H, C1-C6-alkyl or alkylphenyl. R′ is H, CH3, CH2CH3; R and R′ can alternatively, form a heterocycle from 5 to 7 members of formula (III), wherein X represents a residue —O(CH2)n- wherein n is an integer from 1 to 3, or a residue —(CH2)n- wherein n is an integer from 2 to 4, or the ethylene residue —CH═CH—. 2. Compounds according to claim 1 selected from: (R,S)(2-(4-isobutylphenyl)propionamidine hydrochloride (+)(2-(4-isobutylphenyl)propionamidine hydrochloride (−)(2-(4-isobutylphenyl)propionamidine hydrochloride (R,S)2-(3-benzoylphenyl)propionamidine hydrochloride (R,S)2-[(3-fluoro-4-phenyl)phenyl]propionamidine hydrochloride. (R,S)2-(4-trifluoromethanesulfonyloxyphenyl)propionamidine hydrochloride (R,S)2-(5-benzoyl-2-thiophene)propionamidine hydrochloride (R,S)2-(4 isobutylphenyl)-N-[3″-(N′-piperidino)propyl]propionamidine dihydrochloride (R,S)2-(4-isobutylphenyl)-N-methyl-propionamidine hydrochloride (R,S)2-(3-benzoylphenyl)-N-[3-(N,N-dimethylamino)propyl]propionamidine hydrochloride (R,S)2-(4 isobutylphenyl)propionamidine acetate salt (R,S)2-(4-isobutylphenyl)-N-[3-(N,N-dimethylamino)propyl]propionamidine (R,S)2-(4 isobutylphenyl)-N-benzyl propionamidine (R,S)3-[1-(4-isobutylphenyl)ethyl]-5,6-dihydro-2H-1,2,4-oxadiazine (R,S)2-[1-(4 isobutylphenyl)ethyl]4,5-dihydro-2H-1,3,imidazole. 3. Compounds according to claims 1 or 2, for use as medicaments. 4. Use of compounds according to claims 1 or 2 in the preparation of a medicament for the treatment of diseases that involve the chemotaxis of human PMNs induced by interleukin-8. 5. Use of compounds according to claims 1 or 2 in the preparation of a medicament for the treatment of psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigo, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia and reperfusion. 6. Pharmaceutical compositions comprising a compound according to claims 1 or 2 in admixture and a suitable carrier thereof. 7. Use of amidines of formula (I) and pharmaceutically acceptable salts thereof wherein Ar is a phenyl group non-substituted or substituted by one or more groups independently selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, C1-C4-acyloxy, phenoxy, cyano, nitro, amino, C1-C4-acylamino, halogen-C1-C3-alkyl, halogen C1-C3-alkoxy, benzoyl or a substituted or unsubstituted 5-6 membered heteroaryl ring selected from pyridine, pyrrole, tiofene, furane, indole. R is selected from H, C1-C5-alkyl, phenyl, C1-C5-phenylalkyl, C1-C5-cycloalkyl, C1-C5-alkenyl, C1-C5-alkoxy; a residue of formula —(CH2)n-NRaRb wherein n is an integer from 0 to 5 and each Ra and Rb, which may be the same or different, are C1-C6-alkyl, C1-C6-alkenyl or, alternatively, Ra and Rb, together with the nitrogen atom to which they are bound, form a heterocycle from 3 to 7 members of formula (II), wherein W represents a single bond, O, S, N—Rc, Rc being H, C1-C6-alkyl or C1-C6-alkylphenyl. R′ is H, CH3, CH2CH3. R and R′ can alternatively, form a heterocycle from 5 to 7 members of formula (III), wherein X represents a residue —O(CH2)n- wherein n is an integer from 1 to 3, or a residue —(CH2)n- wherein n is an integer from 2 to 4, or the ethylene residue —CH═CH— in the preparation of a medicament for the treatment of diseases that involve the chemotaxis of human PMNs induced by interleukin-8. 8. Use of compounds according to claim 7, wherein R is selected from hydrogen. a residue of formula —(CH2)n—NRaRb, wherein n is an integer from 2 to 3 and the group NraRb is selected from N,N-dimethylamine or 1-piperidyl, and R′ is H, or R and R′ form a heterocycle of formula (III), where X represents a residue —O(CH2)n- wherein n is the integer 1 or 2, or a residue —(CH2)2. 9. Use of compounds according to claims 7 or 8 in the preparation of a medicament for the treatment of psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigo, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia and reperfusion. 10. Process for the preparation of compounds of formula (I) according to claim 1 comprising the reaction of a nitrile derivate of formula (IV), wherein Ar has the same meaning as defined in claim 1, with an amine of formula NHR, wherein R has the same meaning as defined in claim 1. 11. Process for the preparation of compounds of formula (I) according to claim 1, wherein R and R′ groups form an heterocycle of formula (III), comprising the reaction of amidines of formula (I) wherein R′ is H and R is H or OH, with a reagent of formula L-K-L′, in the presence of a base, wherein L and L′ are leaving groups, and, when R and R′ are both H, K represents a residue —(CH2)n- wherein n is an integer from 2 to 4; when R is OH and R′ is H, K represents a residue —(CH2)n- wherein n is an integer from 1 to 3.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to amidines and derivatives thereof and to pharmaceutical compositions containing them, which are used in the prevention and treatment of tissue damage due to the exacerbated recruitment of polymorphonucleated neutrophils (PMN leukocytes) at inflammation sites. STATE OF THE ART Particular blood cells (macrophages, granulocytes, neutrophils, polymorphonucleated) respond to a chemical stimulus (when stimulated by substances called chemokines) by migrating along the concentration gradient of the stimulating agent, through a process called chemotaxis. The main known stimulating agents or chemokines are represented by the breakdown products of complement C5a, some N-formyl peptides generated from lysis of the bacterial surface or peptides of synthetic origin, such as formyl-methionyl-leucyl-phenylalanine (f-MLP) and mainly by a variety of cytokines, including Interleukin-8 (IL-8, also referred to as CXCL8). Interleukin-8 is an endogenous chemotactic factor produced by most nucleated cells such as fibroblasts and macrophages. In some pathological conditions, marked by exacerbated recruitment of neutrophils, a more severe tissue damage at the site is associated with the infiltration of neutrophilic cells. Recently, the role of neutrophilic activation in the determination of damage associated with post ischemia reperfusion and pulmonary hyperoxia was widely demonstrated The biological activity of IL-8 is mediated by the interaction of the interleukin with CXCR1 and CXCR2 membrane receptors which belong to the family of seven transmembrane receptors, expressed on the surface of human neutrophils and of certain types of T-cells (L. Xu et al., J. Leukocyte Biol., 57, 335, 1995). Selective ligand are known which can distinguish between CXCR1 and CXCR2: GRO-α is an example of a CXCR2 selective chemotactic factor. Although CXCR1 activation is known to play a crucial role in IL-8-mediated chemotaxis, it has been recently supposed that CXCR2 activation could play a pathophysiological role in cronic inflammatory diseases such as psoriasis. In fact, the pathophysiological role of IL-8 in psoriasis is also supported by the effects of IL-8 on keratinocyte functions. Indeed, IL-8 has been shown to be a potent stimulator of epidermal cell proliferation as well as angiogenesis, both important aspects of psoriatic pathogenesis (A. Tuschil et al. J Invest Dermatol, 99, 294, 1992; Koch A E et al, Science, 258, 1798, 1992). In addition, there is accumulating evidence that the pathophysiological role of IL-8 in melanoma progression and metastasis could be mediated by CXCR2 activation (L. R Bryan et al., Am J Surg, 174, 507, 1997). Potential pathogenic role of IL-8 in pulmonary diseases Qung injury, acute respiratory distress syndrome, asthma, chronic lung inflammation, and cystic fibrosis) and, specifically, in the pathogenesis of COPD (chronic obstructive pulmonary disease) through the CXCR2 receptor pathway has been widely described (D. W P Hay and H. M. Sarau., Current Opinion in Pharmacology 2001, 1:242-247). Studies on the contribution of single (S) and (R) enantiomers of ketoprofen to the anti-inflammatory activity of the racemate and on their role in the modulation of the chemokine have demonstrated (P. Ghezzi et al., J. Exp. Pharm. Ther., 287, 969, 1998) that the two enantiomers and their salts with chiral and non-chiral organic bases can inhibit in a dose-dependent way the chemotaxis and increase in intracellular concentration of Ca2+ ions induced by IL-8 on human PMN leukocytes (Patent Application U.S. Pat. No. 6,069,172). It has been subsequently demonstrated (C. Bizzarri et al., Biochem. Pharmacol. 61, 1429, 2001) that Ketoprofen shares the property to inhibit the IL-8 biological activity with other molecules belonging to the class of non-steroidal anti-inflammatory (NSAIDs) such as flurbiprofen, ibuprofen and indomethacin. The cyclo-oxygenase enzyme (COX) inhibition activity typical of NSAIDs limits the therapeutical application of these compounds in the context of the treatment of neutrophil-dependent pathological states and inflammatory conditions such as psoriasis, idiopathic pulmonary fibrosis, acute respiratory failure, damages from reperfusion and glomerulonephritis. The inhibition of prostaglandin synthesis deriving from the action on cyclo-oxygenase enzymes involves the increase of the cytokine production which, like TNF-α, play a role in amplifying the undesired pro-inflammatory effects of neutrophils. Novel classes of potent and selective inhibitors of IL-8 biological activities suitable for “in vivo” administration. R-2-arylpropionic acid amides and N-acylsulfonamides have been described as effective inhibitors of IL-8 induced neutrophils chemotaxis and degranulation (WO 01/58852; WO 00/24710). Furthermore, novel R and S-2-phenylpropionic acids have been recently described as potent IL-8 inhibitors completely lacking the undesired COX inhibitory effect has been described in WO 03/043625. DETAILED DESCRIPTION OF THE INVENTION We have now found that a novel class of amidines and derivatives thereof show the ability to effectively inhibit IL-8 induced neutrophils chemotaxis and degranulation. The present invention thus provides amidines and derivatives thereof of formula (I): and pharmaceutically acceptable salts thereof, wherein Ar is a phenyl group non-substituted or substituted by one or more groups independently selected from halogen, C1-C4-alkyl, C1-C4-alkoxy, hydroxy, C1-C4-acyloxy, phenoxy, cyano, nitro, amino, C1-C4-acylamino, halogen-C1-C3-alkyl, halogen C1-C3-alkoxy, benzoyl or a substituted or unsubstituted 5-6 membered heteroaryl ring selected from pyridine, pyrrole, tiofene, furane, indole. R is selected from H, C1-C5-alkyl, phenyl, C1-C5-phenylalkyl, C1-C5-cycloalkyl, C1-C5-alkenyl, C1-C5-alkoxy; a residue of formula —(CH2)n-NRaRb wherein n is an integer from 0 to 5 and each Ra and Rb, which may be the same or different, are C1-C6-alkyl, C1-C6-alkenyl or, alternatively, Ra and Rb, together with the nitrogen atom to which they are bound, form a heterocycle from 3 to 7 members of formula (II) wherein W represents a single bond, O, S, N—Rc, Rc being H, C1-C6-alkyl or C1-C6-alkylphenyl, n is an integer from 0 to 4. R′ is H, CH3, CH2CH3. R and R′ can alternatively, form a heterocycle from 5 to 7 members of formula (III) where X represents a residue —O(CH2)n- wherein n is an integer from 1 to 3, or a residue —(CH2)n- wherein n is an integer from 2 to 4, or the ethylene residue —H═CH—. When R is C1-C5 alkyl, such alkyl group can be optionally interrupted by an heteroatom such as oxygen or sulfur. For example, R can be a residue of formula —CH2—CH2-Z-CH2—CH2OR″ wherein R″ is H or C1-C5-alkyl. Compounds of formula (I) are chiral compounds and the invention provides both the racemic and the single (R) and (S) enantiomers. It is a further object of the present invention compounds of formula (I) as defined above for use as medicaments. In particular, the invention provides the compounds of formula (I) for use as inhibitors of IL-8 induced human PMNs chemotaxis. When Ar is a phenyl group preferred phenyl groups are substituted by: a group in the 3 (meta) position selected from a linear or branched C1-C5 alkyl, C2-C5-alkenyl or C2-C5-alkynyl group, substituted or not-substituted phenyl, linear or branched C1-C5 hydroxyalkyl, C2-C5-acyl, substituted or not-substituted benzoyl; a group in the 4 (para) position selected from C1-C5 alkyl, C2-C5-alkenyl or C2-C5-alynyl group, C3-C6-cycloalkyl, C1-C5-acylamino, substituted or not-substituted benzoylamino, C1-C5-sulfonyloxy, substituted or not-substituted benzenesulfonyloxy, C1-C5-alkanesulfonylamino, substituted or not-substituted benzenesulfonylamino, C1-C5-alkanesulfonylmethyl, substituted or not-substituted benzenesulfonylmethyl, 2-furyl; 3-tetrahydrofuryl; 2 thiophenyl; 2-tetrahydrothiophenyl groups or a C1-C8 (alkanoyl, cycloalkanoyl, arylalkanoyl)-C1-C5-alkylamino, e.g. acetyl-N-methyl-amino, pivaloyl-N-ethyl-amino group; When Ar is a heteroaromatic ring preferred heteroaromatic rings are pyrrole, tiofene, furane. Preferred R groups are H, C1-C5 alkyl, C1-C5-phenylalkyl; a residue of formula —(CH2)n-NRaRb wherein n is an integer from 2 to 3, more preferably 3, and the group NRaRb is N,N-dimethylamine, N,N-diethylamine, 1-piperidyl, 4-morpholyl, 1-pyrrolidyl, 1-piperazinyl, 1-(4-methyl)piperazinyl; More preferably the group NRaRb is N,N-dimethylamine or 1-piperidyl. Preferred R′ group is H; when R and R′ form a heterocycle of formula (III) X preferably represents a residue —O(CH2)n- wherein n is the integer 1 or 2, or a residue —(CH2)2. Particularly preferred Compounds of the invention are: (R,S)(2-(4-isobutylphenyl)propionamidine hydrochloride (+)(2-(4-isobutylphenyl)propionamidine hydrochloride (−)(2-(4-isobutylphenyl)propionamidine hydrochloride (R,S)2-(3-benzoylphenyl)propionamidine hydrochloride (R,S)2-[(3-fluoro-4-phenyl)phenyl]propionamidine hydrochloride (R,S)2-(4-trifluoromethanesulfonyloxyphenyl)propionamidine hydrochloride (R,S)2-(5-benzoyl-2-thiophene)propionamidine hydrochloride (R,S)2-(4-isobutylphenyl)-N-[3″-(N′-piperidino)propyl]propionamidine dihydrochloride (R,S)2-(4-isobutylphenyl)-N-methyl-propionamidine hydrochloride (R,S)2-(3-benzoylphenyl)-N-[3-(N,N-dimethylamino)propyl]propionamidine hydrochloride (R,S)2-(4-isobutylphenyl)propionamidine acetate salt (R,S)2-(4-isobutylphenyl)-N-[3-(N,N-dimethylamino)propyl]propionamidine (R,S)2-(4-isobutylphenyl)-N-benzyl propionamidine (R,S)3-[1-(4-isobutylphenyl)ethyl]-5,6-dihydro-2H-1,2,4-oxadiazine (R,S)2-[1-(4-isobutylphenyl)ethyl]-4,5-dihydro-2H-1,3,imidazole. The compounds of the invention are potent and selective inhibitors of the human PMNs chemotaxis induced by IL-8. The compounds of the invention of formula (I) are generally isolated in the form of their addition salts with both organic and inorganic pharmaceutically acceptable acids. Examples of such acids are selected from hydrochloric acid, sulfuric acid, phosphoric acid, metansolfonic acid, fumaric acid, citric acid. Compounds of formula (I) are obtained by treatment of corresponding nitrile derivatives of formula (IV), wherein Ar has the same meaning as defined above, in a MeOH/HCl solution and subsequent reaction of the imidate intermediates with the amines of formula NHR, wherein R has the same meaning as defined above, in a dry organic solvent such as dichloromethane; Compounds of formula (I) wherein R and R′ groups form an heterocycle of formula (III) are obtained by direct cyclization of amides of formula (V), wherein X has the same meaning as defined above, with a suitable catalyst such as Al(CH3)3. Alternatively, compounds of formula (I), wherein R and R′ groups form an heterocycle of formula (III) are obtained by direct reaction of amidines of formula (I) wherein R′ is H and R is H or OH, with a reagent of formula L-K-L′, in the presence of a base, wherein L and L′ are common leaving groups such as halogens, mesylate, etc, and, when R and R′ are both H, K represents a residue —(CH2)n-, wherein n is an integer from 2 to 4; when R is OH and R′ is H, K represents a residue —(CH2)n-, wherein n is an integer from 1 to 3. The compounds of the invention of formula (I) were evaluated in vitro for their ability to inhibit chemotaxis of polymorphonucleate leukocytes (hereinafter referred to as PMNs) and monocytes induced by the fractions of IL-8 and GRO-α. For this purpose, in order to isolate the PMNs from heparinized human blood, taken from healthy adult volunteers, mononucleates were removed by means of sedimentation on dextran (according to the procedure disclosed by W. J. Ming et al., J. Immunol., 138, 1469, 1987) and red blood cells by a hypotonic solution. The cell vitality was calculated by exclusion with Trypan blue, whilst the ratio of the circulating polymorphonucleates was estimated on the cytocentrifugate after staining with Diff Quick. Human recombinant IL-8 repro Tech) was used as stimulating agents in the chemotaxis experiments, giving practically identical results: the lyophilized protein was dissolved in a volume of HBSS containing 0.2% bovin serum albumin (BSA) so thus to obtain a stock solution having a concentration of 10−5 M to be diluted in HBSS to a concentration of 10−9 M, for the chemotaxis assays. During the chemotaxis assay (according to W. Falket et al., J. Immunol. Methods, 33, 239, 1980) PVP-free filters with a porosity of 5 μm and microchambers suitable for replication were used. The compounds of the invention in formula (I) were evaluated at a concentration ranging between 10−6 and 10−10 M; for this purpose they were added, at the same concentration, both to the lower pores and the upper pores of the microchamber. Evaluation of the ability of the compounds of the invention of formula I to inhibit IL-8-induced chemotaxis of human monocytes was carried out according to the method disclosed by Van Damme J. et al. (Eur. J. Immunol., 19, 2367, 1989). Particularly preferred compounds of the invention are compounds of Formula I in which Ar is groups are 3′-benzoylphenyl, 3′-(4-chloro-benzoyl)-phenyl, 3′-(4-methyl-benzoyl)-phenyl, 3′-acetyl-phenyl, 3′-propionyl-phenyl, 3′-isobutanoyl-phenyl, 4′-trifluoromethanesulfonyloxy-phenyl, 4′-benzenesulfonyloxy-phenyl, 4′-trifluoromethanesulfonylamino-phenyl, 4′-benzenesulfonylamino-phenyl, 4′-benzenesulfonylmethyl-phenyl, 4′-acetoxyphenyl, 4′-propionyloxy-phenyl, 4′-benzoyloxy-phenyl, 4′acetylamino-phenyl, 4′propionylamino-phenyl, 4′-benzoylamino-phenyl, which show the additional property to effectively inhibit the GROα induced PMN chemotaxis; this activity allows the therapeutical use of these compounds in IL-8 related pathologies where the CXCR2 pathway is involved specifically or in conjunction with the CXCR1 signalling. The dual inhibitors of the IL-8 and GRO-α induced biological activities are strongly preferred in view of the therapeutical applications of interest, but the described compounds selectively acting on CXCR1 IL-8 receptor or CXCR2 GRO-α/IL-8 receptor can find useful therapeutical applications in the management of specific pathologies as below described. The compounds of formula I, evaluated ex vivo in the blood in toto according to the procedure disclosed by Patrignani et al., in J. Pharmacol. Exper. Ther., 271, 1705, 1994, were found to be totally ineffective as inhibitors of cyclooxygenase (COX) enzymes. In the most of the cases, the compounds of formula (I) do not interfere with the production of PGE2 induced in murine macrophages by lipopolysaccharides stimulation (LPS, 1 μg/mL) at a concentration ranging between 10−5 and 10−7 M. Inhibition of the production of PGE2 which may be recorded, is mostly at the limit of statistical significance, and more often is below 15-20% of the basal value. The reduced effectiveness in the inhibition of the CO constitutes an advantage for the therapeutical application of compounds of the invention in as much as the inhibition of prostaglandin synthesis constitutes a stimulus for the macrophage cells to amplify synthesis of TNF-α (induced by LPS or hydrogen peroxide) that is an important mediator of the neutrophilic activation and stimulus for the production of the cytokine Interleukin-8. In view of the experimental evidence discussed above and of the role performed by Interleukin-8 (IL-8) and congenetics thereof in the processes that involve the activation and the infiltration of neutrophils, the compounds of the invention are particularly useful in the treatment of a disease such as psoriasis (R. J. Nicholoff et al., Am. J. Pathol., 138, 129, 1991). Further diseases which can be treated with the compounds of the present invention are intestinal chronic inflammatory pathologies such as ulcerative colitis (Y. R. Mahida et al., Clin. Sci., 82, 273, 1992) and melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigo, rheumatoid arthritis (M. Selz et al., J. Clin. Invest., 87, 463, 1981), idiopathic fibrosis (E. J. Miller, previously cited, and P. C. Carré et al., 3. Clin. Invest., 88, 1882, 191), glomerulonephritis (T. Wada et al., J. Exp. Med., 180, 1135, 1994) and in the prevention and treatment of damages caused by ischemia and reperfusion. Inhibitors of CXCR1 and CXCR2 activation find useful applications, as above detailed, particularly in treatment of chronic inflammatory pathologies (e.g. psoriasis) in which the activation of both IL-8 receptors is supposed to play a crucial pathophysiological role in the development of the disease. In fact, activation of CXCR1 is known to be essential in IL-8-mediated PMN chemotaxis (Hammond M et al, J Immunol, 155, 1428, 1995). On the other hand, activation of CXCR2 activation is supposed to be essential in IL-8-mediated epidermal cell proliferation and angiogenesis of psoriatic patients (Kulke R et al., J Invest Dermatol, 110, 90, 1998). In addition, CXCR2 selective antagonists find particularly useful therapeutic applications in the management of important pulmonary diseases like chronic obstructive pulmonary disease COPD (D. W P Hay and H. M. Sarau., Current Opinion in Pharmacology 2001, 1:242-247). It is therefore a further object of the present invention to provide compounds for use in the treatment of psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigo, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of damages caused by ischemia and reperfusion, as well as the use of such compounds in the preparation of a medicament for the treatment of diseases as described above. Pharmaceutical compositions comprising a compound of the invention and a suitable carrier thereof, are also within the scope of the present invention. The compounds of the invention, together with a conventionally employed adjuvant, carrier, diluent or excipient may, in fact, be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. When employed as pharmaceuticals, the amidines of this invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined on the basis of relevant circumstances including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. The pharmaceutical compositions of the invention can be administered by a variety of routes including oral, rectal, transdermaldermal, subcutaneous, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds are preferably formulated as either injectable or oral compositions. The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form. Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Liquid forms, including the injectable compositions described herebelow, are always stored in the absence of light, so as to avoid any catalytic effect of light, such as hydroperoxide or peroxide formation. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As above mentioned, the acid derivative of formula I in such compositions is typically a minor component, frequently ranging between 0.05 to 10% by weight with the remainder being the injectable carrier and the like. The mean daily dosage will depend upon various factors, such as the seriousness of the disease and the conditions of the patient (age, sex and weight). The dose will generally vary from 1 mg or a few mg up to 1500 mg of the compounds of formula (I) per day, optionally divided into multiple administrations. Higher dosages may be administered also thanks to the low toxicity of the compounds of the invention over long periods of time. The above described components for orally administered or injectable compositions are merely representative. Further materials as well as processing techniques and the like are set out in Part 8 of “Remington's Pharmaceutical Sciences Handbook”, 18th Edition, 1990, Mack Publishing Company, Easton, Pa., which is incorporated herein by reference. The compounds of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can also be found in the incorporated materials in the Remington's Handbook as above. The present invention shall be illustrated by means of the following examples which are not construed to be viewed as limiting the scope of the invention. Abbreviations: THF: tetrahydrofuran; DMF: dimethylformamide; AcOEt: ethyl acetate. EXPERIMENTAL PROCEDURES Example 1 Starting from the procedure described in Granik, Russ. Chem. Rev., 52, 377-393 (1983), the following unsubstituted amidines can be prepared: 1a (R,S)(2-(4-isobutylphenyl)propionamidine hydrochloride 2-(4-isobutylphenyl)propionitrile 4-isobutyl-α-methylphenylacetamide (2 g; 9.7 mmol), prepared according the procedure described in WO 00/24710, is dissolved in a solution (2:1) toluene/trichloromethane (30 mL). 20% in toluene phosgene (15.5 mL, 30 mmol) is added and the resulting mixture is left stirring 12 h under inert atmosphere until the complete disappearance of the starting reagent. After solvents evaporation under reduced pressure, the crude is dissolved in ethyl acetate (20 mL), the organic phase is washed with a saturated solution of NaHCO3 (2×20 mL) and with a saturated solution of NaCl (2×15 mL), dried over Na2SO4 and evaporated under vacuum to give 2-(4-isobutylphenyl)propionitrile as colourless oil (1.45 g; 7.76 mmol). Yield 80%. 1H-NMR (CDCl3): δ 7.42 (d, 2H, J=7 Hz); 7.28 (d, 2H, J=7 Hz); 4.05 (q, 1H, J=8 Hz); 2.65 (d, 2H, J=8 Hz); 1.95 (m, 1H); 1.80 (d, 3H, J=8 Hz); 1.05 (d, 6H, J=8 Hz). A solution of 2-(4-isobutylphenyl)propionitrile (0.2 g; 1.07 mmol) in a (1:1) diethyl ether/methyl alcohol mixture (20 mL) is cooled at T=0-5° C. and gaseous HCl is bubbled into the solution for 1 h. Then the temperature is left to arise to r.t. and the mixture stirred overnight. After solvent evaporation under reduced pressure, the crude is dissolved in methyl alcohol (10 mL) and cooled at T=0-5° C. Ammonia is bubbled into for 1 h and the resulting mixture is left stirring overnight at r.t. After solvent evaporation under reduced pressure, the crude is suspended in diethyl ether (15 mL) and left stirring at r.t. for 2 h. The 2-(4 isobutylphenyl)propionamidine hydrochloride (I) is isolated by filtration in vacuo as white solid (0.193 g; 0.80 mmol). Yield 75%. 1H-NMR (DMSO-d6): δ 8.80-8.50 (bs, NH3+Cl−); 7.40 (d, 2H, J=7 Hz); 7.15 (d, 2H, J=7 Hz); 3.98 (q, 1H, J=8 Hz); 2.42 (d, 2H, J=8 Hz); 1.90 (m, 1H); 1.57 (d, 3H, J=8 Hz); 0.88 (d, 6H, J=8 Hz). According to the above described method and using the suitable carboxylic acid, the following compounds have been prepared: 1b (R,S)2-(3-benzoylphenyl)propionamidine hydrochloride from 2-(3′-benzoylphenyl)propionitrile, prepared following the procedure above described, and the corresponding α-methylphenylacetamide. The general preparation in described in WO/0158852. Yield 70%. m.p. 110-113° C. 1H-NMR (DMSO-d6): δ 7.86 (s, 1H); 7.80-7.50 (m, 8H+ NH2++NH2); 4.13 (q, 1H, J=7 Hz); 1.60 (d, 3H, J=7 Hz). 1c (R,S)2-[(3-fluoro-4-phenyl)phenyl]propionamidine hydrochloride From 2-(3-fluoro-4-phenyl)propionitrile, prepared following the procedure above described, and the corresponding α-methylphenylacetamide. The general preparation in described in WO/0158852. Yield 53%. m.p. 143-145° C. 1H-NMR (DMSO-d6): δ 9.18 (bs, NH2+Cl−); 8.85 (bs, NH2); 7.67-7.30 (m, 8H); 4.15 (q, 1H, J=7 Hz); 1.62 (d, 3H, J=7 Hz). 1d (R,S)2-(4-trifluoromethanesulfonyloxyphenyl)propionamidine hydrochloride From 2-(4′-trifluoromethanesulfonyloxyphenyl)propionitrile, prepared following the procedure above described, and the corresponding α-methylphenylacetamide. Yield 68%. 1H-NMR (DMSO-d6): δ 7.47 (d, 2H, J=8 Hz); 7.25 (d, 2H, J=8 Hz); 6.55 (bs, NH2+NH2+Cl−); 3.92 (q, 1H, J=7 Hz); 1.56 (d, 3H, J=7 Hz). 1e (R,S)2-(5-benzoyl-2-thiophene)propionamidine hydrochloride From 2-(5-benzoyl-2-thiophene)propionitrile, prepared following the procedure above described, and the corresponding propionamide. Yield 60% 1H-NMR (DMSO-d6): δ 7.9 (d, 2H, J=8 Hz); 7.7-7.4 (m, 4H); 7.0 (d, 1H, J=8 Hz); 6.55 (bs, NH2+NH2+Cl−); 3.9 (q, 1H, J=7 Hz); 1.56 (d, 3H, J=7 Hz). Optical Resolution of (R,S)(2-(4-isobutylphenyl)propionamidine Single (+) and (−) enantiomers of (2-(4-isobutylphenyl)propionamidine have been obtained by optical resolution starting from (R,S)(2-(4-isobutylphenyl)propionamidine hydrochloride. The free base has been obtained by treatment of the hydrochloride salt with strongly basic AMBERLITE IRA-910 resin. Corresponding (L) and (D) tartrate salts have been prepared by treatment of (R,S)(2-(4-isobutylphenyl)propionamidine with (L) and (D) tartrate in methanol. Optically pure (+) and (−) (2-(4-isobutylphenyl)propionamidine isomers have been obtained by sequential cristallization steps of the tartrate salts from isopropanol (or acetone) solution. The free bases have been obtained by treatment of the tartrate salt with strongly basic AMBERLITE IRA-910 resin. 1f (+)(2-(4-isobutylphenyl)propionamidine [α]D=+28.1 (c=0.5, MeOH) 1g (−)(2-(4 isobutylphenyl)propionamidine [α]D=−28.0 (c=0.5, MeOH) Example 2 2a (R,S)2-(4-isobutylphenyl)-N-[3-N-piperidino)propyl]propionamidine dihydrochloride A solution of 2-(4-isobutylphenyl)propionitrile (0.15 g; 0.80 mmol) in a (1:1) diethyl ether/methyl alcohol mixture (10 mL) is cooled at T=0-5° C. and gaseous HCl is bubbled into the solution for 1 h. Then the temperature is left to arise to r.t. and the mixture stirred overnight. After solvent evaporation under reduced pressure, the crude is dissolved in methyl alcohol (10 mL) and cooled at T=0-5° C. A solution of 3-piperidinopropylamine (0.15 g; 0.96 mmol) in methyl alcohol (5 mL) is added dropwise and the resulting mixture is left under stirring overnight at r.t. After solvent evaporation under reduced pressure, the crude oil is suspended in 2N HCl (solution pH=2) and the product is extracted with dichloromethane (3×15 mL). The combined organic extracts are washed back with a saturated solution of NaCl (2×15 mL), dried over Na2SO4 and evaporated under vacuum to give 2-(4′-isobutylphenyl)-N-[3-(N-piperidino)propyl]propionamidine dihydrochloride as glassy solid (0.193 g; 0.48 mmol). Yield 60%. 1H-NMR (CDCl3): δ 10.88 (bs, NH+Cl−); 10.22 (bs, NH+Cl−); 9.82 (bs, NH+Cl−); 7.64 (bs, NH); 7.41 (d, 2H, J=8 Hz); 7.15 (d, 2H, J=8 Hz); 4.39 (q, 1H, J=8 Hz); 3.78 (m, 2H); 3.45 (m, 2H); 3.10 (m, 2H); 2.75 (m, 2H); 2.46 (d, 2H, J=8 Hz); 2.32-2.05 (m, 3H); 2.00-1.68 (m, 9H); 0.90 (d, 6H, J=8 Hz). According to the above described method and using the suitable amine as free base, the following compounds have been prepared: 2b (R,S)2-(4-isobutylphenyl)-N-methyl-propionamidine hydrochloride from 2-(4-isobutylphenyl)propionitrile, prepared following the procedure described in Example 1, and the corresponding α-methylphenylacetamide. Yield 75%. 1H-NMR (DMSO-d6): δ 10.15 (bs, NH+Cl−); 7.12 (m, 4H); 4.25 (bs, NH2); 3.71 (m, 1H); 2.90 (s, 3H); 2.48 (d, 2H, J=8 Hz); 1.91 (m, 1H); 1.55 (d, 3H, J=8 Hz); 0.93 (d, 6H, J=8 Hz). 2c (R,S)2-(3-benzoylphenyl)-N-[3-(N,N-dimethylamino)propyl]propionamidine hydrochloride From 2-(3-benzoylphenyl)propionitrile, prepared following the procedure described in Example 1, and the corresponding α-methylphenylacetamide. Yield 48%. 1H-NMR (DMSO-d6): δ 7.81 (d, 2H, J=8 Hz); 7.74 (s, 1H); 7.67 (d, 1H, J=8 Hz); 7.59 (d, 1H, J=8 Hz); 7.52-7.27 (m, 4H+ NH); 3.65 (q, 1H, J=7 Hz); 3.25 (t, 2H, J=6 Hz); 2.27 (t, 2H, J=6 Hz); 2.09 (s, 6H); 1.66 (m, 2H); 1.46 (d, 6H, J=7Hz). Example 3 (R,S)2-(4-isobutylphenyl)propionamidine acetate salt As alternative procedure for the preparation of 2-(4-isobutylphenyl)propionamidines the method described in Judkins B. D., Allen D. G. Cook T. A., Evans B. and Sardharwala T. E., Synth. Comm., 26(23), 4315-4367 (1996) has been followed: (R,S)2-(4-isobutylphenyl)-N-hydroxy-propionamidine A mixture of hydroxylamine hydrochloride (0.38 g, 5.32 mmol) and sodium tert-butoxide (0.5 g, 5.28 mmol) in ethyl alcohol (10 mL) is stirred at r.t. for 15′; the precipitate is filtered off and the mother liquors are added dropwise to a solution of 2-(4-isobutylphenyl)propionitrile (0.11 g, 0.49 mmol) in absolute ethyl alcohol (3 mL). The resulting solution is refluxed 18 h. After cooling at r.t. the solvents are evaporated under reduced pressure and the crude residue is diluted in trichloromethane (25 mL), washed with 5% solution of citric acid (2×15 mL), then with a saturated solution of NaCl (2×15 mL), dried over Na2SO4 and evaporated under vacuum to give 2-(4-isobutylphenyl)-N-hydroxy-propionamidine isolated as white solid after crystallisation from n-hexane (0.075 g, 0.34 mmol). Yield 70%. m.p. 75-78° C. 1H-NMR (CDCl3): δ 7.25 (d, 2H, J=7 Hz); 7.12 (d, 2H, J=7 Hz); 5.030 (bs, 1H, NH), 4.35 (bs, 2H, NH—OH); 3.58 (q, 1H, J=8 Hz); 2.48 (d, 2H, J=8 Hz); 1.87 (m, 1H); 1.50 (d, 3H, J=8 Hz); 0.92 (d, 6H, J=8 Hz). 2-(4-isobutylphenyl)-N-hydroxy-propionamidine (0.097 g, 0.44 mmol) is dissolved in acetic acid (3 mL) and treated at r.t. with acetic anhydride (0.06 mL, 0.66 mmol). 10% Pd on activated charcoal (0.03 g) is added and H2 is bubbled into the flask until the complete disappearance of the starting reagent. Methyl alcohol (5 mL) is added, the catalyst filtered off on a Celite cake and the solvents evaporated under reduced pressure to give an oily residue. Crystallisation of the crude residue from n-hexane gives 2-(4-isobutylphenyl)propionamidine acetate salt as white solid (0.106 g, 0.4 mmol). Yield 91%. m.p.>220° C. 1H-NMR (DMSO-d6): δ 8.70-8.50 (bs, NH3++NH); 7.42 (d, 2H, J=7 Hz); 7.23 (d, 2H, J=7 Hz); 3.85 (q, 1H, J=8 Hz); 2.52 (d, 2H, J=8 Hz); 1.97 (m, 1H); 1.75 (s, 3H); 1.60 (d, 3H, J=8 Hz); 0.95 (d, 6H, J=8 Hz). Example 4 The alternative method described in Weintraub L., Oles S. R. and Kalish N, J. Org. Chem., 33(4), 1679-1681 (1968) has been followed for the preparation of 2-(4-isobutylphenyl)-N-alkyl-propionamidines. 4a (R,S)2-(4-isobutylphenyl)-N-[3-(N,N-dimethylamino)propyl]propionamidine 4-isobutyl-α-methylphenylacetamide (1 g; 4.9 mmol), prepared according the procedure described in WO 00/24710, is dissolved in dry dichloromethane (10 mL) under inert atmosphere at r.t and treated with triethyloxonium tetrafluoroborate (1.0 M in CH2Cl2, 5 mL, 5 mmol). The resulting solution is left stirring overnight at r.t. After solvent evaporation under reduced pressure, the crude intermediate is diluted in diethyl ether (5 mL) at r.t. and under inert atmosphere and treated with 3-(dimethylamino)propylamine (0.61 mL, 4.9 mmol). The resulting solution is refluxed for 2 h. After cooling at r.t. the solvents are evaporated under reduced pressure and the crude is purified by flash chromatography (eluent: CHCl3/cyclohexane/CH3OH/H4OH 60:24:17:2). The pure 2-(4-isobutylphenyl)-N-[3-(N,N-dimethylamino)propyl]propionamidine is obtained as pale yellow oil (0.82 g, 2.84 mmol). Yield 58%. 1H-NMR (DMSO-d6): δ 7.39 (d, 2H, J=8 Hz); 7.14 (d, 2H, J=8 Hz); 4.15 (q, 1H, J=7 Hz); 3.25 (t, 2H, J=7 Hz); 2.42 (d, 2H, 1=7 Hz); 2.16 (t, 2H, J=7 Hz); 2.06 (s, 3H); 1.80 (m, 1H); 1.65 (m, 2H); 1.53 (d, 3H, J=7 Hz); 0.84 (d, 6H, J=7 Hz). According to the above described method and using the N-benzylamine, the following compound has been prepared: 4b (R,S)2-(4-isobutylphenyl)-N-benzyl-propionamidine Yield 65%. 1H-NMR (CDCl3): δ 7.35-7.18 (m, 5H); 7.15 (d, 2H, J=8 Hz); 7.0.5 (d, 2H, J=8 Hz); 5.05 (bs, 2H, NH); 4.30 (s, 2H); 3.65 (q, 1H, J=7 Hz); 2.45 (d, 2H, J=7 Hz); 1.91 (m, 1H); 1.55 (d, 3H, J=7 Hz); 0.95 (d, 6H, J=7 Hz). Example 5 (R,S)3-[1-(4-isobutylphenyl)ethyl]-5,6-dihydro-2H-1,2,4-oxadiazine (R,S)2-(4-isobutylphenyl)-N-hydroxy-propionamidine (50 mg, 0.23 mmol, preparation described in Example 3) is dissolved in 10 ml chloroform at room temperature. Excess sodium carbonate and 0.28 mmol 1,2-dichloroethane (28 mg; 20% excess) are added to this solution at r.t. The suspension is refluxed for 5 hours. After cooling, the inorganic salts are filtered off and the solution washed with brine (2×10 mL). The solvent is removed under reduced pressure and the title compound purified by column silica gel chromatography (n-hexane/ethyl acetate 9/1) to give 29 mg as a pale yellow oil (yield 51%) 1H-NMR (CDCl3): δ 7.35 (d, 2H, J=7 Hz); 7.15 (d, 2H, J=7 Hz); 3.70 (q, 1H, J=8 Hz); 3.6-3.4 (m, 4H); 2.42 (d, 2H, J=8 Hz); 2.3-2.1 (m, 2H); 1.90 (m, 1H); 1.57 (d, 3H, J=8 Hz); 0.88 (d, 6H, J=8 Hz). Example 6 (R,S)2-[1-(4-isobutylphenyl)ethyl]-4,5-dihydro-2H-1,3,imidazole) (R,S)-2-[(4-isobutyl)phenyl]-propionamidine hydrochloride (100 mg, 0.49 mmol, preparation described in Example 1a) were suspended in 25 mL dry chloroform at room temperature under inert atmosphere, then treated with a large excess (10-50 eq) of tButOK. To the suspension 0.59 mmol) 1,2-dichloroethane (58 mg; 20% excess) was added. The suspension was then refluxed for 24 hour. At room temperature the suspended solid was filtered and the solution washed with 5% phosphate buffer pH 5 and brine. The solution dried over sodium sulphate was evaporated; the residue oil was chromatographed on silica gel column to obtain the pure title compound (73 mg; 65% Yield). 1H-NMR (CDCl3): δ 7.40 (d, 2H, J=7 Hz); 7.15 (d, 2H, J=7 Hz); 3.75 (q, 1H, J=8 Hz); 3.5-3.6 (m, 4H); 2.42 (d, 2H, J=8 Hz); 1.90 (m, 1H); 1.57 (d, 3H, J=8 Hz); 0.88 (d, 6H, J=8 Hz). The chemical structure of the compounds of examples 1-6 is reported in table 1. TABLE 1 Example N. Chemical name Structure Formula 1a (R,S) 2-(4-isobutylphenyl)-propionamidine hydrochloride 1b (R,S) 2-(3-benzoylphenyl)propionamidine hydrochloride 1c (R,S) 2-(3-fluoro-4-phenyl)phenlpropionamidine hydrochloride 1d (R,S) 2-(4-trifluoromethanesulphonyloxy) phenylpropionamidine hydrochloride 1e (R,S) 2-(5-benzoyl-2-thiophene)propionamidine hydrochloride 2a (R,S) 2-[(4-isobutyl)phenyl]-N-[3-N- piperidinopropyl] propionamidine dihydrochloride 2b (R,S) 2-[(4-isobutyl)phenyl]-N-methyl-propionamidine 2c (R,S) N-[(3-(N,N-dimethylamino)-propyl]-2-(3- benzoylphenyl)propionamidine 3 (R,S) 2-(4-isobutylphenyl)-propionamidine acetate 4a (R,S) 2-(4-isobutylphenyl)-N-(3- dimethylaminopropyl)-propionamidine 4b (R,S) 2-(4-isobutylphenyl)-N-benzyl propionamidine 5 (R,S) 3-[1-(4-isobutylphenyl)ethyl]-5,6-dihydro- 2H-1,2,4-oxadiazine 6 (R,S) 2-[1-(4-isobutylphenyl)ethyl]-4,5-dihydro-2H- 1,3,imidazole)

<SOH> BRIEF DESCRIPTION OF THE INVENTION <EOH>The present invention relates to amidines and derivatives thereof and to pharmaceutical compositions containing them, which are used in the prevention and treatment of tissue damage due to the exacerbated recruitment of polymorphonucleated neutrophils (PMN leukocytes) at inflammation sites.

20070105

20100309

20070705

98087.0

A61K31553

HABTE, KAHSAY

AMIDINES AND DERIVATIVES THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Flow meter filter system and method

A flow meter filter system (200) according to an embodiment of the invention includes a noise pass filter (203) configured to receive a first version of a flow meter signal and filter out the flow meter data from the flow meter signal to leave a noise signal, a noise quantifier (204) configured to receive the noise signal from the noise pass filter (203) and measure noise characteristics of the noise signal, a damping adjuster (205) configured to receive the noise characteristics from the noise quantifier (204) and generate a damping value based on the noise characteristics, and a filter element (206) configured to receive a second version of the flow meter signal and receive the damping value from the damping adjuster (205), with the filter element (206) being further configured to damp the second version of the flow meter signal based on the damping value in order to produce a filtered flow meter signal.

1. A flow meter filter system (200) comprising: a noise pass filter (203) configured to receive a first version of a flow meter signal and filter out the flow meter data from the flow meter signal to leave a noise signal; a noise quantifier (204) configured to receive the noise signal from the noise pass filter (203) and measure noise characteristics of the noise signal; a damping adjuster (205) configured to receive the noise characteristics from the noise quantifier (204) and generate a damping value based on the noise characteristics; and a filter element (206) configured to receive a second version of the flow meter signal and receive the damping value from the damping adjuster (205), with the filter element (206) being further configured to damp the second version of the flow meter signal based on the damping value in order to produce a filtered flow meter signal. 2. The flow meter filter system (200) of claim 1, with the noise pass filter (203) comprising an Alternating Current (AC) coupling filter. 3. The flow meter filter system (200) of claim 1, with the noise pass filter (203) comprising a second-order Infinite Impulse Response (IIR) digital filter. 4. The flow meter filter system (200) of claim 1, wherein the noise characteristics include a maximum noise amplitude and a zero offset. 5. The flow meter filter system (200) of claim 1, wherein the damping adjuster (205) is further configured to receive an error signal generated by the filter element (206), with the error signal comprising a difference between the second version of the flow meter signal and the filtered flow meter signal. 6. The flow meter filter system (200) of claim 1, wherein the damping adjuster (205) is further configured to receive a predetermined maximum flow value. 7. The flow meter filter system (200) of claim 1, wherein the damping adjuster (205) is further configured to divide the zero offset by the predetermined maximum flow value in order to determine whether the noise signal is substantially centered around zero. 8. The flow meter filter system (200) of claim 1, wherein the damping adjuster (205) is further configured to input the noise characteristics into a damping table in order to generate the damping value. 9. The flow meter filter system (200) of claim 1, wherein the damping adjuster (205) is further configured to generate the damping value based on the noise characteristics and on a damping delay coefficient. 10. The flow meter filter system (200) of claim 1, with the filter element (206) comprising a second-order filter. 11. The flow meter filter system (200) of claim 1, with the filter element (206) comprising an Infinite Impulse Response (IIR) digital filter. 12. The flow meter filter system (200) of claim 1, with the filter element (206) comprising a second order Infinite Impulse Response (IIR) digital filter. 13. The flow meter filter system (200) of claim 1, wherein the noise signal has a frequency in the range of about 0.025 Hz to about 1.0 Hz. 14. The flow meter filter system (200) of claim 1, wherein the noise signal comprises cyclic noise. 15. The flow meter filter system (200) of claim 1, wherein the noise signal comprises cross-talk noise. 16. The flow meter filter system (200) of claim 1, wherein the flow meter signal comprises a Coriolis flow meter signal. 17. A method of removing noise from a flow meter signal, comprising the steps of: receiving the flow meter signal; applying a large damping value to the flow meter signal in order to produce a filtered flow meter signal if the flow meter signal is substantially quiescent; and applying a small damping value to the flow meter signal in order to produce the filtered flow meter signal if the flow meter signal is experiencing a transition. 18. The method of claim 17, further comprising the steps of: normalizing the flow meter signal from an original value to a normalized value prior to the damping; and scaling the filtered flow meter signal of the damping step substantially back to the original flow meter signal magnitude. 19. The method of claim 17, further comprising the steps of: filtering a noise signal substantially out of a first version of the flow meter signal; measuring the noise signal to obtain noise characteristics; and determining a damping value from the noise characteristics, with the damping value being selected to substantially remove the noise signal from the flow meter signal and produce the filtered flow meter signal. 20. The method of claim 17, further comprising the steps of: filtering a noise signal substantially out of a first version of the flow meter signal; measuring the noise signal to obtain noise characteristics; determining a damping value from the noise characteristics, with the damping value being chosen to substantially remove the noise signal from the flow meter signal; determining an error value between the second version of the flow meter signal and the filtered flow meter signal; and feeding the error value back into the step of determining the damping value, wherein the error value is included in the damping value determination. 21. The method of claim 17, wherein the noise signal has a frequency in the range of about 0.025 Hz to about 1.0 Hz. 22. The method of claim 17, wherein the noise signal comprises cyclic noise. 23. The method of claim 17, wherein the noise signal comprises cross-talk noise. 24. The method of claim 17, wherein the flow meter signal comprises a Coriolis flow meter signal. 25. The method of claim 17, further comprising the steps of: dividing a zero offset of the noise characteristics by the maximum flow value to obtain a noise value; comparing the noise value to a predetermined quiescent threshold; using the noise value for determining a new damping value if the noise value is less than the predetermined quiescent threshold; and using a current damping value if the noise value is not less than the predetermined quiescent threshold. 26. A method of removing noise from a flow meter signal, comprising the steps of: receiving the flow meter signal; filtering a noise signal substantially out of a first version of the flow meter signal; measuring the noise signal to obtain noise characteristics; determining a damping value from the noise characteristics, with the damping value being selected to substantially remove the noise signal from the flow meter signal; and damping the noise substantially out of a second version of the flow meter signal using the damping value in order to produce a filtered flow meter signal. 27. The method of claim 26, further comprising the steps of: normalizing the flow meter signal from an original value to a normalized value prior to the damping; and scaling the filtered flow meter signal of the damping step substantially back to the original flow meter signal magnitude. 28. The method of claim 26, further comprising the steps of: determining an error value between the second version of the flow meter signal and the filtered flow meter signal; and feeding the error value back into the step of determining the damping value, wherein the error value is included in the damping value determination. 29. The method of claim 26, with the damping further comprising the steps of: applying a large damping value to the flow meter signal if the flow meter signal is substantially quiescent; and applying a small damping value to the flow meter signal if the flow meter signal is experiencing a transition. 30. The method of claim 26, further comprising sampling the first version of the flow meter signal before the filtering. 31. The method of claim 26, wherein the noise characteristics include a noise amplitude and a zero offset. 32. The method of claim 26, wherein the noise signal has a frequency in the range of about 0.025 Hz to about 1.0 Hz. 33. The method of claim 26, wherein the noise signal comprises cyclic noise. 34. The method of claim 26, wherein the noise signal comprises cross-talk noise. 35. The method of claim 26, wherein the flow meter signal comprises a Coriolis flow meter signal. 36. The method of claim 26, further comprising the steps of: dividing a zero offset of the noise characteristics by the maximum flow value to obtain a noise value; comparing the noise value to a predetermined quiescent threshold; using the noise value in the determining step for determining a new damping value if the noise value is less than the predetermined quiescent threshold; and using a current damping value in the damping step if the noise value is not less than the predetermined quiescent threshold.

BACKGROUND OF THE INVENTION 1. Field of the Invention The invention is related to the field of removing noise from a flow meter signal, and in particular, to removing cyclic noise, such as cross-talk noise, from the flow meter signal. 2. Statement of the Problem Flow meters are used to measure the mass flow rate, density, and other information for flowing materials. The flowing materials can include liquids, gases, combined liquids and gases, solids suspended in liquids, and liquids including gases and suspended solids. For example, flow meters are widely used in the well production and refining of petroleum and petroleum products. A flow meter can be used to determine well production by measuring a flow rate (i.e., by measuring a mass flow through the flow meter), and can even be used to determine the relative proportions of the gas and liquid components of a flow. In a production or processing environment, it is common to have multiple flow meters connected to the same process line and/or mounted in such a manner that vibration from one flow meter can reach another flow meter. Although this results in efficiency in measuring flow, the multiple flow meters can interfere with each other in the form of cross-talk noise. Cross-talk is a phenomena when the flow meter signal from a first meter influences and corrupts a flow meter signal from a second flow meter (and vice versa). Cross-talk noise in a flow meter environment commonly is a relatively large, slow-moving signal typically no faster than 1 Hertz (Hz). The noise can degrade accuracy of the flowmeter signal and can lead to extremely large indicated flow errors. In addition, noise can occur due to other factors and other sources. FIG. 1 is a graph of a flow meter output signal taken over time. The figure shows how a flow meter signal is influenced by other flow meters. The time periods 101 and 103 in the figure show a flow meter signal when three flow meters are generating output, with two other flow meters therefore generating cross-talk noise in the current flow meter output. Time period 102 is a flow meter signal when only one other interfering flow meter is active. Note that the generated noise varies in both amplitude and frequency throughout the graph. The prior art has attempted to address noise and cross-talk noise through use of traditional filtering techniques, such as high-pass filtering. However, due to the relatively small difference in frequencies between cross-talk noise and the actual flow meter data, and due to the low frequency data signals outputted by flow meters, it has been difficult to remove noise without degrading the flow meter data. SUMMARY OF THE SOLUTION The invention helps solve the above problems with removing noise from a flow meter signal. A flow meter filter system (200) is provided according to an embodiment of the invention. The flow meter filter system (200) comprises a noise pass filter (203) configured to receive a first version of a flow meter signal and filter out the flow meter data from the flow meter signal to leave a noise signal. The flow meter filter system (200) further comprises a noise quantifier (204) configured to receive the noise signal from the noise pass filter (203) and measure noise characteristics of the noise signal. The flow meter filter system (200) further comprises a damping adjuster (205) configured to receive the noise characteristics from the noise quantifier (204) and generate a damping value based on the noise characteristics. The flow meter filter system (200) further comprises a filter element (206) configured to receive a second version of the flow meter signal and receive the damping value from the damping adjuster (205), with the filter element (206) being further configured to damp the second version of the flow meter signal based on the damping value in order to produce a filtered flow meter signal. A method of removing noise from a flow meter signal is provided according to an embodiment of the invention. The method comprises the steps of receiving the flow meter signal, applying a large damping value to the flow meter signal in order to produce a filtered flow meter signal if the flow meter signal is substantially quiescent, and applying a small damping value to the flow meter signal in order to produce the filtered flow meter signal if the flow meter signal is experiencing a transition. A method of removing noise from a flow meter signal is provided according to an embodiment of the invention. The method comprises the steps of receiving the flow meter signal, filtering a noise signal substantially out of a first version of the flow meter signal, measuring the noise signal to obtain noise characteristics, determining a damping value from the noise characteristics, with the damping value being selected to substantially remove the noise signal from the flow meter signal, and damping the noise substantially out of a second version of the flow meter signal using the damping value in order to produce a filtered flow meter signal. One aspect of the invention comprises normalizing the flow meter signal from an original value to a normalized value prior to the damping, and scaling the filtered flow meter signal of the damping step substantially back to the original flow meter signal magnitude. In another aspect of the invention, the method determines an error value between the second version of the flow meter signal and the filtered flow meter signal, and feeds the error value back into the determining of the damping value, wherein the error value is included in the damping value determination. In another aspect of the invention, the noise pass filter and the filter element comprise digital filters. In another aspect of the invention, the noise pass filter and the filter element comprise Infinite Impulse Response (IIR) digital filters. In another aspect of the invention, the noise pass filter and the filter element comprise second-order IIR digital filters. In another aspect of the invention, the damping adjuster is further configured to generate the damping value based on the noise characteristics and on a damping delay coefficient. In another aspect of the invention, the flow meter signal comprises a Coriolis flow meter signal. DESCRIPTION OF THE DRAWINGS The same reference number represents the same element on all drawings. FIG. 1 is a graph of a flow meter output signal taken over time; FIG. 2 is a flow meter filter system according to an embodiment of the invention; FIG. 3 shows the magnitude and phase responses for the noise pass filter according to one embodiment of the invention; FIG. 4 is a flowchart of a method of removing noise from a flow meter signal according to another embodiment of the invention; FIG. 5 is a flowchart of a method of removing noise from a flow meter signal according to an embodiment of the invention; FIG. 6 is a graph that illustrates damping removal of noise from a flow meter signal; FIG. 7 is a diagram of the damping adjuster according to an embodiment of the invention; FIG. 8 is a graph of various damping values that can be implemented in the flow meter filter system according to an embodiment of the invention; and FIG. 9 is a graph that shows a ramping of the damping value according to an embodiment of the invention. DETAILED DESCRIPTION OF THE INVENTION FIGS. 2-9 and the following description depict specific examples of the invention to teach those skilled in the art how to make and use the best mode of the invention. For the purpose of teaching inventive principles, some conventional aspects of the invention have been simplified or omitted. Those skilled in the art will appreciate variations from these examples that fall within the scope of the invention. Those skilled in the art will appreciate that the features described below can be combined in various ways to form multiple variations of the invention. As a result, the invention is not limited to the specific examples described below, but only by the claims and their equivalents. Flow Meter Filter System—FIG. 2 FIG. 2 is a flow meter filter system 200 according to an embodiment of the invention. The flow meter filter system 200 receives a flow meter signal from one or more flow meters and substantially filters out noise in the flow meter signal. The flow meters can comprise any type of flow meter, including Coriolis flow meters, turbine flow meters, magnetic flow meters, etc. The flow meter filter system 200 in the embodiment shown includes a normalizer 201, a scaler 202, a noise pass filter 203, a noise quantifier 204, a damping adjuster 205, and a filter element 206. It should be understood that other flow meter filter configurations are contemplated, and the embodiment shown is provided for illustration. The normalizer 201 receives the flow meter signal and a maximum flow value, and has an output that is connected to the filter element 206. The noise pass filter 203 also receives the flow meter signal (i.e., a first version of the flow meter signal), and has an output that is connected to the noise quantifier 204. The noise quantifier 204 receives the output of the noise pass filter 203, and has a maximum noise output and a zero offset output that are connected to the damping adjuster 205. The damping adjuster 205 also receives the maximum flow value, receives the maximum noise output and the zero offset outputted from the noise quantifier 204, and receives an error value outputted from the filter element 206. The damping adjuster 205 has a damping value output. The filter element 206 receives the normalized flow meter signal (i.e., a second version of the flow meter signal) outputted from the normalizer 201 and the damping value outputted from the damping adjuster 205, and has as outputs the error value and a filtered flow meter signal with the noise damped out. The scaler 202 receives the filtered flow meter signal that is outputted from the filter element 206 and also receives a version of the maximum flow value, and outputs a scaled, filtered version of the flow meter signal. In operation, a flow meter signal is input into the flow meter filter system 200. The flow meter filter system 200 measures noise characteristics of the noise, and from the noise characteristics determines a damping value that is input into the filter element 206. The filter element 206 damps the flow meter signal according to the damping value. The noise, such as cross-talk noise, is typically of a faster frequency/response time than the flow meter data output and therefore is damped out by the filter element 206. The flow meter filter system 200 therefore removes the noise without substantially affecting or degrading the flow meter data. In addition to filtering cross-talk noise, the flow meter filter system 200 is also capable of minimizing external noise from other sources, such as from physical movement or vibration. For example, a positive displacement pump puts cyclic variation into the flow being measured. In some cases, it is advantageous to eliminate this cyclic noise in order to measure and report only the average flow signal. Damping refers to preventing changes in signal swing based on frequency. Damping can be used to remove a noise signal when the noise signal is changing at a faster rate than an underlying flow meter signal. Damping can therefore remove a noise signal superimposed on a flow meter data signal. The damping value can be selected from a table, for example. The selection can be based on one or more inputs, such as a noise amplitude range (see Table 1 and accompanying discussion below). In a digital filter embodiment, the damping value can represent filter coefficients. However, in order to prevent the damping from adversely influencing/degrading the flow meter signal when a flow rate change occurs, the damping value can be selected to be less during a transition in the flow meter signal. A transition is a relatively large or rapid change in the flow meter data. For example, a transition can occur when a flow meter is taken on-line or off-line, when the quantity of flow material passing through a flow meter changes by a significant amount, when bubbles or pockets of gas are present in a liquid flow material, etc. In one embodiment, the response time of the flow meter filter system 200 is reduced during transitions. Therefore, the noise is damped out at a lesser level until the transition has passed and the flow meter signal has again become substantially quiescent (i.e., stable). At that time, the damping value can be increased. The damping according to the invention is therefore dynamically controlled in order to optimally damp out most or all of the noise signal. The normalizer 201 converts the flow meter signal into a normalized flow meter signal, based upon the inputted maximum flow value. The maximum flow value is an upper limit on the flow meter signal, and can be a value determined by a calibration process, set according to a meter type or a flow material type, etc. The maximum flow value can be a constant, or can be time-variable and changeable. Using the maximum flow value, the normalizer 201 normalizes the flow meter signal input to be no greater than the maximum flow value. This can be done so that the flow meter filter system 200 can be used with any type of flow meter and any flow signal level, i.e., the flow meter filter system 200 is independent of the type of flow meter and the flow conditions. In one embodiment, the normalization is done according to the formula: Normalized_Flow = Flow_Meter ⁢ _Signal Max_Flow ⁢ _Value ( 1 ) The scaler 202 is the complement of the normalizer 201. The scaler 202 receives the filtered, normalized flow meter signal from the filter element 206 and scales it back to substantially the same amplitude as the inputted flow meter signal. This is done by multiplying the filtered output by the maximum flow value. The multiplication by the maximum flow value is the complement of the division of the flow meter signal by the maximum flow value in the normalizer 201. The noise pass filter 203 receives the non-normalized flow meter signal (a second version) and passes only a noise signal (i.e., the flow meter data is blocked). The purpose of the noise pass filter 203 is to determine the magnitude of any cross-talk noise present in the flow meter signal. The noise pass filter 203 can be any filter that substantially passes frequencies in the range of about 0.025 Hertz (Hz) to about 1 Hz, such as an implementation of a high pass or band-pass filter, for example. In one embodiment, the noise pass filter 203 comprises an Alternating Current (AC) coupling filter (i.e., an analog filter). In another embodiment the noise pass filter 203 comprises an Infinite Impulse Response (IIR) digital filter, including a second-order IIR digital filter. The noise pass filter 203 preferably has filter coefficients that have been selected to provide unity gain and a zero phase for frequencies above 0.025 Hz. In one embodiment, the noise pass filter 203 has a transfer function represented by: H ⁡ ( Z ) = 0.9993 - 1.9986 * Z - 1 + 0.9993 * Z - 2 1 - 1.9986 * Z - 1 + 0.9986 * Z - 2 ( 2 ) where the Z transform variable Z−1 is a previous output at time (t−1), the Z transform variable Z−2 is a previous output at time (t−2), and the numerical values 0.9993, 1.9986, etc., are the filter coefficients. The Z transform variable is commonly used to represent; Z=e−jω (3) It should be understood that the numerical filter coefficients given above are just an example provided for illustration, and the invention is not limited to the values given. The filter coefficients can be varied according to the type of filter, the number of filters generating noise, flow conditions, environmental conditions, etc. Noise Pass Filter Magnitude and Phase Graphs—FIG. 3 FIG. 3 shows the magnitude and phase responses for the noise pass filter 203 according to one embodiment of the invention. In the example shown, the frequency has been normalized to a value of one. Because the noise pass filter 203 response at the low end of the frequency range is the main concern, it is possible in a digital filter embodiment to improve the performance of the noise pass filter 203 by adjusting the sampling rate of the input signal. Ideally, the noise pass filter 203 should not attenuate the noise signal component and would output a noise component having a magnitude of 0 dB and a zero degree phase shift at frequencies above 0.025 Hz. With a 20 Hz sampling rate, the output magnitude of a 0.20 Hz noise signal in an actual digital filter implementation has been measured at about −0.22 dB. With a sampling rate of 5 Hz, the magnitude has been measured at about −0.0141 dB, a significant improvement. However, a down side of a slower sampling rate is a larger delay in response time. The sampling rate is therefore an adjustable parameter that can be configured during calibration or during operation. Referring again to FIG. 2, the noise quantifier 204 measures the noise signal outputted by the noise pass filter 203 and generates noise characteristics of the noise signal. In one embodiment, the noise quantifier 204 measures a maximum noise level and a zero offset level of the noise signal (i.e., an offset from zero of an average noise content). The zero offset/average noise content serves as an indicator as to whether the noise pass filter 203 has settled down to a substantially constant (i.e., quiescent) state (see FIG. 8 and the accompanying discussion). The noise quantifier 204 in one embodiment accumulates noise data over a sample period and measures the noise characteristics for the sample period. This can be done in order to accurately characterize the noise and to prevent noise anomalies from unduly affecting the characterization. Since the slowest expected noise signal is defined as at least 0.025 Hz (which gives a wave period of 40 seconds), it is important to compute the average noise content value on a sample that contains at least 40 seconds of data. The damping adjuster 205 generates a damping value that is used to damp the noise out of the flow meter signal. The purpose of the damping adjuster 205 is to adaptively change the damping value of the filter element 206 based on current noise levels and current flow variations. The damping adjuster 205 receives as inputs the noise characteristics from the noise quantifier 204 and the maximum flow value, along with an error value generated by the filter element 206. The error value comprises feedback on how completely the noise is being damped out of the normalized flow meter signal. The damping adjuster divides the zero offset by the maximum flow value in order to determine whether the noise signal is substantially centered around zero (i.e., the damping adjuster 205 determines if the average noise content is below a predetermined quiescent threshold). One embodiment of the damping adjuster 205 is discussed in detail below in conjunction with FIG. 7. The damping adjuster 205 in one embodiment uses the inputted noise and error values as inputs into a damping values table and looks up an appropriate damping value. Table 1 below is an example of one embodiment of a damping value table. TABLE 1 Damping Value Lower Range Upper Range 0 NC * (1 + RC * 0.256) 1 NC * (1 + RC * 0.128) NC * (1 + RC * 0.256) 2 NC * (1 + RC * 0.064) NC * (1 + RC * 0.128) 4 NC * (1 + RC * 0.032) NC * (1 + RC * 0.064) 8 NC * (1 + RC * 0.016) NC * (1 + RC * 0.032) 16 NC * (1 + RC * 0.008) NC * (1 + RC * 0.016) 32 NC * (1 + RC * 0.004) NC * (1 + RC * 0.008) 64 NC * (1 + RC * 0.002) NC * (1 + RC * 0.004) 128 NC * (1 + RC * 0.001) NC * (1 + RC * 0.002) 256 NC * (1 + RC * 0.0005) NC * (1 + RC * 0.001) 512 NC * (1 + RC * 0.0005) where NC is the normalized noise data constant which is the noise floor and RC is a predetermined scaling constant. The predetermined scaling constant RC is an optional feature, and can be included in order to make global scaling changes to the table. The normalized error value is compared to the lookup table to determine the damping value. The damping adjuster 205 in one embodiment can ramp the damping value from a current damping value to a new damping value, and may not immediately make a full change in the damping value. While it is important to allow quick transitions from slow to fast damping values, it is also important to limit how fast the damping adjuster 205 moves back to slow damping values. If the new damping value is faster than the preceding damping value (i.e., it is a smaller damping value), then the new damping value gets sent directly to the filter element 206. However, if the new damping value is slower than the preceding damping value (i.e., it is a larger damping value), then the outputted damping value is slowly ramped up to the new damping value (see FIG. 7 and the accompanying discussion). The filter element 206 is configured to receive the damping value and damp the normalized flow meter signal. The filter element 206 in one embodiment comprises a second-order filter. In another embodiment, the filter element 206 comprises an IIR digital filter, including a second-order IIR digital filter. An advantage of using a digital filter, as opposed to an analog filter, is that the digital filter can be dynamically controlled during operation. Therefore, the amount of damping can be changed in order to optimally remove noise without influencing the flow meter data signal. In one embodiment, the filter element 206 comprises a second-order IIR digital filter that has the transfer functions of: X t = X t - 1 + ( U t - X t - 1 ) Damping_Value ( 4 ) and Y t = Y t - 1 + ( X t - Y t - 1 ) Damping_Value ( 5 ) Where t is a time sample value, Ut is a current input sample, Xt is determined from the current input sample Ut and a previous X value Xt−1, and Yt is defined as the output determined from the current input sample Ut, the computed value Xt, and the previous output value Yt−1. A digital filter such as the one described above can be implemented in a processing system, such as in a Digital Signal Processor (DSP) device, for example. Flow Meter Filtering Method—FIG. 4 FIG. 4 is a flowchart 400 of a method of removing noise from a flow meter signal according to an embodiment of the invention. In step 401, a flow meter signal is received. The flow meter signal can be pre-processed in any manner, including normalization of the flow meter signal. In step 402, if the flow meter signal is substantially quiescent, the method branches to step 403; otherwise the method branches to step 404. In step 403, because the flow meter signal is substantially quiescent, a large damping value is applied to the flow meter signal. Because the flow meter signal is changing relatively slowly, a large amount of damping can be applied without affecting the flow meter data in the flow meter signal, and only the noise component of the flow meter signal is attenuated by the heavy damping. In step 404, because the flow meter signal is experiencing large or rapid changes in value, a small damping value is applied to the flow meter signal. In this manner, the noise component of the flow meter signal is substantially removed but without affecting the flow meter data. Flow Meter Filtering Method—FIG. 5 FIG. 5 is a flowchart 500 of a method of removing noise from a flow meter signal according to another embodiment of the invention. In step 501, a flow meter signal is received, as previously discussed. In step 502, the flow meter data is substantially filtered out of a first version of the flow meter signal in order to obtain a substantially pure noise signal. The measurement can be performed in order to characterize the noise and dynamically damp the noise out of the flow meter signal. For example, the data can be removed by a high pass or band-pass filter, as previously discussed. In step 503, the noise is measured and noise characteristics are thereby obtained. The noise characteristics can include a maximum noise amplitude and a zero offset, as previously discussed. It should be understood that the noise characteristics are dynamic and can change over time. For example, the noise characteristics commonly vary when other flow meters are connected in the process line and therefore generating cross-talk noise. However, other noise sources are also contemplated, such as environmental noise from pumping equipment, for instance. In step 504, a damping value is determined from the current noise characteristics. The damping value represents an amount of damping that will substantially remove the noise from the flow meter signal but without substantially impacting the flow meter signal. In step 505, the damping value and the flow meter signal are inputted into a filter element 206 and the filter element 206 damps out the noise using the damping value. In addition, the damping can be ramped from a current damping value to a new damping value. Graph of Damping Effect—FIG. 6 FIG. 6 is a graph that illustrates damping removal of noise from a flow meter signal. The graph includes a flow meter signal 601 and a noise signal 602. It can be seen from the figure that when the noise signal 602 is damped out, the flow meter signal 601 can approximate a square wave. When a step change occurs at time 605, the filter system's response time changes to a very fast response time filter. During this time, the filtered signal will more closely resemble the original flow meter signal until eventually the filter system 200 reverts back to a heavily damped signal. Damping Adjuster—FIG. 7 FIG. 7 is a diagram of the damping adjuster 205 according to an embodiment of the invention. The damping adjuster 205 in this embodiment includes absolute value blocks 701 and 703, product blocks 702 and 706, switching blocks 704 and 710, unit delay blocks 705 and 712 (such as 1/Z unit delay blocks, for example), an interface 707, a damping value block 708, a relational operator block 709, and a damping delay coefficient block 711. The damping adjuster 205 includes the error, maximum noise, maximum flow value, and zero offset inputs as previously discussed, and outputs the damping value. The product block 702 divides the zero offset by the maximum flow value in order to generate a noise value. The noise value is representative of the average noise content and indicates the distance from the noise signal to zero. If this noise value is less than a predetermined quiescent threshold, then the noise level is determined to be substantially quiescent and is therefore accurate enough to be used in the damping value lookup block 708. The absolute value blocks 701 and 703 take the absolute values of their respective inputs. The absolute value block 703 outputs a positive noise value to the switching block 705. The absolute value block 701 outputs a positive error value to the interface 707. The switching block 704 receives the maximum noise value, the noise value, and a unit delay produced by the unit delay block 705. The switching block 704 is configured to output the noise value if the noise value is less than the maximum noise value, and output the maximum noise value otherwise. In addition, the switching block 704 can output the previous switch output (from the unit delay block 705) when not outputting either the noise value or the maximum noise value. The output of the switching block 704 is connected to the input of the unit delay block 705 and to the product block 706. The product block 706 also receives the noise value and the maximum flow value. The product block 706 divides the maximum flow value by the noise value in order to produce a normalized noise value that is outputted to the interface 707. The interface 707 passes the normalized error signal and the normalized noise signal to the damping value lookup block 708. The interface 707 in one embodiment multiplexes the normalized noise signal and the normalized error signal into a vector format, wherein the damping value lookup block 708 receives a single input. The damping value lookup block 708 generates the damping value from the normalized error and normalized noise inputs. In one embodiment, the damping value lookup block 708 performs a table lookup in order to obtain the damping value, such as Table 1, discussed in conjunction with FIG. 2, above. The damping value lookup block 708 outputs the damping value to the relational operator block 709. The final stage of the damping adjuster 205 (i.e., the components 709-712) control the rate at which the damping value can be changed. The relational operator block 709 compares the new damping value (outputted by the damping value lookup block 708) to the current damping value available at the output of the damping adjuster 205. The relational operator block 709 generates a relational output that indicates whether the new damping value is smaller than the current damping value. The switching block 710 has as inputs the new damping value, the current damping value, and the relational output. The switching block 710 is configured to select and output either the new damping value or the current damping value, depending on the relational output. If the new damping value is smaller than the current damping value, then the switching block 710 feeds the new damping value directly to the output. However, if the new damping value is larger than the current damping value, then the switching block 710 channels the new damping value through the damping delay coefficient 711 and the unit delay 712 and ramps the damping value output from the current damping value to the new damping value by multiplying the new damping value by a delay coefficient. The switching block 710 outputs the selected damping value to the damping delay coefficient 711. The damping delay coefficient 711 defines a damping rate and controls how quickly the damping adjuster 205 can ramp to the new damping value. The damping delay coefficient 711 in one embodiment is a number slightly larger than one. The output of the damping delay coefficient 711 is inputted into the unit delay 712. The unit delay 712 delays the damping value by a predetermined delay period. The predetermined delay period can be a constant value, for example, or can be obtained from a table. The output of the unit delay 712 is the damping value output of the damping adjuster 205. The damping adjuster 205 therefore generates the damping value based on the noise characteristics and on the damping delay coefficient 711. Graph of Damping Values—FIG. 8 FIG. 8 is a graph of various damping values that can be implemented in the flow meter filter system 200 according to an embodiment of the invention. The figure shows normalized flow rate over time for various damping values. It can be seen that a damping value can be selected not only based on the desired amount of damping, but on the time period required in order to achieve the desired noise damping. For example, a damping value of 1 has a much faster response than a damping value of 256. Graph of Damping Value Ramping—FIG. 9 FIG. 9 is a graph that shows a ramping of the damping value according to an embodiment of the invention. The straight line 900 is a desired damping value, while the curve 901 is a damping value that is being ramped up over time. The ramping rate can be selected in order to ramp from a beginning point to the target damping value over a predetermined period of time. Advantageously, the flow meter filtering according to the invention enables noise to be filtered out of a flow meter signal, including cross-talk noise. The filtering is accomplished without degrading the flow meter data in the flow meter signal. In addition, the filtering accommodates data transitions in the flow meter data. Another advantage provided by the invention is size. Analog filters constructed for low frequencies typically require physically large components. A digital filter implementation according to some of the described embodiments accomplishes more optimal filtering, but with physically smaller components. In some embodiments, the flow meter filter system 200 can be implemented in an Application Specific Integrated Circuit (ASIC), for example. Another advantage of using a digital filter, as opposed to an analog filter, is that the digital filter can be dynamically controlled during operation. The filtering can be dynamically controlled according to noise conditions and according to flow conditions/levels. Therefore, the amount of damping can be changed in order to optimally remove noise without influencing the flow meter data signal. This is in contrast to an analog filtering scheme, wherein a fixed amount of filtering is performed. Such a fixed filtering scheme only works well when the data signal and the noise signal are predictable and well-behaved.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The invention is related to the field of removing noise from a flow meter signal, and in particular, to removing cyclic noise, such as cross-talk noise, from the flow meter signal. 2. Statement of the Problem Flow meters are used to measure the mass flow rate, density, and other information for flowing materials. The flowing materials can include liquids, gases, combined liquids and gases, solids suspended in liquids, and liquids including gases and suspended solids. For example, flow meters are widely used in the well production and refining of petroleum and petroleum products. A flow meter can be used to determine well production by measuring a flow rate (i.e., by measuring a mass flow through the flow meter), and can even be used to determine the relative proportions of the gas and liquid components of a flow. In a production or processing environment, it is common to have multiple flow meters connected to the same process line and/or mounted in such a manner that vibration from one flow meter can reach another flow meter. Although this results in efficiency in measuring flow, the multiple flow meters can interfere with each other in the form of cross-talk noise. Cross-talk is a phenomena when the flow meter signal from a first meter influences and corrupts a flow meter signal from a second flow meter (and vice versa). Cross-talk noise in a flow meter environment commonly is a relatively large, slow-moving signal typically no faster than 1 Hertz (Hz). The noise can degrade accuracy of the flowmeter signal and can lead to extremely large indicated flow errors. In addition, noise can occur due to other factors and other sources. FIG. 1 is a graph of a flow meter output signal taken over time. The figure shows how a flow meter signal is influenced by other flow meters. The time periods 101 and 103 in the figure show a flow meter signal when three flow meters are generating output, with two other flow meters therefore generating cross-talk noise in the current flow meter output. Time period 102 is a flow meter signal when only one other interfering flow meter is active. Note that the generated noise varies in both amplitude and frequency throughout the graph. The prior art has attempted to address noise and cross-talk noise through use of traditional filtering techniques, such as high-pass filtering. However, due to the relatively small difference in frequencies between cross-talk noise and the actual flow meter data, and due to the low frequency data signals outputted by flow meters, it has been difficult to remove noise without degrading the flow meter data.

<SOH> SUMMARY OF THE SOLUTION <EOH>The invention helps solve the above problems with removing noise from a flow meter signal. A flow meter filter system ( 200 ) is provided according to an embodiment of the invention. The flow meter filter system ( 200 ) comprises a noise pass filter ( 203 ) configured to receive a first version of a flow meter signal and filter out the flow meter data from the flow meter signal to leave a noise signal. The flow meter filter system ( 200 ) further comprises a noise quantifier ( 204 ) configured to receive the noise signal from the noise pass filter ( 203 ) and measure noise characteristics of the noise signal. The flow meter filter system ( 200 ) further comprises a damping adjuster ( 205 ) configured to receive the noise characteristics from the noise quantifier ( 204 ) and generate a damping value based on the noise characteristics. The flow meter filter system ( 200 ) further comprises a filter element ( 206 ) configured to receive a second version of the flow meter signal and receive the damping value from the damping adjuster ( 205 ), with the filter element ( 206 ) being further configured to damp the second version of the flow meter signal based on the damping value in order to produce a filtered flow meter signal. A method of removing noise from a flow meter signal is provided according to an embodiment of the invention. The method comprises the steps of receiving the flow meter signal, applying a large damping value to the flow meter signal in order to produce a filtered flow meter signal if the flow meter signal is substantially quiescent, and applying a small damping value to the flow meter signal in order to produce the filtered flow meter signal if the flow meter signal is experiencing a transition. A method of removing noise from a flow meter signal is provided according to an embodiment of the invention. The method comprises the steps of receiving the flow meter signal, filtering a noise signal substantially out of a first version of the flow meter signal, measuring the noise signal to obtain noise characteristics, determining a damping value from the noise characteristics, with the damping value being selected to substantially remove the noise signal from the flow meter signal, and damping the noise substantially out of a second version of the flow meter signal using the damping value in order to produce a filtered flow meter signal. One aspect of the invention comprises normalizing the flow meter signal from an original value to a normalized value prior to the damping, and scaling the filtered flow meter signal of the damping step substantially back to the original flow meter signal magnitude. In another aspect of the invention, the method determines an error value between the second version of the flow meter signal and the filtered flow meter signal, and feeds the error value back into the determining of the damping value, wherein the error value is included in the damping value determination. In another aspect of the invention, the noise pass filter and the filter element comprise digital filters. In another aspect of the invention, the noise pass filter and the filter element comprise Infinite Impulse Response (IIR) digital filters. In another aspect of the invention, the noise pass filter and the filter element comprise second-order IIR digital filters. In another aspect of the invention, the damping adjuster is further configured to generate the damping value based on the noise characteristics and on a damping delay coefficient. In another aspect of the invention, the flow meter signal comprises a Coriolis flow meter signal.

20060221

20070814

20061123

72121.0

G01F2500

TSAI, CAROL S W

FLOW METER FILTER SYSTEM AND METHOD

UNDISCOUNTED

ACCEPTED

G01F

ACCEPTED

Methods and Systems for Facilitating Transactions Between Commercial Banks and Pooled Depositor Groups

Methods and systems for facilitating transactions (200) between commercial banks and pooled depositor groups are disclosed. Employees of a control center determine interest rate return needs of pooled depositor groups (210), such as trust departments at commercial banks. The control center employees aggregate (204) the funds to produce a stable funds source and communicate the availability of the stable funds source to commercial banks for core deposits (210). The commercial banks communicate cash needs to the control center (202). The control center sets an interest rate (206) to be paid to the pooled depositor groups for use of the funds to at least the depositor groups'expected rate of return and below and the rate that commercial banks are willing to pay for the funds. The banks post master NOW accounts and the pooled depositor groups deposit funds in the master NOW accounts (212).

1. (canceled) 2. (canceled) 3. (canceled) 4. (canceled) 5. A method for facilitating financial transactions between depositor groups and commercial banks, the method comprising: (a) determining deposit needs of a plurality of depositor groups; (b) aggregating the deposit needs of the depositor groups to provide a stable funds source; (c) notifying commercial banks of the availability of the stable funds source and an amount of funds available in the stable funds source; (d) setting an interest rate to be paid to the depositor groups to a predetermined value based on an interest rate that the commercial banks are willing to pay for the stable funds source and an interest rate the depositor groups expect as a return for use of funds in the stable funds source; (e) receiving account postings from the commercial banks; (f) depositing funds from the stable funds source in the accounts; and (g) allowing the depositor groups to withdraw funds from the accounts on a demand basis without penalty, wherein determining deposit needs of a plurality of depositor groups includes determining deposit needs of different corporations and wherein aggregating the deposit needs includes aggregating funds from the corporations. 6. (canceled) 7. (canceled) 8. (canceled) 9. A method for facilitating financial transactions between depositor groups and commercial banks, the method comprising: (a) determining deposit needs of a plurality of depositor groups; (b) aggregating the deposit needs of the depositor groups to provide a stable funds source; (c) notifying commercial banks of the availability of the stable funds source and an amount of funds available in the stable funds source; (d) setting an interest rate to be paid to the depositor groups to a predetermined value based on an interest rate that the commercial banks are willing to pay for the stable funds source and an interest rate the depositor groups expect as a return for use of funds in the stable funds source; (e) receiving account postings from the commercial banks; (f) depositing funds from the stable funds source in the accounts; and (g) allowing the depositor groups to withdraw funds from the accounts on a demand basis without penalty, wherein setting the interest rate to be paid to the depositor groups to a predetermined value includes setting the interest rate to a value equal to the interest rate that the commercial banks are willing to pay for the funds. 10. (canceled) 11. (canceled) 12. The method of claim 9 comprising receiving incoming deposits and withdrawal requests from the depositor groups, satisfying the incoming withdrawal requests using the incoming deposits, and updating account records to change ownership of deposited funds without withdrawing funds from the commercial banks. 13. (canceled) 14. The method of claim 9 wherein depositing funds in the accounts includes depositing funds in excess of a federal deposit insurance limit from a single depositor group in a master NOW account of a single commercial bank and providing federal deposit insurance or a collateral for the entire deposit. 15. The method of claim 9 wherein the commercial banks report the funds deposited in the accounts as core deposits. 16. The method of claim 9 wherein the depositor groups comprise pooled depositor groups and wherein the accounts comprise master negotiated order of withdrawal accounts. 17. (canceled) 18. A method for facilitating financial transactions between commercial banks and depositors, the method comprising: (a) receiving deposit account postings from a plurality of different commercial banks; (b) determining a deposit need of at least one depositor; and (c) matching the deposit need with the deposit account postings in a manner that provides deposit insurance for funds deposited by the depositor. 19. The method of claim 18 wherein the depositor comprises an individual entity. 20. The method of claim 19 wherein the individual entity comprises a human being. 21. The method of claim 19 wherein the individual entity comprises a corporation. 22. The method of claim 18 wherein matching the deposit need with the deposit account posting includes auctioning available deposits to the commercial banks. 23. (canceled) 24. (canceled) 25. (canceled) 26. (canceled) 27. A computer program product comprising computer-executable instructions embodied in a computer-readable medium for performing steps comprising: (a) determining deposit needs of a plurality of depositor groups; (b) aggregating the deposit needs of the depositor groups to provide a stable funds source; (c) notifying commercial banks of the availability of the stable funds source and an amount of funds available in the stable funds source; (d) setting an interest rate to be paid to the depositor groups to a predetermined value based on an interest rate that the commercial banks are willing to pay for the stable funds source and an interest rate the depositor groups expect as a return for use of funds in the stable funds source; (e) receiving account postings from the commercial banks; (f) depositing funds from the stable funds source in the accounts; and (g) allowing depositor groups to withdraw funds from the accounts on a demand basis without penalty, wherein determining deposit needs of a plurality of depositor groups includes determining deposit needs of different corporations and wherein aggregating the deposit needs includes aggregating funds from the corporations. 28. (canceled) 29. (canceled) 30. (canceled) 31. A computer program product comprising computer-executable instructions embodied in a computer-readable medium for performing steps comprising: (a) determining deposit needs of a plurality of depositor groups; (b) aggregating the deposit needs of the depositor groups to provide a stable funds source; (c) notifying commercial banks of the availability of the stable funds source and an amount of funds available in the stable funds source; (d) setting an interest rate to be paid to the depositor groups to a predetermined value based on an interest rate that the commercial banks are willing to pay for the stable funds source and an interest rate the depositor groups expect as a return for use of funds in the stable funds source; (e) receiving account postings from the commercial banks; (f) depositing funds from the stable funds source in the accounts; and (g) allowing depositor groups to withdraw funds from the accounts on a demand basis without penalty, wherein setting the interest rate to be paid to the depositor groups to a predetermined value includes setting the interest rate to a value equal to the interest rate that the commercial banks are willing to pay for the funds. 32. (canceled) 33. (canceled) 34. The computer program product of claim 31 comprising receiving incoming deposits and withdrawal requests from the depositor groups, satisfying the incoming withdrawal requests using the incoming deposits, and updating account records to change ownership of deposited funds without withdrawing funds from the commercial banks. 35. (canceled) 36. The computer program product of claim 31 wherein depositing funds in the accounts includes depositing funds in excess of a federal deposit insurance limit from a single depositor group in a master NOW account of a single commercial bank and providing federal deposit insurance or collateral for the entire deposit. 37. The computer program product of claim 31 wherein the commercial banks report the funds deposited in the accounts as core deposits. 38. The computer program product of claim 31 wherein the depositor groups comprise pooled depositor groups and wherein the accounts comprise master negotiated order of withdrawal accounts. 39. (canceled) 40. (canceled) 41. (canceled) 42. (canceled) 43. (canceled) 44. (canceled) 45. (canceled) 46. (canceled) 47. (canceled) 48. (canceled) 49. (canceled) 50. (canceled) 51. (canceled) 52. (canceled) 53. (canceled) 54. (canceled) 55. (canceled) 56. (canceled) 57. (canceled) 58. (canceled) 59. (canceled) 60. (canceled)

RELATED APPLICATIONS This application is a continuation-in-part of U.S. patent application Ser. No. 10/645,778 filed Aug. 21, 2003, the disclosure of which is incorporated herein by reference in its entirety. TECHNICAL FIELD The present invention relates to methods, systems, and computer program products for facilitating financial transactions between commercial banks and pooled depositor groups. More particularly, the present invention relates to methods and systems for providing liquid deposit opportunities for pooled depositor groups and for providing deposit funds from the pooled depositor groups to commercial banks that the commercial banks may be permitted by regulatory authorities to count as stable deposits. BACKGROUND ART In the banking industry, it is desirable to maintain a certain percentage of core deposits. Core deposits are deposits that do not change significantly in amount with fluctuations in the interest rate paid on the deposits. Savings account deposits are one example of a bank's core deposits. In the United States, the percentage of core deposits affects the bank's ability to maintain a favorable regulatory rating. In addition to core deposits, banks often rely on non-core funding sources, such as brokered CDs. Brokered CDs are offered by a bank to retail customers through a deposit broker. Brokered CDs are less stable as a source of funds for banks than core deposits because depositors in brokered CDs are typically sensitive to interest rate fluctuations. Another problem with using brokered CDs to obtain cash is that in the United States, if a bank maintains too high of a percentage of brokered deposits, the bank may be sanctioned by a regulatory agency, such as the Federal Reserve for federally chartered banks or a state banking agency for state chartered banks. Yet another problem associated with using brokered deposits is that banks are required to pay a broker's commission for brokered deposits. Thus, in the banking industry, there exists a need for a new way for banks to obtain stable funds. Pooled depositor groups, such as trust departments, pension funds, government entities, insurance companies, and any entities that are allowed to make deposits into a negotiated order of withdrawal (NOW) account, are constantly looking for safe, insured deposit vehicles for their funds. In addition, it is desirable for individual depositors in a pooled depositor group to be able to access funds without penalty on a short-term basis. Conventionally, pooled depositor groups have invested in money market funds. However, investing in money market funds is undesirable because money market funds have historically paid low interest rates. Certificates of deposit are undesirable because money is not accessible on a short-term basis without paying a penalty. In addition, under current FDIC regulations, an individual's deposits at a single institution in excess of $100,000 are not federally insured. As a result, in order to fully insure a depositor's funds, a trust department is required to divide a depositor's assets in excess of $100,000 among multiple banks. Accordingly, in light of these difficulties associated with conventional cash management vehicles, there exists a need for an insured or collateralized deposit vehicle for pooled depositor groups. Other entities, such as individual depositors (including corporations and human beings) may also seek insured, liquid deposit opportunities for their funds. These entities face the same difficulties as those described above for pooled depositor groups. Accordingly, there exists a need for an insured or collateralized deposit vehicle for individual depositors. Yet another problem that exists in financial transactions is unrelated to insurance. It may be desirable to provide a method for depositors to spread deposits among multiple commercial banks for security reasons. For example, it may be desirable for depositors to deposit funds in commercial banks in different countries to avoid risks associated with economic and political instability. Currently there is no efficient system for matching depositors' deposit needs to commercial banks' cash flow needs when the banks are located in different countries. Accordingly, there exists a long felt need for improved methods and systems for allowing depositors to distribute deposits among commercial banks. DISCLOSURE OF THE INVENTION In order to address the aforementioned problems associated with providing cash to commercial banks and providing insured, liquid deposit opportunities for pooled depositor groups and individual depositors, one aspect of the invention includes a method and associated computer software for facilitating transactions between depositors and commercial banks. In one exemplary method, banks and depositors register with a control center. Control center employees may solicit deposit cash from different depositors and aggregate the deposit cash of the multiple pooled depositor groups to produce a stable source of funds. Alternatively, if a single depositor has a large amount of excess cash that the entity is willing to deposit, aggregation of cash from different sources may not be required. The control center may then notify banks of the stable source of funds and inquire as to the interest rate that banks are willing to pay for the stable source of funds. In order to receive funds from the stable source of funds, a bank will post a deposit account with an appointed custodian. For government entities, trust departments, pension funds, and non-profit organizations, the deposit account may be a master NOW account. For other entities, such as individuals (including human beings or corporations), the deposit account may be a money market deposit account (MMDA) or other time or interest bearing deposit accounts. The control center sets an interest rate to be paid on the deposit accounts based on the rate that the bank is willing to pay for all or a portion of the stable funds source and the rate of return that the depositors expect on their deposits. The control center notifies the depositors of the availability of the deposit account at the specified interest rate. The depositor then deposits funds in the deposit account. The control center monitors transactions between the depositors and the custodian and between the custodian and the banks and generates reports. Because the control center can aggregate deposit funds of multiple pooled depositor groups, the pooled depositor groups should be able to offer a stable source of funds to commercial banks. As a result, banks are permitted to treat the funds received from the pooled depositor groups as stable deposits. In addition, money deposited in the master NOW accounts are FDIC insured up to $100,000 for any single depositor within the pooled depositor group. Through the control center, funds in excess of $100,000 to any single depositor are deposited in separate banks to insure FDIC coverage or the banking institution collateralizes the funds in excess of $100,000. However, by using a master NOW account, funds from a depositor group in excess of $100,000 can be fully insured provided that funds from individual depositors within the group do not exceed $100,000, as per a recent statement from the FDIC. Thus, if a depositor group of 100 depositors with $50,000 each deposits funds in a master NOW account with a single bank, the entire amount will be FDIC insured. Another advantage of using master NOW accounts is that depositors are allowed to withdraw money from a master NOW account on a daily basis without penalty. As a result, using master NOW accounts provides a liquidity advantage over conventional certificates of deposit. The following definitions apply to the corresponding terms used herein: 1. Commercial bank: A bank chartered by a state or federal agency with the ability to receive time and demand deposits, to make commercial and mortgage loans, and to have insured deposits. In the United States, the deposits of a commercial bank are insured by the Federal Deposit Insurance Corporation (FDIC). 2. NOW account: A NOW account refers to a negotiated order of withdrawal account, which is an account with a commercial bank that permits unlimited activity with regard to deposits and withdrawals. 3. Master NOW account: A NOW account having a predetermined limit as to the total amount that can be deposited against the account. This limit may be determined by an agreement between the commercial bank posting the account and the control center. 4. Custodian: An entity, such as a bank, with the power granted by a state or federal agency to hold assets on behalf of a pooled depositor group or a commercial bank. 5. Core deposit: A class of deposits deemed by an agency, such as the FDIC, to be stable (constant, minimum fluctuation in total amount, and available at a reasonable cost.) 6. Pooled depositor group: A group of individuals or entities that pool funds for deposit purposes and that are permitted to deposit funds in a NOW account. Examples of pooled depositor groups include trust departments, pension funds, and government entities. Currently, commercial businesses are not permitted to deposit funds in a NOW account. 7. Certificate of deposit: A certificate showing evidence of funds deposited for a specific period of time at a specific rate. The funds in a CD are not available for early withdrawal without specified penalties. CDs in excess of $100,000 are negotiable and are traded by dealers in money market investments. 8. Control center: A point through which information flows for controlling transactions between commercial banks and pooled depositor groups is controlled. 9. Stable funds: Pooled funds offered to commercial banks that preferably do not fluctuate significantly in amount as the interest rate changes. 10. Hot funds: Funds available from a pooled depositor group for a short-term deposit or a specific transaction. A different rate may be negotiated for each transaction. 11. Term funds: Funds available from a pooled depositor group offered to investment entities that need money for specified terms, such as 30 days, 60 days, 90 days, or 120 days. Conventionally, such funds have gone into CDs. However, community banks can pay higher rates for these funds because they are instant and avoid going to the brokerage CD market. Rates may be negotiated on individual transactions. As indicated above, the custodian's duties are to hold assets on behalf of pooled depositor groups and commercial banks. In addition custodians may have the following duties: 1. Establish a custody account for the control center in which the following transactions will be reflected. 2. Within the custody account, establish an asset record for each commercial bank master NOW account. The asset amount will reflect the total deposit by all depositors in each NOW account. The control center will provide instructions regarding the setup of new NOW accounts within a reasonable period of time prior to the funding of particular NOW accounts. 3. Receive funds transfers, such as federal wire transfers and automated clearing house transfers, on a daily basis from various depositors who have signed agreements with the control center. The funds must be received within a reasonable period of time to be invested on the same day. 4. In conjunction with each incoming wire, accept written direction from the control center (e.g., by fax or e-mail) with regard to the application of funds. Direction must be received within a reasonable period of time for same-day deposit and will include the amount to be received and the name of the bank to which funds will be wired (for deposit-purchase into the selected NOW account). If volumes increase dramatically, the deadline for directions may be changed to an earlier time. 5. Wire funds received within a reasonable period of time from depositors to various commercial banks on a daily basis, as instructed by the control center, before the close of business on the day the funds are received. 6. Reconcile holdings in the custody account to statements received from NOW account issuers (commercial banks). 7. As earnings are added to NOW accounts each month, post the addition of those earnings to each NOW account held in the custody account in order to bring the custody account holdings current with issuing commercial bank records. 8. As depositors request funds, withdraw principal from various NOW accounts on a daily basis (e.g., via funds wires) as instructed by the control center. 9. Wire withdrawn monies back to depositors on a daily basis as instructed by the control center. 10. Once a month, receive by wire an earnings spread on the NOW accounts from each issuing commercial bank and wire to the control center the earnings spread minus the custodian fee. The earnings spread will be determined on each NOW account by the control center. The control center may choose a different method for distribution: the earnings spread may be wired directly to the control center by the issuing commercial bank, rather than through the custodian. If this method of payment is chosen, the custodian will send a monthly invoice to the control center, which will be paid within 30 days of receipt. Accordingly, it is an object of the invention to provide improved methods and systems for facilitating transactions between commercial banks and pooled depositor groups. It is another object of the invention to provide a short-term liquid deposit vehicle for pooled depositor groups that is fully FDIC insured up to $100,000 or is collateralized from any single individual within a pooled depositor group. Some of the objects of the invention having been stated hereinabove, and which are addressed in whole or in part by the present invention, other objects will become evident as the description proceeds when taken in connection with the accompanying drawings as best described hereinbelow. BRIEF DESCRIPTION OF THE DRAWINGS Preferred embodiments of the invention will now be explained with reference to the accompanying drawings of which: FIG. 1 is a block diagram of a system for facilitating financial transaction between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 2 is a flow chart illustrating exemplary steps for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 3 is a tree diagram illustrating an exemplary web site map for a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 4 is block diagram of an exemplary login screen of a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 5 is a block diagram illustrating an exemplary market information screen for a pooled depositor group in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 6 is a block diagram illustrating an exemplary deposit screen for a pooled depositor group in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 7 is a block diagram of an exemplary withdrawal screen for a pooled depositor group in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 8 is a block diagram illustrating an exemplary account screen for a pooled depositor group in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 9 is a block diagram illustrating an exemplary transaction screen for a pooled depositor group in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 10 is a block diagram illustrating an exemplary business rules screen for a pooled depositor group in that may be associated with a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 11 is a block diagram of an exemplary market information screen for a commercial bank in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 12 is a block diagram illustrating an exemplary borrow screen for a commercial bank in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 13 is a block diagram illustrating an exemplary repay screen for a commercial bank in a system for facilitating transactions between commercial and pooled depositor groups according to an embodiment of the present invention; FIG. 14 is a block diagram illustrating an exemplary accounts screen for a commercial bank in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 15 is a block diagram of an exemplary transactions screen for a commercial bank in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 16 is a block diagram of an exemplary business rules screen for a commercial bank in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 17 is a block diagram of an exemplary market management screen for a custodian in a system for facilitating transactions between a commercial bank and a pooled depositor group according to an embodiment of the present invention; FIG. 18 is a block diagram illustrating an exemplary lenders screen for a custodian in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 19 is a block diagram illustrating an exemplary borrowers screen for a custodian in a system for facilitating transactions between commercial banks and pooled depositors groups according to an embodiment of the present invention; FIG. 20 illustrates an exemplary accounts screen for a custodian in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 21 is a block diagram illustrating an exemplary transactions screen for a custodian in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 22 is a block diagram illustrating an exemplary business rules screen for a custodian in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; and FIG. 23 is a block diagram illustrating an exemplary customer screen for an administrator a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION FIG. 1 illustrates a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention. In FIG. 1, block 100 represents pooled depositor groups that have available cash to invest in insured, liquid deposit opportunities. A depositor interface 102 is provided for these groups to access insured, liquid deposit opportunities created based on cash needed by commercial banks for core deposits. The cash that pooled depositor groups 100 have available for deposit may originate from deposits, represented by block 104. The deposits may be from individual trusts, taxpayers, retirement funds, or other suitable cash source. A custodian 108 may be provided as a trusted intermediary through which pooled depositor groups 100 may make their deposit cash available. In one example, custodian 108 may be a known financial institution, such as a national bank. However, the present invention is not limited to using a custodian to facilitate transactions between commercial banks and pooled depositor groups. In one implementation, custodian 108 may be omitted and control center 106 may function as a custodian for the commercial banks and the pooled depositor groups. In the illustrated example, both control center 106 and custodian 108 include software interfaces 110 and 112. Software interface 110 at control center 106 allows control center 110 to view transactions made through custodian 108. Custodian interface 112 allows custodian 108 to view accounts and transfer cash to and from the accounts. On the right hand side of the diagram, commercial banks 114 may need cash for core deposits to cover loans 116. Alternatively, or in addition, banks 114 may need term funds or hot funds. In order to obtain needed funds, banks 114 register with control center 106 and post master NOW accounts with custodian 108. Commercial banks software interface 118 allows banks to post to master NOW accounts and notifies banks 114 of the interest rate to be paid on cash obtained by banks 114 from custodian 108. In order to provide an insured, liquid deposit opportunity for depositors 100 and cash to banks 114, an interest rate that is attractive to both depositors 100 and commercial banks 114 must be determined. In a preferred embodiment of the invention, depositors 100 are offered a first interest rate, and commercial banks pay a second interest rate, where the second interest rate is higher than the first interest rate. The owners of control center 106 may be able to obtain favorable interest rates from commercial banks 114 by aggregating cash from multiple pooled depositor groups. Based on the difference in interest rates, the owners of control center 106 may fund operations and preferably make a profit. Once the interest rates are set, control center 106 communicates the first interest rate to depositors 100 via depositor interface 102 and communicates the second interest rate to banks 114 via commercial banks interface 118. Both interest rates are preferably guaranteed for a fixed term, such as one month. In addition, depositors 100 are preferably allowed to withdraw cash deposited without penalty in predetermined amounts at predetermined time intervals. For example, the cash deposited by depositors 100 may be made available without penalty to the depositors in denominations of $1 on a daily basis. The present invention is not limited to offering different interest rates to depositors 100 than commercial banks 114 are willing to pay. In an alternate implementation of the invention, the rate offered by commercial banks 114 may be the same rate that is provided to depositors 100. In return for providing access to aggregate depositors 100, commercial banks 114 may pay the owners of control center 114 a predetermined commission or fee. Thus, by facilitating transactions between depositors and commercial banks, control centers 106 may be able to provide better interest rates on deposits, provide cash to commercial banks, and may do so in a manner that earns a profit. Because the software illustrated in FIG. 1 provides a convenient deposit vehicle for commercial banks to obtain stable money for core deposits and term funds, commercial banks 114 can reduce their percentages of brokered deposits and thereby increase the likelihood of a favorable regulatory rating. In addition, the system and software illustrated in FIG. 1 provides a convenient liquid deposit opportunity for depositors. Thus, the system illustrated in FIG. 1 facilitates transactions between commercial banks and pooled depositor groups. FIG. 2 is a flow chart illustrating exemplary steps that may be performed by control center 106 in facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention. Referring to FIG. 2, in step 200, banks and depositor groups register with control center 106. For the banks, the registration may include qualifying as a commercial bank in accordance with predetermined standards, such as federal or state regulatory standards. For pooled depositor groups 100, registration may also include qualifying as an entity permitted to make deposits in a NOW account and guaranteeing a predetermined amount of deposit cash. After registration, a pooled depositor group 100 may contact control center 106 with a deposit need. For example, pooled depositor group 100 may indicate to control center 106 that depositor group 100 desires to deposit $10 million, wants a return of 2%, and desires for individual depositors to be able to access the money on a daily basis. Step 202 may occur multiple times as the operators of control center 106 determine available cash from different pooled depositor groups. In step 204, control center 106 aggregates the deposit needs of multiple pooled depositor groups to produce a stable funds source. As discussed above, providing a stable funds source to commercial banks is important so that the commercial banks can consider the funds core deposits. In step 206, control center 106 notifies commercial banks of the amount of money available, and inquires as to the interest rate that the banks are willing to pay for the money. For example, a bank may agree to pay 235 basis points for $10 million, where basis point is equal to one one-hundredth of one percent. In step 208, banks 114 post master NOW accounts with custodian 108. In step 210, control center 106 sets the interest rate to be paid to the pooled depositor group lower than rate that the bank is willing to pay and at or above the rate that the pooled depositor group expects and notifies the depositor group of the availability of a NOW account at the interest rate. Continuing with the example, if the depositor group expects 200 basis points, control center 106 may set the interest rate to be paid to the trust department to at least 200 basis points. Since the bank is willing to pay 235 basis points, control center 106 can generate up to 35 basis points in revenue. In step 212, the depositor group deposits funds with custodian 108. Custodian 108 places the funds in one or more master NOW accounts in accordance with instructions from control center 106. In step 214, control center 106 manages transactions and generates reports to both the depositor group 100 and commercial banks 114. Managing transactions may include providing wiring instructions to depositor 100, custodian 108, and banks 114. In addition, managing transactions may include providing sub-accounting information to custodian 108 regarding individual depositors in a pooled depositor group so that individual depositors' deposits can be FDIC insured. Managing transactions may also include collecting interest paid by commercial banks 114 and distributing the interest to depositors. Yet another aspect of managing the transactions may include coordinating withdrawals made by depositors 100 in a manner that reduces transactions and wiring expenses. Two methods for coordinating withdrawals will be described in detail below. Because the money is deposited in master NOW accounts, pooled depositor groups are allowed to withdraw funds without penalty on a daily basis. Thus, the invention provides an advantage to depositor groups over conventional certificates of deposit. Although the example described above relates primarily to banks posting master NOW accounts, the present invention is not limited to using master NOW accounts. For example, corporations are not permitted to deposit money in master NOW accounts. Accordingly, receiving money from corporations and having commercial banks post accounts that are equivalent to master NOW accounts in which corporations are permitted to deposit cash is intended to be within the scope of the invention. In one exemplary implementation, in order to receive deposits from corporations, the present invention may include using a money market deposit account (MMDA) account. Thus, although the examples described herein relate to master NOW accounts, it is understood that MMDA accounts may be used without departing from the scope of the invention. In one exemplary implementation, a system for facilitating transactions between commercial banks and pooled depositor groups may be implemented using a web server that provides the interfaces illustrated in FIG. 1. Such a web server may be implemented using any suitable commercially available web server platform, such as an Apache web server. Each interface illustrated in FIG. 1 may be implemented as an application capable of executing on such a platform. FIG. 3 is a tree diagram illustrating an exemplary website map for a web implemented system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention. Referring to FIG. 3, an exemplary website map 300 includes a login screen 302 that provides access to interfaces 102, 110, 112, and 118 illustrated in FIG. 1. Each interface may include a series of computer screens or web pages tailored to the functionality provided by the interface. In the illustrated example, pooled depositor group interface 102 includes a market information page 304, a deposit page 306, a withdrawal page 308, an accounts page 310, a transactions page 312, a business rules page 314, and a profile page 316. Each of the pages 304-316 are preferably tailored to allow pooled depositor groups to obtain rate information provided by commercial banks, deposit money in master NOW accounts, withdraw money from the master NOW accounts on a daily basis, and view transaction information. Commercial banks interface 118 includes a market information page 318, a borrow page 320, a repay page 322, an accounts page 324, a transactions page 326, a business rules page 328, and a profile page 330. Pages 318-330 are preferably tailored to allow a commercial bank to post master NOW accounts, to view the status of master NOW accounts, to repay obligations on master NOW accounts, and to perform other actions related to obtaining deposit cash from pooled depositor groups. Custodian interface 112 includes a market management page 332, a lenders page 334, a borrowers page 336, an accounts page 338, a transactions page 340, and a business rules page 342. Pages 332-342 are preferably tailored to allow a custodian to manage transactions between commercial banks and pooled depositor groups. Administrator interface 110 includes a market management page 344, a customers page 346, an accounts page 348, an FDIC information page 350, a business rules page 352, a reports page 354, and a system administration page 356. Pages 344-356 are preferably structured to allow administrator interface 110 to control transactions between pooled depositor groups and commercial banks. Each of the web pages illustrated in FIG. 3 will now be described in further detail. FIG. 4 illustrates an example of a login screen 302. In the example login screen, a user is requested to enter a user ID and a password. Based on the user ID and the password, the user will be directed to the appropriate interface 102, 110, 112, or 118. FIG. 5 illustrates an example of market information page 304 for a pooled depositor group. In the illustrated example, web page 304 includes a toolbar 500 that allows a pooled depositor group to access other pages associated with pooled depositor group interface 102. In the illustrated example, pooled depositor group interface 304 includes a market information section including market information of interest to a pooled depositor group. In the illustrated example, market information section 502 includes a cash demand field 504, a cash available field 506, a current interest rate field 508, a start date field 510, an end date field 512, and a terms and conditions field 514. Cash demand field 504 stores demand for cash by commercial banks 114. This number may be updated by control center 106 on a daily basis based on demand received from commercial banks. Cash available field 506 may display cash available from the particular pooled depositor group. Current interest rate field 508 may display the current interest rate to be paid to the pooled depositor group set by control center 106. Start and end date fields 510 and 512 may display the start and end dates at which the current interest rate is available. Finally, terms and conditions field 514 may store terms and conditions associated with payback of the funds. FIG. 6 illustrates an example of a deposit page 306 that may be displayed to a pooled depositor group. In the illustrated example, deposit page 306 includes various fields that allow a pooled depositor group to make a deposit. These fields may include a from account field 600, a to account field 602, an amount field 604, a deposit date field 606, a terms and conditions field 608, and a submit button 610. From account field 600 is an input field that allows a pooled depositor group to indicate an account from which a deposit is authorized. To account field 602 may indicate master NOW accounts issued by various pooled depositor groups. Amount field 604 may store an amount that a pooled depositor group desires to withdraw from an account and deposit in a master NOW account. Deposit date field 606 is an input field that allows a depositor to input a date on which a deposit is to occur. Terms and conditions field 608 may display terms and conditions associated with the transaction. Finally, support button 610 may initiate functionality for depositing the funds in an account associated with a commercial bank. FIG. 7 illustrates an exemplary withdrawal page 308 associated with pooled depositor group interface 102. In the illustrated example, withdrawal page 308 includes various fields for allowing a pooled depositor group to withdraw money from an account with custodian 108. These fields may include a from account field 700, a to account field 702, an amount field 704, a withdrawal date field 706, and a submit button 610. From account field 700 allows a pooled depositor group to specify an account with custodian 108 from which funds are to withdrawn. To account field 702 allows a pooled depositor group to specify an account to which the funds are to be deposited. Amount field 704 specifies an amount of the withdrawal. Withdrawal date field 706 allows the pooled depositor group to specify a withdrawal date for the funds. Submit button 610 allows the pooled depositor group to initiate steps to complete the transaction. As discussed above, funds deposited in master NOW accounts are preferably accessible by pooled depositor groups on a daily basis without penalty, thus providing liquidity advantages over conventional certificates of deposit. FIG. 8 illustrates an example of an accounts page 310 associated with pooled depositor group interface 102. In FIG. 8, accounts page 310 includes an accounts data section 800 that stores date regarding accounts of a pooled depositor group. In FIG. 8, accounts data section 310 includes an account field 802, a manager field 804, a total value field 806, a last value field 808, a last date field 810, an edit field 812, and a delete field 814. Account field 802 may identify accounts of a pooled depositor group. Manager field 804 may indicate the custodian managing the account. Total value field may indicate the total value of the account. Last value field 808 may indicate the last value of the account on a particular date. Last date field 810 may indicate the date on which the last value was provided. Finally, edit and delete fields 812 and 814 may allow the depositor group to edit or delete information in accounts section 800. FIG. 9 illustrates an example of a transactions page 312 associated with pooled depositor group interface 102. In the illustrated example, transactions page 312 includes a transaction history section 900 that stores a history of deposits and withdrawals made by the pooled depositor group. In the illustrated example, transaction history section includes a number field 902, a date field 904, an operation field 906, a from account field 908, a to account field 910, an amount field 912, and a terms field 914. Number field 902 may store a transaction number for a particular transaction of a pooled depositor group. Date field 904 may store the date of the transaction. Operation field 906 may store the type of transaction, i.e., whether the transaction was a deposit or a withdrawal. From account field 908 specifies the account of the pooled depositor group from which funds were withdrawn. To account field 910 stores the master NOW account to which funds were deposited. Amount field 912 stores the amount of the transaction. Finally, terms field 914 may display terms associated with the transaction, such as the interest rate or the time period for the deposit. FIG. 10 illustrates an exemplary business rules page 314 associated with pooled depositor group interface 102. In the illustrated example, business rules page 314 includes a business rules section 1000 that stores business rules of a pooled depositor group. Examples of business rules that may be stored in business rules section 1000 include a type or rating status of banks that the commercial pooled depositor group that the depositor group would be willing to deposit funds and whether or not to re-deposit proceeds. These rules may be used by control center 106 when determining the aggregate money supply available to a particular bank. For example, different amounts of funds may be made available to different banks depending on the banks' relative regulatory ratings. FIG. 11 illustrates an example of a market information page 318 that may be associated with commercial bank interface 118. In the illustrated example, commercial banks market information page 318 includes the same fields described above with regard to the market information page 304 associated with pooled depositor group interface 102. In FIG. 11, these fields are renumbered 1102-1112. Fields 1102-1112 display to the commercial bank information regarding cash demand, available cash, current interest rate, start date and end date for the interest rate, and terms and conditions. As discussed above, the values for these fields may be set by control center 106. However, the interest rate displayed in current interest field 1106 of commercial bank market information page 318 is preferably different from that displayed in the corresponding field of market information page 304 of pooled depositor groups interface 102. As discussed above, the interest rates provided and displayed to pooled depositor groups and commercial banks may be set by the owners of control center 106. FIG. 12 illustrates an example of a borrow page 320 of commercial banks interface 118. In FIG. 12, borrow page 320 includes functionality for allowing a commercial bank to borrow money made available by pooled depositor groups 100. This functionality may be implemented in a plurality of input fields that receive data from the commercial bank and provide the data to control center 106. These fields may include a from account field 1202, a to account field 1204, an amount field 1206, a borrow date field 1208, a terms and conditions field 1210, and a submit button 610. A commercial bank uses from account field 1202 to specify a depositor group's account posted with custodian 108 from which the commercial bank desires to borrow money. To account field 1204 allows the commercial bank to specify a master NOW account into which the borrowed funds are to be received. Amount field 1206 is used to specify the amount that the commercial bank desires to borrow. The commercial bank uses borrow date field 1208 to specify the date on which the funds are to be borrowed. Terms and conditions field 1210 specifies the terms and conditions of the transaction. Finally, submit button 610 initiates a borrow transaction. FIG. 13 illustrates an exemplary repay page of commercial banks interface 118. Repay page 322 includes functionality for allowing a commercial bank to repay funds borrowed from a pooled depositor group. In the illustrated example, this functionality includes a from field 1300, a to field 1302, an amount field 1304, and a repayment date field 1306. From field 1302 allows a commercial bank to specify one of its accounts from which payment is to be withdrawn. To account field 1302 allows the commercial bank to specify a pooled depositor group account to which payment is to be made. Amount field 1304 allows the commercial bank to specify a repayment amount. Repayment date field 1306 allows the commercial bank to specify a date for making the repayment. Finally, submit button 610 initiates the repayment transaction. FIG. 14 illustrates an exemplary accounts page 324 of commercial banks interface 118. In the illustrated example, accounts page 324 includes an accounts table 1400 for providing information regarding a master NOW account posted by a commercial bank. In the illustrated example, accounts table 1400 includes an account field 1400, a manager field 1402, a total value field 1406, a last traded value field 1408, a last traded date field 1410, an edit field 1412, and a delete field 1414. Account field 1400 stores an account identifier such as an account number. Manager field 1404 displays the manager of the account. Total value field 1406 displays the current value of the account. Last value field 1408 displays the last traded value of the account. Last traded date field 1410 stores the last date on which the account was traded. Finally, edit and delete fields 1412 and 1414 allows the commercial bank to edit any of the account data. FIG. 15 illustrates an exemplary transactions page 326 of commercial banks interface 118. In the illustrated example, transaction page 326 includes a transactions history table 1500 for storing information regarding transfers to and from a commercial bank's accounts with custodian 108. Transactions history table 1500 may include a transaction number field 1502, a date field 1504, an operation field 1506, a from account field 1508, a to account field 1510, an amount field 1512, and a terms field 1514. Transaction number field 1502 stores a number for a particular transaction. Date field 1504 stores the date of a transaction. Operation field 1506 stores the operation being performed, such as a withdrawal or a deposit. From account field 1508 specifies an account of a commercial bank from which funds are being withdrawn. To account field 1510 stores an account to which funds are being deposited. Amount field 1512 stores an amount of funds affected by the transaction. Finally, terms field 1514 stores the terms associated with a transaction. FIG. 16 illustrates an exemplary business rules page 328 for commercial banks interface 118. In FIG. 16, the business rules page includes a business rules table 1600 for storing business rules particular to commercial banks. In the illustrated example, business rules table 1600 includes a number field 1602, a date created field 1604, condition fields 1606, 1608, and 1610, an action field 1612, a current status field 1614, and edit and delete fields 1616 and 1618. Number field 1602 stores an identifier for a particular business rule. Date created field 1604 stores a date on which a business rule is created. Condition field 1606, 1608, and 1610 store business rules for a commercial bank. Examples of business rules for a commercial bank may include terms over which funds would be needed. Action field 1612 stores an action to be performed if the conditions in fields 1606, 1608, and 1610 are met. Current status field 1614 stores the current status of a particular business rule. Finally, edit and delete fields 1616 and 1618 allow a commercial bank to edit or delete a business rule. FIG. 17 illustrates an exemplary market management page that may be displayed to custodian 108. In the illustrated example, market management page 332 includes a market information section 1700 for displaying overall market information to custodian 108. The market information section 1700 may include a cash demanded field 1702, a cash available field 1704, a start date field 1706, a borrower interest field 1708, a lender interest field 1712, and a terms and conditions field 1714. Cash demanded field 1702 may display cash demanded by commercial banks 114. Cash available field 1704 may display cash available from pooled depositor groups 100. Start date field 1706 may display the date on which cash is available. Borrower interest field 1708 may display the rate currently being paid by commercial banks 114. Lender interest field 1710 may display the interest rate being paid to pooled depositor groups 100. End date field 1712 may store the end date for a particular transaction. Finally, terms and conditions field 1714 may store terms and conditions associated with the current market. FIG. 18 illustrates an exemplary lenders page 324 associated with custodian interface 112. In the illustrated example, lenders page 324 includes a lender information table 1800 that displays information regarding a pooled depositor group. Lenders table 1800 includes a customer ID field 1800, an American Banker's Association (ABA) field 1804, an account number field 1806, a contact field 1808, and edit and delete fields 1810 and 1812. Customer ID field 1802 displays values for identifying a particular customer. American Banker's Association (ABA) field 1804 displays a unique identifier for each lender. Account number field 1806 stores account numbers associated with NOW accounts posted by a particular commercial bank. Contact field 1808 may store contact information for individuals responsible for posting accounts with custodian 108. Edit and delete fields 1810 and 1812 allow custodian 108 to change any of the data in the table. FIG. 19 illustrates an exemplary borrowers page 336 of custodian interface 112. In the illustrated example, borrowers page 336 includes a borrowers table 1900 for displaying information about commercial banks 114. Borrowers table 1900 includes a customer ID field 1902, an ABA field 1904, an account number field 1906, a contact field 1908, and edit and delete fields 1910 and 1912. Customer ID field 1902 displays identifiers for a particular commercial bank. ABA field 1904 stores a unique identifier for each borrower. Account number field 1906 stores and displays account numbers associated with a particular commercial bank. Contact field 1908 stores and displays contact information associated with an individual at a commercial bank in charge of posting master NOW accounts. Edit and delete fields 1910 and 1912 allow custodian 108 to modify information in borrowers table 1900. FIG. 20 illustrates an exemplary accounts page 338 associated with custodian interface 112. In the illustrated example, accounts page 338 includes an accounts table 2000 for storing information about accounts with custodian 108. Accounts table 2000 includes an account field 2002, a manager field 2004, a total value field 2006, a last traded value field 2008, a last traded date field 2010, and edit and delete fields 2012 and 2014. Account field 2002 stores identifiers for identifying a particular account. Manager field 2004 identifies the manager of a particular account. Total value field 2006 stores the total value of an account. Last traded value field 2008 stores the last traded value of a particular account. Last traded date field 2010 stores the last date on which the account was traded. Finally, edit and delete fields 2012 and 2014 allow custodian 108 to modify fields in account table 2000. FIG. 21 illustrates an exemplary transactions page 340 of custodian interface 112. In the illustrated example, transactions page 340 includes a transaction table 2100 for storing and displaying information regarding transactions between pooled depositor groups 100 and commercial banks 114. Transactions table 2100 may include a customer ID field 2102, a transaction number field 2104, a date field 2106, an operation field 2108, a from account field 2110, a to account field 2112, an amount field 2114, and a terms field 2116. Customer ID field 2102 may store an identifier for a customer initiating a transaction. Number field 2104 may store an identifier for the transaction field. Date field 2106 may store the date on which the transaction occurred. Operation field 2108 may identify the type of transaction, i.e., withdrawal or deposit. From account field 2110 stores an account from which funds are being withdrawn. To account field 2112 stores an account to which funds are being deposited. Amount field 2114 stores the amount of the transaction. Terms field 2116 stores and displays terms associated with the transaction. FIG. 22 illustrates an exemplary business rules page 342 of custodian interface 112. In the illustrated example, business rules page 342 includes a business rules table 2200 for storing business rules particular to a custodian. Custodian table 2200 may include a number field 2102, a date created field 2204, condition fields 2206, 2208, and 2210, an action field 2212, a current status field 2214, and edit and delete fields 2216 and 2218. Number field 2202 stores an identifier for a particular business rule. Date created field 2204 stores and displays the date on which a business rule is created. Condition fields 2206, 2208, and 2210 store conditions associated custodian created business rule. Examples of custodian business rules include list of depositor groups from which to receive deposits, lists of banks to which deposits are to be made, maximum amounts for deposits, and cut-off times for deposits on given days. Action field 2212 stores an action associated with a particular business rule. Current status field 2214 stores the current status of a business rule. Finally, edit and delete fields 2216 and 2218 allow custodian 108 to modify business rules in table 2200. FIG. 23 illustrates an exemplary customers page that may be associated with control center administration interface 110. In the illustrated example, customers page 346 includes a customer section 2300 and a customer profile section 2302. Customer section 2300 includes a table having a customer ID field, an ABA field, an account number field, a contact information field, and edit and delete fields 2312 and 2314. Customer field 2304 stores identifiers for particular customers, including commercial banks and pooled depositor groups. ABA field 2306 stores a unique identifier for each customer. Account number field 2308 stores account numbers for each customer. Contact field 2310 stores and displays a contact person associated with each customer. Edit and delete fields 2312 and 2314 allow an administrator alter each field. Customer profile section 2302 includes a customer ID field 2316, a full name field 2318, a short name field 2320, a taxpayer identification number (TI N) field 2322, an ABA number field 2324, an account field 2306, and a notes field 2308. Each of the fields in customer profile section 2312 is used to add customer entries to customer table 2300. Customer ID field 2316 is adapted to receive a customer name. Full name field 2318 receives the full name of a customer. Short name field 2320 may receive a shortened version of the customer name. TIN field 2322 receives a tax identification number. ABA field 2324 receives a unique identifier for each customer. Account number field 2326 receives account numbers for a particular customer. Notes field 2328 stores notes associated with a particular customer. Once an administrator has completed the fields in customer profile section 2302, the administrator may select submit button 610 to create a new entry in customers table 2300. The remaining screens of administration interface 110 may be similar in format to those previously described. Administration interface 110 preferably allows the owners of control center 106 to collect sub-accounting information and transaction information from inventors 100. Administration interface 110 may also include functionality for allowing the owners of control center 106 to collect demand information from commercial banks 114. Administration interface 110 preferably also includes functionality for allowing control center 106 to instruct custodian 108 to transfer cash between depositors 100 and commercial banks 114. Yet another function that may be provided by administration interface 110 is the ability to calculate fees to be paid by commercial banks 114 to depositors 100 and to distribute these fees to the appropriate parties. EXAMPLE TRANSACTION As discussed above, the present invention facilitates transactions between pooled depositor groups 100 and commercial banks 114 by providing a convenient software interface for these groups to perform financial transactions. In one exemplary transaction, a commercial bank may register with control center 106 by accessing a registration web page provided by control center 106 and providing information that may be used by control center 106 to qualify the entity as a commercial bank. Once control center 106 qualifies the entity as a commercial bank, control center 106 provides a NOW account agreement to the commercial bank. Once the NOW account agreement is executed, control center 106 provides the commercial bank with a password and login ID to access a personalized commercial banks interface 118. The commercial bank uses commercial banks interface 118 to define its business rules and communicate deposit needs to custodian 108. A depositor seeking to provide funds for deposit purposes accesses the registration web page provided by control center 106 and provides information usable by control center 106 to qualify the depositor. As discussed above, a pooled depositor group may be any group that is permitted to deposit funds in a NOW account. Such groups include municipalities, trust departments, pension funds, or any other group that can invest in a NOW account. Control center 106 also enters a deposit agreement with the depositor group. Once the agreement has been executed, control center 106 provides the depositor group with a password and login ID. Once the depositor group receives its password and login ID, the depositor group accesses depositor interface 102 using the password and login ID and customizes the depositor interface to meet the depositor's business needs. For example, customizing the interface may include defining business rules associated with the particular depositor and specifying an amount of funds available for deposit. One particular business rule that the depositor may define includes whether or not all funds of all depositors are to be FDIC insured. In order to deposit money, the depositor accesses depositor interface 102 and receives, in real time, the amount of money needed collectively by commercial banks 114 and the interest rate currently being paid for the money. If the interest rate is agreeable to the depositor group, the depositor group inputs information as to the amount of funds to be deposited, sub-accounting information, and when the funds are to be made available. This information is provided to control center 106. Control center 106 provides the sub-accounting information to custodian 108. Control center 106 also provides wiring instructions for the depositor group to transfer the money to custodian 108. Control center 106 informs custodian 108 to post the funds in a particular master NOW account. Custodian 108 may notify the commercial banks whose NOW accounts are being affected of the incoming cash. Control center 106 preferably also provides instructions to custodian 108 as to which banks to wire the funds. As indicated above, the system illustrated in FIG. 1 preferably allows depositors 100 to withdraw funds deposited in a master NOW account on a daily basis without penalty. One method for withdrawing funds includes identifying the bank in which a particular depositor's funds are deposited and providing wiring instructions for the bank to wire the requested funds to be withdrawn to custodian 108 and wiring the funds from custodian 108 to the requesting depositor group. While this method works, it is expensive due to the wiring transaction fees involved in delivering the funds from commercial banks 114, to custodian 108, and to depositors 100. In addition, this method unnecessarily displaces cash currently held by banks 114. In order to reduce transaction expenses associated withdrawals and to reduce displacement of cash held by commercial banks, custodian 108 may identify incoming deposits and withdrawal requests from depositors 100 on a given day, and, rather than requesting funds from a bank to satisfy withdrawal requests and then providing funds to the bank from an incoming deposit, custodian 108 may satisfy a withdrawal request from one depositor group using incoming funds from another depositor group. When this occurs, custodian 108 may simply update its accounting records so that ownership of the deposited funds of the depositor group requesting the withdrawal is changed to reflect that the depositor group whose incoming funds were used to satisfy the withdrawal is now the owner of the deposited funds. For example, if depositor group A requests a $50,000 withdrawal and depositor group B simultaneously deposits $100,000, custodian 108 may satisfy depositor group A's withdrawal request with $50,000 of depositor group B's incoming funds. Custodian 108 then updates its accounting records so that $50,000 of depositor group A's funds deposited in a particular NOW account are now owned by depositor group B. The remaining incoming funds from depositor group B may then be deposited in any master NOW account posted by commercial banks 114. By satisfying incoming withdrawal requests with incoming funds, custodian 108 reduces transaction fees and increases the depositor's return. Although the methods and systems described above relate primarily to providing a convenient interface for pooled depositor groups and commercial banks that allows the pooled depositor groups to have a liquid, fully insured deposit, the present invention is not limited to such an embodiment. In an alternate embodiment, depositors 100 illustrated in FIG. 1 may desire to deposit funds in multiple commercial banks for other reasons, such as security reasons. For example, depositors 100 may desire to deposit funds in commercial banks in multiple countries to reduce risks related to political or economic instability in the individual countries. In such an embodiment, commercial banks interface 118 may receive account postings from banks in different individual countries and may post the accounts with custodian 108. Depositors 100 may view the account postings via depositor interface 102 and select banks in different countries with which to deposit money based on the account postings. Control center 106 may then complete the transaction between the depositor and the individual banks selected by the depositor. Thus, the present invention may also be used to reduce the risk of depositing funds in banks in individual countries. The methods and systems described above may also be utilized to allow the owners of control center 106 to auction funds to commercial banks. For example, if demand for cash deposits exceeds supply, the owners of control center 106 may auction funds to commercial banks in order to obtain a higher rate of return for depositors, a higher fee for providing access to a stable funds source, or both. Thus, as described above, the present invention provides a convenient software interface for facilitating transactions between commercial banks and pooled depositor groups. The software interface may be implemented as web pages displayed to a custodian, pooled depositor groups, commercial banks, and an administrator. By aggregating deposit needs of multiple pooled depositor groups, the control center produces a stable source of funds for commercial banks that the commercial banks can consider as core deposits. In addition, because of the stable nature and volume of such funds, the commercial banks may be willing to pay a higher interest rate than the pooled depositor groups expect. As a result, the owners of the control center can generate revenue for facilitating the transactions. It will be understood that various details of the invention may be changed without departing from the scope of the invention. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation, as the invention is defined by the claims as set forth hereinafter.

<SOH> BACKGROUND ART <EOH>In the banking industry, it is desirable to maintain a certain percentage of core deposits. Core deposits are deposits that do not change significantly in amount with fluctuations in the interest rate paid on the deposits. Savings account deposits are one example of a bank's core deposits. In the United States, the percentage of core deposits affects the bank's ability to maintain a favorable regulatory rating. In addition to core deposits, banks often rely on non-core funding sources, such as brokered CDs. Brokered CDs are offered by a bank to retail customers through a deposit broker. Brokered CDs are less stable as a source of funds for banks than core deposits because depositors in brokered CDs are typically sensitive to interest rate fluctuations. Another problem with using brokered CDs to obtain cash is that in the United States, if a bank maintains too high of a percentage of brokered deposits, the bank may be sanctioned by a regulatory agency, such as the Federal Reserve for federally chartered banks or a state banking agency for state chartered banks. Yet another problem associated with using brokered deposits is that banks are required to pay a broker's commission for brokered deposits. Thus, in the banking industry, there exists a need for a new way for banks to obtain stable funds. Pooled depositor groups, such as trust departments, pension funds, government entities, insurance companies, and any entities that are allowed to make deposits into a negotiated order of withdrawal (NOW) account, are constantly looking for safe, insured deposit vehicles for their funds. In addition, it is desirable for individual depositors in a pooled depositor group to be able to access funds without penalty on a short-term basis. Conventionally, pooled depositor groups have invested in money market funds. However, investing in money market funds is undesirable because money market funds have historically paid low interest rates. Certificates of deposit are undesirable because money is not accessible on a short-term basis without paying a penalty. In addition, under current FDIC regulations, an individual's deposits at a single institution in excess of $100,000 are not federally insured. As a result, in order to fully insure a depositor's funds, a trust department is required to divide a depositor's assets in excess of $100,000 among multiple banks. Accordingly, in light of these difficulties associated with conventional cash management vehicles, there exists a need for an insured or collateralized deposit vehicle for pooled depositor groups. Other entities, such as individual depositors (including corporations and human beings) may also seek insured, liquid deposit opportunities for their funds. These entities face the same difficulties as those described above for pooled depositor groups. Accordingly, there exists a need for an insured or collateralized deposit vehicle for individual depositors. Yet another problem that exists in financial transactions is unrelated to insurance. It may be desirable to provide a method for depositors to spread deposits among multiple commercial banks for security reasons. For example, it may be desirable for depositors to deposit funds in commercial banks in different countries to avoid risks associated with economic and political instability. Currently there is no efficient system for matching depositors' deposit needs to commercial banks' cash flow needs when the banks are located in different countries. Accordingly, there exists a long felt need for improved methods and systems for allowing depositors to distribute deposits among commercial banks.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Preferred embodiments of the invention will now be explained with reference to the accompanying drawings of which: FIG. 1 is a block diagram of a system for facilitating financial transaction between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 2 is a flow chart illustrating exemplary steps for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 3 is a tree diagram illustrating an exemplary web site map for a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 4 is block diagram of an exemplary login screen of a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 5 is a block diagram illustrating an exemplary market information screen for a pooled depositor group in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 6 is a block diagram illustrating an exemplary deposit screen for a pooled depositor group in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 7 is a block diagram of an exemplary withdrawal screen for a pooled depositor group in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 8 is a block diagram illustrating an exemplary account screen for a pooled depositor group in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 9 is a block diagram illustrating an exemplary transaction screen for a pooled depositor group in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 10 is a block diagram illustrating an exemplary business rules screen for a pooled depositor group in that may be associated with a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 11 is a block diagram of an exemplary market information screen for a commercial bank in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 12 is a block diagram illustrating an exemplary borrow screen for a commercial bank in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 13 is a block diagram illustrating an exemplary repay screen for a commercial bank in a system for facilitating transactions between commercial and pooled depositor groups according to an embodiment of the present invention; FIG. 14 is a block diagram illustrating an exemplary accounts screen for a commercial bank in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 15 is a block diagram of an exemplary transactions screen for a commercial bank in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 16 is a block diagram of an exemplary business rules screen for a commercial bank in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 17 is a block diagram of an exemplary market management screen for a custodian in a system for facilitating transactions between a commercial bank and a pooled depositor group according to an embodiment of the present invention; FIG. 18 is a block diagram illustrating an exemplary lenders screen for a custodian in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 19 is a block diagram illustrating an exemplary borrowers screen for a custodian in a system for facilitating transactions between commercial banks and pooled depositors groups according to an embodiment of the present invention; FIG. 20 illustrates an exemplary accounts screen for a custodian in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 21 is a block diagram illustrating an exemplary transactions screen for a custodian in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; FIG. 22 is a block diagram illustrating an exemplary business rules screen for a custodian in a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention; and FIG. 23 is a block diagram illustrating an exemplary customer screen for an administrator a system for facilitating transactions between commercial banks and pooled depositor groups according to an embodiment of the present invention. detailed-description description="Detailed Description" end="lead"?

20060905

20110222

20071129

67629.0

G06Q4000

FIELDS, BENJAMIN S

METHODS AND SYSTEMS FOR FACILITATING TRANSACTIONS BETWEEN COMMERCIAL BANKS AND POOLED DEPOSITOR GROUPS

UNDISCOUNTED

CONT-ACCEPTED

G06Q

ACCEPTED

Wireless device with dynamic fragmentation threshold adjustment

A wireless communication device comprises an input/output terminal configured to communicate data with a processor. A memory (112) is configured to store parameters relevant to a wireless communication protocol. A modem (110) is coupled to the input/output terminal and the memory (112) and configured to operate a wireless protocol over a wireless channel with other modems (120) based at least in part on the parameters stored in the memory (112). A logic circuit (114) is coupled to the modem and the memory (112) and configured to receive information related to wireless channel conditions and update at least one parameter in the memory (112). In one aspect of the invention, the wireless protocol is 802.11. Advantages of the invention include the ability to achieve higher wireless communication throughput due to the dynamic setting of the communication parameters, for example, the fragmentation threshold.

1. A wireless communication device comprising: an input/output terminal configured to communicate data with a processor; a memory configured 112 to store parameters relevant to a wireless communication protocol; a modem 110 coupled to the input/output terminal and the memory 112 and configured to communicate using a wireless protocol over a wireless channel with at least one other modem 120 based at least in part on the parameters stored in the memory 112; and a logic circuit 114 coupled to the modem 120 and the memory 112 and configured to receive information related to wireless channel performance and update at least one parameter in the memory 112. 2. The wireless communication device of claim 1, wherein: the memory 112 is configured to store a fragmentation threshold; the modem 110 is configured to use the fragmentation threshold to frame outgoing data packets; and the logic circuit 114 is configured to periodically update the fragmentation threshold. 3. The wireless communication device of claim 2, wherein: the information related to wireless channel conditions includes an impulse response signal from the receiver side of the modem and the logic circuit 114 is configured to periodically update the fragmentation threshold based at least in part on the impulse response signal. 4. The wireless communication device of claim 2, wherein: the information related to wireless channel conditions includes a frame error rate and impulse response signal from the receiver; and the logic circuit 114 is configured to periodically update the fragmentation threshold based at least in part on the frame error rate and impulse response signal. 5. A method of communicating between wireless modems using a wireless protocol, comprising the steps of: storing parameters relevant to the wireless communication protocol; communicating using the wireless protocol over a wireless channel with at least one other modem based at least in part on the parameters stored in the memory; and receiving information related to wireless channel conditions and updating at least one parameter in the memory. 6. The method of claim 5, wherein: the storing step include the step of storing a fragmentation threshold; the operating step includes the step of using the fragmentation threshold to frame outgoing data packets; and the updating step includes the step of periodically updating the fragmentation threshold. 7. The method of claim 6, wherein: the information related to wireless channel conditions includes an impulse response signal from the receiver; and the updating step includes the step of periodically updating the fragmentation threshold based at least in part on the impulse response signal. 8. The method of claim 6, wherein: the information related to wireless channel conditions includes a frame error rate and impulse response signal from the receiver; and the updating step includes the step of periodically updating the fragmentation threshold based at least in part on the frame error rate and impulse response signal.

The present invention relates to communications in a wireless network. In particular, the invention relates to dynamic fragmentation threshold adjustment in a wireless network. Wireless communications are becoming very popular because allow users to move freely without being tied to a desk or wire. However, users are continually demanding greater performance and better communication with their wireless devices. Consequently, techniques that improve the performance of wireless devices are extremely useful and may have great commercial value. One aspect that can be improved has to do with the way messages are fragmented so that they may be efficiently communicated between devices. In wireless communication standards such as 802.11 Wireless Local Area Network (WLAN) standard, a technique called fragmentation divides large messages into smaller fragments so that they can be transmitted efficiently between devices. Ordinarily, the fragment length is fixed, however, the longer the fragments the more likely that they will be corrupted during the communication. On the other hand, the smaller fragmentation length means larger overhead and more transmit and acknowledge (ACK) rounds which will decrease the system throughput. So if the channel condition is good, the longer fragment length will increase the system throughput. Some techniques for manually modifying the fragment size or for dynamically modifying the fragment size are known in the art, but they do not adequately take into account certain channel parameters and variables that would be useful for optimizing the fragment length. In the 802.11 specification FIG. 1 is provided to show the standard fragmentation process of partitioning a media access control (MAC) service data unit (MSDU) into smaller MAC level frames, MAC protocol data units (MPDUs). Fragmentation creates MPDUs smaller than the original MSDU length to increase reliability, by increasing the probability of successful transmission of the MSDU or MMPDU in cases where channel characteristics limit reception reliability for longer frames. The invention is directed to a technique for optimizing the fragment length, especially under the 802.11 WLAN standard. The present invention addresses the identified problems and provides a wireless communication device with a dynamic fragmentation threshold. This dynamic setting allows the wireless communication device to achieve an optimized throughput based on the quality of the wireless communication channel. A wireless communication device comprises an input/output terminal configured to communicate data with a processor. A memory is configured to store parameters relevant to a wireless communication protocol. A modem is coupled to the input/output terminal and the memory and configured to operate a wireless protocol over a wireless channel with other modems based at least in part on the parameters stored in the memory. A logic circuit is coupled to the modem and the memory and configured to receive information related to wireless channel conditions and update at least one parameter in the memory. In one aspect of the invention, the wireless protocol is 802.11. In one aspect of the invention, the memory is configured to store a fragmentation threshold, the modem is configured to use the fragmentation threshold to frame outgoing data packets, and the logic circuit is configured to periodically update the fragmentation threshold. In one aspect of the invention, the information related to wireless channel conditions includes an impulse response signal from the receiver, and the logic circuit is configured to periodically update the fragmentation threshold based at least in part on the impulse response signal. In one aspect of the invention, the information related to wireless channel conditions includes a frame error rate and impulse response signal from the receiver, and the logic circuit is configured to periodically update the fragmentation threshold based at least in part on the frame error rate and impulse response signal Advantages of the invention include the ability to achieve higher wireless communication throughput due to the dynamic setting of the communication parameters, for example, the fragmentation threshold. This dynamic setting increases communication quality by setting the fragmented packet length to an optimum threshold, thereby increasing throughput while reducing frame error rate over the wireless link. The invention will be described with reference to the following figures in which: FIG. 1 is a diagram showing fragmentation under the 802.11 communication protocol specification; FIG. 2 is a simplified block diagram showing two wireless devices using an exemplary 802.11 WLAN standard according to an embodiment of the invention; FIG. 3 is an exemplary wireless frame structure according to the 802.11 specification; FIG. 4 is a diagram showing an internal functional block diagram of the modem according to an embodiment of the invention; FIG. 5 is a diagram showing an internal functional block diagram of the logic circuit according to an embodiment of the invention; FIG. 6 is a chart showing an equalizer operating on a received signal according to an embodiment of the invention; and FIG. 7 is a flowchart showing the inventive operating steps according to an embodiment of the invention. The invention is described with reference to a number of embodiments, which may include specific implementations. The invention is intended to describe the best mode of the invention, but other similar techniques and technologies can be used to perform the invention. For example, reference is made to the 802.11 wireless protocol, but other protocols may be implemented in the invention. Likewise, while reference is made to a logic circuit for updating modem parameters, the invention can also be performed in software by a processor or other device. A. Fragmentation Using Wireless Protocol Standard (802.11) As shown in FIG. 1, a media access control (MAC) device may fragment and reassemble directed MAC service data units (MSDUs) or MAC management protocol data units (MMPDUs). Each of these fragments in referred to as a frame in communication between the wireless devices. Fragmentation is described in detail in the 802.11 specification, which is available on the Internet at the IEEE web site, http://www.ieee.org. However, while the specification describes standard techniques for performing fragmentation based on a fragmentation threshold, the specification does not specify or suggest a technique for dynamically setting the fragmentation threshold as described herein. FIG. 2 is a simplified block diagram showing two wireless devices 102 and 104 using an exemplary 802.11 communication protocol according to an embodiment of the invention. The exemplary devices 102 and 104 are the same so reference is made to one of the devices, e.g. 102. A modem 110 is constructed that is coupled to a memory 112 for storing communication parameters and a logic circuit for managing the wireless communication. The invention employs a technique that permits the logic circuit to dynamically set parameter in the memory in order to optimize communication performance, described in detail below. FIG. 3 is an exemplary wireless frame 200 according to the 802.11 specification, where the frame represents one of the fragments as described above. The modem 110 performs the fragmentation and constructs the frame including the frame body, which can be 0-2312 bytes long, depending on the fragmentation threshold stored in the memory 112. B. Channel Parameters and Fragmentation Threshold Computation As described above, the logic circuit 114 periodically set the fragmentation threshold stored in the memory 112. FIGS. 4 and 5 show an internal functional block diagram of the modem according to an embodiment of the invention. The modem 110 includes a number of components, for example, a transmitter and receiver. In addition, the modem includes a decoder, deframer and equalizer, etc. Some of these components is capable of providing a channel related information to imply the quality of communication between the wireless devices 102, 104. For example, the receiver can provide a received signal strength indicator (RSSI) as well as a frame error rate (FER) since it receives the acknowledge (ACK) signal when a frame is successfully transmitted to the other device. Likewise, the equalizer can provide a characterization of the channel impulse response because it is dynamically set to compensate the channel distortion effect in order to equalize the channel. These signals in combination represent the channel conditions that are generated by the modem 110 and fed to the logic circuit 114. In particular, the signals of interest include: (a) RSSI, (b) symbol energy, (c) incoming FER, (d) outgoing FER, and (e) impulse response energy. In one aspect of the invention, the RSSI is provided directly by the receiver. In one aspect of the invention, the symbol energy is derived from the Barker decoder (e.g. in 802.11). In one aspect of the invention, the incoming FER is provided by the decoder. In one aspect of the invention, the outgoing FER is provided by the decoder based on correctly decoded ACK signals. In one aspect of the invention, the impulse response energy is provided by the equalizer. It may be useful to expand the description somewhat on the impulse response that is provided by the equalizer. The main role of an equalizer in a wireless receiver is to compensate or equalize the channel distortion to the transmitted signal so that the received signal can be easily decoded by the decoder. This relationship is shown in FIG. 6, in a chart showing an equalizer operating on a received signal. The equalized signal Y(n) can be written as follows: Y(n)=X(n)*h(n)*w(n) where X(n) is the transmitted signal, h(n) is the channel impulse response, w(n) is the impulse response of the equalizer and * is a convolution operation. Ideally, if the channel effect on the transmitted signal can be fully compensated by the equalizer, the output signal Y(n) should be the delay and scaled version of X(n), which means: h(n)*w(n)=Cδ(n−m) where C is a constant (which can be assumed as 1 if Automatic Gain Control is implemented in the system), δ(n) is Kronecker delta function and m is the delay. If the channel can be modeled as a finite impulse response (FIR) filter, we can to estimate the channel effect on the transmitted signal X(n) and we can observe the equalizer weight by using some metrics. Here, we propose to measure the power of the equalizer weight as: P=Σ|w(j)|2 for j=0 to N where N is the length of the equalizer weight w(j). The larger the value of P, the weaker the channel. The invention will set a lower fragmentation threshold for a weaker channel since there is a greater likelihood of losing long packets. The fragmentation threshold parameter is calculated according to the following exemplary formula, where the input parameters are p1=RSSI, p2=symbol energy, p3=incoming FER, p4=outgoing FER and p5=Impulse Response Energy FrameN FragmentationThreshold=f1(P1N-1−P1N-2)+f2(p2N-1−p2N-2)+f3(p3N-1−P3N-2)+f4(p4N-1−p4N-2)+f5(p5N-1−p5N-2), where all functions f( ) are monotone increasing functions. C. Method of Operation FIG. 7 is a flowchart showing the inventive operating steps according to an embodiment of the invention. In step 502, the fragmentation threshold is set to an initial number, which may be factory set, set by default on power up, set by a user, or set by other means. In step 504, the modem creates the channel signals related to the wireless communication channel. In step 506, the logic circuit calculates the new fragmentation threshold based on the selected channel signals and functions. In step 508, the logic circuit updates the fragmentation threshold parameter in the memory so that the transmitter framer can then use that parameter to fragment future frames. The logic circuit may also update additional parameters as desired in order to perform future calculations or to create a log of certain desired parameters. D. Conclusion Advantages of the invention include the ability to achieve higher wireless communication throughput based on dynamically setting of the communication parameters, for example, the fragmentation threshold. This dynamic setting increases communication quality by setting the fragmented packet length to an optimum threshold, thereby increasing throughput while reducing lost packets over the wireless link. Having disclosed exemplary embodiments and the best mode, modifications and variations may be made to the disclosed embodiments while remaining within the subject and spirit of the invention as defined by the following claims.

20061218

20090811

20070419

63634.0

H04B138

JIANG, CHARLES C

WIRELESS DEVICE WITH DYNAMIC FRAGMENTATION THRESHOLD ADJUSTMENT

UNDISCOUNTED

ACCEPTED

H04B

ACCEPTED

Control of a grinding device with grinding rollers on winding shafts

The invention describes a control unit for a sanding machine, which winds and unwinds the abradant paper over a contact device. This control unit continuously detects the position of one or more of these sanding machines, the abradant unwinding, the movement of the transport system and the position of the workpiece. These parameters are used to regulate the sanding machine(s) in such a way that the workpieces are fed through and the sanding operation executed without interruption.

1. Control unit for a sanding machine, which winds and unwinds a sanding belt over a contact mechanism, characterized in that the detection, control and optimization of the position of one or more of these sanding machines, abradant unwinding, feed movement and positioning of the workpiece makes possible the machine feed and sanding operation in continuum.

The invention describes the use of a control unit on a sanding machine with rolls which, to perform the sanding operation, are wound around rollers and an intermediate contact device. The subject of the invention is the connection of such a sanding machine to a control system in such a way that the workpieces can be fed through nonstop and the sanding process can occur without interruption. The invention is illustrated by: Drawing 1, with the projection of a form of standard sanding system with flexible abradant, comprising an endless sanding belt (11), which rotates around a contact device (12) longitudinally aligned with the workpiece transport system (13), around a drive roller (14) and a deflecting roller (15). Drawing 2 with the projection of the type of sanding system at the base of the invention, comprising a roll of flexible abradant (16) on a winding axis (17) inclined to the feed direction and rotating in the feed direction r, a rotating winding roller (18) parallel to it, and a contact device (12) running at an angle to the workpiece transport (13) between the two shafts and with pre and post-positioned deflecting rollers (19, 20), a feed system (21), and a machine infeed with a barrier regulated by the control unit (23) described in the invention. The standard form of flexible abradant used in throughfeed surface sanding is the endless belt, commonly configured as shown in Drawing 1. The disadvantages of the endless belts are their relatively complicated and costly packaging, their bulky shape for transport and storage, short application times due to the limits placed on their lengths, and their qualitative imperfections, due to their attachment points and rapid repetition of grain imperfections on the piece. Since their use to date has been indispensable, a relatively high sanding speed has been necessary for the most common type of workpieces, and therefore the need for a correspondingly rapid, continuous supply of abradant for the sanding process, and it has not been possible to change the sanding direction and obtain qualitatively identical results on conventional workpieces (e.g. wood, e.g. due to its fibrous structure). Only the continuous winding of the sanding belt makes nonstop workplace feed possible. The sanding machine which is the subject of the invention consists of an unwinding roller (17), on which a roll (16) of abradant on backing material, usually sanding paper, is placed, a contact device (12) and winding roller (18), which takes up the unwound roll of abradant. The contact device is usually a contact roller or a bar that is continuous or made up of segments; i.e. a so-called sanding block. The sanding paper is wound backwards and forwards until the abradant is completely consumed, whereby after every pass the winding roller becomes the unwinding roller, and vice-versa. Such a sanding device was described by Paul Ernst (Patent GB 1484851, Aug. 9, 1977). Subject of the invention is the combination of the sanding device described above with a control system (23), which solves the problem of the discontinuity in the feed and the sanding operations. The sanding device in the form described in Paul Ernst's patent claim in practice can only be used for sanding small batches or single pieces. After reaching the end of the abradant roll, this machine cannot continue with workpiece feed until the rotation direction has been reversed. For materials which, due to their structure, must always be sanded in the same direction as the feed direction (e.g. wood, usually in the contrary direction), the entire roll of abradant must first be rewound to its original position before work may continue. For the usual abrasive speeds for conventional materials (e.g. wood around 20 m/sec) and the common abradant roll lengths (round 50-200 metres) such a machine experiences a feed interruption about every 2-8 seconds. This limitation is the reason that these machines have not been widely disseminated. This invention takes into account the changing demands which new materials, surfaces and sanding processes involve. These (e.g. the sanding of painted surfaces) often involve homogeneous surfaces, on which sanding patterns remain the same even with opposing sanding directions. In addition, considerably lower sanding intensities are required, which in turn require lower sanding speeds (e.g. 5 m/sec) with consequently extended roll throughtimes. Furthermore and above all electronic control can regulate the machine feed as a function of the abradant preparation; i.e. the problem of discontinuity in the abradant feed has been solved. The control system (23), integral part of the invention, can manage various parameters, namely (the following list is not all-inclusive): I. Rotation Direction of the Winding Shafts If the sanding result is independent of the sanding direction (inclined, longitudinal, with or contrary to the feed direction), it is sufficient that the winding shafts be arranged as shown in Drawing 2, and when the sanding paper roll reaches the end, the rotation direction be simply reversed. This procedure is sufficient for many homogeneous, i.e. non-fibrous materials. II. Positioning of the Sanding Device Itself If the sanding direction needs to be constant for all workpieces of a series, then the entire sanding unit is turned at the end of the abradant roll end, in order to maintain the same direction. The arrangement shown in Drawing 2 allows the sanding unit to be rotated for this purpose 180 degrees around axis a of the feed direction. The sanding direction, however, can be rotated to any angle, whether in inclined, lateral or longitudinal alignment. III. Use of Single Assemblies If the sanding direction needs to be constant, a number of sanding units—in the following referred to as assemblies—can be employed. As One assembly is engaged in the sanding process, a second (after reaching the end of the roll) rewinds the abradant rapidly, or the assembly is turned. The control system manages the respective sanding, rewinding and turning operations for the various assemblies. IV. Positioning of the Workpiece Mechanically, optically or in another way, the position of the workpiece is detected and its feed through the machine controlled by the machine itself or via the contact device (12). This can be, for example, a regulating bather (22) at the infeed (to synchronise with the winding operation) and/or through regulating the feed mechanism itself. V. Workpiece Transport Speed Depending on the position of the workpiece relative to the winding mechanism or the abradant, the speed of the transport system (21) is correspondingly regulated, i.e. raised/lowered/stopped/started. VI. Winding of the Abradant The control system calculates the remaining abradant on the roll and time till changeover, and calculates the optimal braking time of the winding, in accordance with the use of single assemblies (see III). The control unit can optimise the time used for the sanding process via the winding speed. Only the combination of the sanding machine on the principle of winding rollers with a control unit as described here can produce a significant improvement in the efficiency of the sanding process with practical results. SUMMARY The invention describes a control unit (23) for a sanding machine, which winds and unwinds the abradant paper (16) over a contact device (12). This control unit (23) continuously detects the position of one or more of these sanding machines, the abradant unwinding, the movement of the transport system (21) and the position of the workpiece (13). These parameters are used to regulate the sanding machine(s) in such a way that the workpieces (13) are fed through and the sanding operation executed without interruption.

<SOH> SUMMARY <EOH>The invention describes a control unit ( 23 ) for a sanding machine, which winds and unwinds the abradant paper ( 16 ) over a contact device ( 12 ). This control unit ( 23 ) continuously detects the position of one or more of these sanding machines, the abradant unwinding, the movement of the transport system ( 21 ) and the position of the workpiece ( 13 ). These parameters are used to regulate the sanding machine(s) in such a way that the workpieces ( 13 ) are fed through and the sanding operation executed without interruption. detailed-description description="Detailed Description" end="tail"?

20110211

20121127

20110602

57632.0

B24B2100

ELEY, TIMOTHY V

CONTROL OF A GRINDING DEVICE WITH GRINDING ROLLERS ON WINDING SHAFTS

SMALL

ACCEPTED

B24B

ACCEPTED

Virtual-antenna receiver

The invention is directed to the reception of high rate radio signals (for example DVB-T signals) while the receiver is moving at a high speed (for example in or with a car). Two or more antennas (12, 16) are closely spaced and arranged behind each other in the direction of motion (v) for receiving the radio signals. A signal is obtained which represents a virtual antenna (26) that is at least temporarily stationary with respect to the environment, despite the movement of the receiver. The receiving signal of the virtual antenna (26) suffers at least less distortions than a signal received by one of the first and second antennas (12, 16). In accordance with the invention the signal which represents the virtual antenna (26) is obtained under the control of a feedback signal (SYNC) of the receiver.

1. A receiver comprising a first receiving branch (10) having associated thereto a first antenna (12) and at least a second receiving branch (14) having associated thereto a second antenna (16), the receiver comprising first means (18) for obtaining from a first signal (20) on the first receiving branch (10) and a second signal (22) on the second receiving branch (14) a third signal (24) representing a first virtual antenna (26) being at least temporarily stationary with respect to the environment when the receiver is moving with a speed (v), the first means (18) being controlled by a feedback signal (SYNC) of the receiver. 2. The receiver according to claim 1, wherein the first antenna (12) and the second antenna (16) are spaced by a distance (d) and arranged behind each other in the direction of motion (v) of the receiver. 3. The receiver according to claim 1, wherein the first means (18) comprise adaptive combiner means (27) for linearly interpolating between the first signal (20) and the second signal (22) to obtain the third signal (24). 4. The receiver according to claim 3, wherein the first means (26) are additionally controlled by a parameter related to the speed (v) of the receiver. 5. The receiver according to claim 1, comprising second means (28) for obtaining a fourth signal (30) representing a second virtual antenna (32) being at least temporarily stationary with respect to the environment when the receiver is moving with the speed (v). 6. The receiver according to claim 5, wherein the second means (28) obtain the fourth signal (30) from the first signal (20) on the first receiving branch (10) and the second signal (22) on the second receiving branch (14). 7. The receiver according to claim 5, wherein the first means (18) and the second means (28) are controlled such that one of the first virtual antenna (26) and the second virtual antenna (32) is stationary with respect to the environment, at least when the other is not. 8. The diversity receiver according to claim 5, wherein one or more of the first means (18) and the second means (28) are fully or in part realized by hardware interacting with software or by discrete components. 9. The receiver according to claim 1, wherein the receiver is adapted to be used in one or more of the following systems: Orthogonal Frequency Division Multiplexing (OFDM) systems, Digital Audio Broadcasting (DAB) systems, Digital Video Broadband (DVB) systems, for example DVB-T systems, Digital Terrestrial Television Broadcasting (DTTB) systems, Code Division Multiple Access (CDMA) systems, for example cellular CDMA systems, Universal Mobile Telecommunications Systems (UMTS), the Global System for Mobile communications (GSM), Digital Enhanced Cordless Telecommunication (DECT) systems, wireless local area network systems, for example according to the standard 802.11a, 802.11g, or HIPERLAN II. 10. The receiver according to claim 1, wherein the receiver performs a Fast Fourier Transformation and/or an Inverse Fast Fourier Transformation, and wherein the feedback signal (SYNC) of the receiver is at least partially obtained before the Fast Fourier Transformation and/or the Inverse Fast Fourier Transformation is performed. 11. The receiver according to claim 1, wherein the receiver performs a Fast Fourier Transformation and/or an Inverse Fast Fourier Transformation, and wherein the feedback signal (SYNC) of the receiver is at least partially obtained after the Fast Fourier Transformation and/or the Inverse Fast Fourier Transformation is performed. 12. A method for canceling or at least reducing signal distortions of a radio signal received by a moving receiver comprising a first receiving branch (10) having associated thereto a first antenna (12) and at least a second receiving branch (14) having associated thereto a second antenna (16), wherein the first antenna (12) and the second antenna (16) are spaced by a distance (d) and arranged behind each other in the direction of motion (v) of the receiver, said method comprising the following steps: obtaining a first signal (20) on the first receiving branch (10) and a second signal (22) on the second receiving branch (14); and obtaining from the first signal (20) and the second signal (22) a third signal (24) representing a first virtual antenna (26) being at least temporarily stationary with respect to the environment when the receiver is moving with a speed (v), wherein the third signal (24) is obtained under control of a feedback signal (SYNC) of the receiver. 13. The method according to claim 12, wherein the third signal (24) is obtained by linearly interpolating between the first signal (20) and the second signal (22). 14. The method according to claim 12, wherein a fourth signal (30) representing a second virtual antenna (32) is obtained from the first signal (20) on the first receiving branch (10) and the second signal (22) on the second receiving branch (14), wherein one the first virtual antenna (26) and the second virtual antenna (32) is stationary with respect to the environment, at least when the other is not. 15. The method according to claim 12, wherein a Fast Fourier Transformation and/or an Inverse Fast Fourier Transformation is performed, and wherein the feedback signal (SYNC) of the receiver is at least partially obtained before the Fast Fourier Transformation and/or the Inverse Fast Fourier Transformation is performed. 16. The method according to claim 12, wherein a Fast Fourier Transformation and/or an Inverse Fast Fourier Transformation is performed, and wherein the feedback signal (SYNC) of the receiver is at least partially obtained after the Fast Fourier Transformation and/or the Inverse Fast Fourier Transformation is performed. 17. A computer program stored on a record carrier or made available for download, said computer program being adapted to carry out the method according to claim 12.

The present invention relates to a receiver comprising a first receiving branch having associated thereto a first antenna and at least a second receiving branch having associated thereto a second antenna, the receiver comprising first means for obtaining from a first signal on the first receiving branch and a second signal on the second receiving branch a third signal representing a first virtual antenna being at least temporarily stationary with respect to the environment when the receiver is moving with a speed. Furthermore, the present invention relates to a method for canceling or at least reducing signal distortions of a radio signal received by a moving receiver comprising a first receiving branch having associated thereto a first antenna and at least a second receiving branch having associated thereto a second antenna, wherein the first antenna and the second antenna are spaced by a distance and arranged behind each other in the direction of motion of the receiver, said method comprising the following steps: obtaining a first signal on the first receiving branch and a second signal on the second receiving branch; and obtaining from the first signal and the second signal a third signal representing a first virtual antenna being at least temporarily stationary with respect to the environment when the receiver is moving with a speed. Finally, the present invention relates to a computer program stored on a record carrier or made available for download, said computer program being adapted to carry out the method in accordance with the present invention. In mobile reception, radio signals experience channel conditions that vary (often rapidly) with time. This is mainly caused by multipath radio signal propagation, wherein reflected waves may cancel each other at one location, but may enhance each other elsewhere. A well known model to describe this effect, which is referred to as “fading”, is to assume that the received signal consists of multiple reflected waves, each arriving from a different angle at the moving receive antenna. This results in slightly different Doppler shifts for each wave. The collection of Doppler shifts is called Doppler spread of a signal. In general, the fading effects for a moving receiver are seen as time variations of the radio channel. Diversity is a known method to improve the reliability of reception of radio signals. In a diversity system at least two antennas are used to receive the radio signal. Signals from the at least two antennas are combined to improve the reliability of reception. If the channel is fading, an adaptation method is used to continuously ensure that the signals from the multiple antennas are combined in a constructive way. JP-A-04-185130 discloses a diversity receiver of the above mentioned type. To reduce the effect of a multipath and to attain stable transmission reception, there is provided a second antenna parted spatially with respect to a first antenna. The distance between the two antennas is spatially parted by λ/3 (wherein λ is a wavelength of a carrier) or over that, so that a reception signal from the one antenna and a reception signal from the other antenna are almost in non-correlation. A further approach for improving the reliability of reception is to process the received signal in order to mitigate the effects of channel variations. In particular for Orthogonal Frequency Division Multiplexing (OFDM) modulation methods, it is known that rapid channel variations lead to a degradation of the reliability of the radio link. OFDM is a modulation method in which multiple user symbols are transmitted in parallel using different sub-carriers. The OFDM receiver structure allows relatively straightforward signal processing. A practical implementation of the OFDM modulation method typically involves a (Fast) Fourier Transformation of the user bits, before and after radio transmission. As a result, the data are divided into many parallel streams. Each stream is modulated on a different sub-carrier frequency. In general, OFDM systems are designed such that each data symbol waveform is located around a particular sub-carrier frequency, and that its bandwidth is small enough to experience frequency-flat fading, when the signal is received over a (moderately) frequency-selective channel. The modulated sub-carriers comprise overlapping side lobes. In many existing systems the rectangular pulse shape leads to a spectrum according to a sinc function. These signal waveforms are carefully spaced in frequency and thereby designed to be orthogonal, i.e. not interfering with each other. A Doppler spread, for example caused by fading, is detrimental to this orthogonality of the OFDM sub-carrier signals since arriving waves will interfere with other waves having different frequency offsets. This is called inter-carrier interference (ICI). Although with diversity receivers, for example of the type disclosed in JP-A-04-185130, and the approached mentioned above the reliability of reception may be improved, especially in the context of reception of high rate radio signals and receivers moving at a high speed there is still a problem in that channel conditions vary too rapidly with time. To improve the receiving characteristics of a moving receiver, especially of a receiver moving at a high speed, it is already known to create a virtual stationary antenna, i.e. a virtual antenna that is moved between the first antenna and the second antenna with the same speed as the receiver, but in the opposite direction. With this solution the deteriorations of the receiving characteristics that are caused by the movement of the receiver may be compensated at least partly. Such a solution is for example disclosed in the IEEE publication 0-7803-6728-6/01, pages 1249 to 1252 “Array Antenna Assisted Adaptive Modulation in a Fast Fading Channel”. This publication discloses a receiver and a method of the type mentioned at the beginning in connection with a two-way system where the TDD transmit/receive cycle dictates the fixing moment and place of the virtually stationary position. It is the object of the present invention to further develop the receivers and the methods of the type mentioned above such that they may also be used in connection with broadcast signals, i.e. in connection with one-way systems. The above object is solved by the features of the independent claims. Further developments and preferred embodiments of the invention are outlined in the dependent claims. In accordance with a first aspect of the present invention, the above object is solved by a receiver of the type mentioned at the beginning which is characterized in that the first means are controlled by a feedback signal of the receiver. In accordance with a second aspect of the present invention, the above object is solved by a method of the type mentioned at the beginning which is characterized in that the third signal is obtained under control of a feedback signal of the receiver. The above mentioned aspects of the present invention are based on the finding that a stationary or fixed effective receive position of the virtual antenna can in practice only be realized for limited period of time, since for example a vehicle comprising the receiver may move over prolonged distances that largely extend the physical dimensions of the antenna structure. In such case the virtual antenna position must be changed at discrete moments, to follow the long-term motion of the vehicle. Preferably this switching of the antenna position coincides with the end of individual data blocks, for example OFDM blocks, but does not occur during the reception of one such block. In this connection the moment of switching to a new virtually fixed position of the virtual antenna is preferably controlled by a feedback signal coming from the synchronization mechanism of the receiver, for example a OFDM block or frame synchronization mechanism of the receiver. Although most of the following features are only claimed in connection with the receiver, it is to be noted that the person skilled in the art may suitably adapt these features without problem such that they may also be used advantageously in connection with the method and in accordance with the present invention. The first antenna and the second antenna are preferably spaced by a distance and arranged behind each other in the (main) direction of motion of the receiver only. In this case the second antenna follows at least substantially the same spatial path as the first one, but with a slight time lag. The direction of motion particularly may be the direction of motion of a vehicle comprising the receiver. With preferred embodiments the first means comprise adaptive combiner means for linearly interpolating between the first signal and the second signal to obtain the third signal. It is preferred that the first means are additionally controlled by a parameter related to the speed of the receiver. To keep the virtual antenna in place with respect to the environment, it is additionally necessary to control the interpolation between the first signal and the second signal on the basis of the speed of the receiver. For example, if the receiver in accordance with the invention is mounted to a car, the necessary speed information may be obtained via the speedometer. Furthermore, embodiments are possible wherein the receiver comprises second means for obtaining a fourth signal representing a second virtual antenna being at least temporarily stationary with respect to the environment when the receiver is moving with the speed. With this solution the advantages of know stationary diversity receivers having multiple antennas may for example be achieved. In this context it is preferred that the second means obtain the fourth signal also from the first signal on the first receiving branch and the second signal on the second receiving branch to keep the complexity of the circuitry as low as possible. However, the invention is not limited to such solutions and it is for example also possible to use more than one set of antennas to create the virtual antennas. Further advantages may be achieved, if the first means and the second means are controlled such that one of the first virtual antenna and the second virtual antenna is stationary with respect to the environment, at least when the other is not. For example it is possible to rearrange the first virtual antenna close to the first antenna before the second virtual antenna, which to be stationary with respect to the environment is moved towards the second antenna with respect to a system of coordinates moving with the receiver, reaches the second antenna. One or more of the first means and the second means may for example fully or in part be realized by hardware interacting with software or by discrete components. Without being limited thereto, it is preferred that the receiver in accordance with the present invention is adapted to be used in one or more of the following systems: Orthogonal Frequency Division Multiplexing (OFDM) systems, Digital Audio Broadcasting (DAB) systems, Digital Video Broadband (DVB) systems, for example DVB-T systems, Digital Terrestrial Television Broadcasting (DTTB) systems, Code Division Multiple Access (CDMA) systems, for example cellular CDMA systems, Universal Mobile Telecommunications Systems (UMTS), the Global System for Mobile communications (GSM), Digital Enhanced Cordless Telecommunication (DECT) systems, wireless local area network systems, for example according to the standard 802.11a, 802.11g, or HIPERLAN II. With preferred embodiments the receiver performs a Fast Fourier Transformation and/or an Inverse Fast Fourier Transformation, wherein the feedback signal of the receiver is at least partially obtained before the Fast Fourier Transformation and/or the Inverse Fast Fourier Transformation is performed. Additionally or alternatively it is possible that the receiver performs a Fast Fourier Transformation and/or an Inverse Fast Fourier Transformation, wherein the feedback signal of the receiver is at least partially obtained after the Fast Fourier Transformation and/or the Inverse Fast Fourier Transformation is performed. In cases where the feedback signal is partially obtained before and after the Fast Fourier Transformation and/or the Inverse Fast Fourier Transformation is performed, the part obtained before the transformation may be responsible for a coarse timing synchronization while the part obtained after the transformation may be responsible for a fine timing synchronization. In such a case a timing signal combiner is preferably provided for suitably combining fine and the coarse timing signals. It is a gist of the present invention to recognize that a diversity antenna system comprising at least two distinguishable active elements and a signal processing algorithm may be used together to create a virtually-stationary antenna, i.e. an antenna that effectively has a temporarily fixed position despite of the motion of the receiver, to cancel or at least reduce signal distortions caused by a (fast) movement of the receiver. FIG. 1 illustrates the creation of a virtual antenna in accordance with a preferred embodiment of the present invention; FIG. 2 shows a simplified schematic block diagram of a first embodiment of a receiver in accordance with the present invention, and it further illustrates the method in accordance with the invention; FIG. 3 shows a simplified schematic block diagram of a second embodiment of a receiver in accordance with the present invention; and FIG. 4 shows a simplified schematic block diagram illustrating a preferred possibility to obtain the feedback signal of the receiver. FIG. 1 illustrates the creation of a virtual antenna in accordance with a preferred embodiment of the present invention. FIG. 1 schematically shows a car 34 moving with a speed v in the direction of the arrow 42. The car 34 comprises a receiver in accordance with the invention of which only a first antenna 12 and a second antenna 16 are shown. The first antenna 12 and the second antenna 16 are arranged with a distance d1 which is shown exaggerated large. In practice this distance d1 may for example be smaller than λ/2 (or even smaller than λ/3), wherein λ is the wavelength of a signal transmitted by a transmitter 40 and to be received by the receiver in accordance with the invention. However, the present invention, for example to enhance positive diversity effects, is not limited to embodiments having a smaller distance than λ/2 between the first antenna 12 and the second antenna 16, although smaller distances are preferred. Furthermore, in FIG. 1 there is shown a first system of coordinates 36, which is stationary with respect to the car 34, and a second system of coordinates 38 which is stationary with respect to the environment. Both systems of coordinates 36, 38 show, depending on the time d the position d of a first virtual antenna 26 which is created by the receiver in accordance with the invention (in a way described in detail with reference to FIG. 2). The first virtual antenna 26 is controlled to move between the first antenna 12 and the second antenna 16 with a speed −v, i.e. with the magnitude v but in the opposite direction as the car moves (see arrow 44). Thereby, as may be seen from the second systems of coordinates 38, the virtual antenna is stationary with respect to the environment for a time interval [0, t1]. However, within the time interval [0, t1] the virtual antenna 26 moves with respect to the car 34 as may be seen from the first system of coordinates 36. The fixed effective receive position can in practice only be realized for a limited period of time, since the vehicle may move over prolonged distances that largely extend the physical dimensions of the antenna structure. Thus, the first virtual antenna 26 will “collide” with the second antenna 16. In such case at the latest the position of the first virtual antenna must be changed to follow the long-term motion of the vehicle. As indicated in the first and second systems of coordinates 36, 38, the first virtual antenna 26 in a time interval [t1, t2] is repositioned close to or coinciding with the first antenna 12. For example in connection with the reception of OFDM signals, repositioning or switching of the position of the first virtual antenna 26 coincides the end of individual OFDM blocks, but does not occur during the reception of one such block. In accordance with the invention, the moment of switching to a new virtually-fixed position is controlled by a feedback signal SYNC coming from the (OFDM block or frame) synchronization mechanism of the receiver. FIG. 2 shows a simplified schematic block diagram of a first embodiment of a receiver in accordance with the present invention, and it further illustrates the method in accordance with the invention. In FIG. 2 there is shown a first receiving branch 10 having associated thereto the first antenna 12 and a second receiving branch 14 having associated thereto the second antenna 16. A first signal 20 on the first receiving branch 10 is a signal r(t0,d0), i.e. a signal that is received at the moment t0 at the position d0. Similar, a second signal 22 on the second receiving branch 14 is a signal r(t0, d1), i.e. a signal that is also received at the moment t0 but at the position d1. The first and second signals 20, 22 are fed to first means 18 which calculate a third signal 24 representing the first virtual antenna 26, i.e. a signal r(t0, d01) that would have been received at the moment t0 by an antenna located at the position d01. With the embodiment shown in FIG. 2, to obtain the third signal 24, the first means comprise adaptive combiner means 27 which linearly interpolate between the first signal 20 and the second signal 22 to create the virtual antenna 26. To keep the virtual antenna 26 stationary with respect to the environment, the virtual antenna 26 has to be virtually moved with the magnitude of the speed v. Therefore, the speed v is supplied as an input signal to the first means 18. Furthermore the synchronization signal SYNC from the receiver is supplied to the first means 18. As mentioned in connection with FIG. 1, this SYNC signal is used for the timing of the switching to a new virtual position of the first virtual antenna 26. FIG. 3 shows a simplified schematic block diagram of a second embodiment of a receiver in accordance with the present invention. This embodiment comprises all the equipment shown in FIG. 2 and additionally second means 28 for obtaining a fourth signal 30 representing a second virtual antenna 32. The fourth signal 30 corresponds to a signal r(t0, d02) that would have been received at the moment t0 by an antenna located at the position d02. To obtain the fourth signal 30, the second means 28 also comprise adaptive combiner means 46 which linearly interpolate between the first signal 20 and the second signal 22. Although the switching to new positions of the first virtual antenna 26 and the second virtual antenna 32 is performed depending on the synchronization signal SYNC, with the embodiment of FIG. 2 it is possible to have at least one virtual antenna stationary at every moment. This may facilitate the switching operations. Furthermore, for relative large time intervals it is possible to create two stationary virtual antennas at different positions. This for example may be used to achieve the advantages of known stationary diversity receivers. As regards the necessary synchronization, with alternative solutions it is possible to obtain this synchronization without the feedback SYNC from the main receiver. For example the synchronization may be obtained from a first free running oscillator, giving a pulse at instants N·T, with N=0, 1, . . . , and a second oscillator giving a pulse at instants Na·T, with Na=0.5, 1.5, 2.5, . . . , wherein T for example may be the sampling rate and N and Na, respectively, may be the number of bits for which a serial to parallel conversion is performed. Thus, the third signal 24 and the fourth signal 30 will experience synchronization discontinuities, and consequently bursts of errors at the instants N·T and NaT, respectively. Since N·T and Na·T in this case occur at different instances, the burst errors, both signals can be advantageously combined. FIG. 4 shows a simplified schematic block diagram illustrating a preferred possibility to obtain the feedback signal of the receiver. As regards the components or blocks 12 to 24, reference is made to the description of FIG. 2 since the respective components or parts correspond to each other. In FIG. 4 the components of an OFDM receiver in accordance with the prior art are summarized as a block 34. This block 34 contains serial to parallel converter means 36 that are also used to select the window for a Fast Fourier Transformation that is carried out in Block 38. After the Fast Fourier Transformation (FFT) a data detection, possibly with a channel equalization and an error correction is performed in block 40 which outputs an output signal 42. In block 46 there is performed a pre-FFT timing recovery to provide a coarse timing synchronization. Additionally, in block 44 there is performed a post-FFT timing recovery to provide a fine timing synchronization. The coarse and the fine timing synchronizations are combined by a combiner 48 which creates the synchronization signal SYNC which in accordance with the invention is used to control the first means 18. As already mentioned above, the invention also encompasses embodiments where only one of the pre-FFT and the post-FFT timing recovery is used. In such a case the combiner 48 can be omitted. With the invention described above, for a moving receiver it is possible to efficiently cancel or at least reduce signal distortions in connection with the receipt of broadcast signals by creating at least one virtual antenna which is at least temporarily stationary with respect to the environment. Thereby it is for example possible to receive high rate radio signals (for example video signals having for example a rate of 5 Mbits/sec) with a receiver moving at a high speed (for example a receiver located in a car). All means mentioned in the description and the claims may be realized, depending on the special embodiment, by components known in the art. In this connection discrete components and/or hardware interacting with software may form one or more of the mentioned means in part or as a whole. Furthermore, any reference signs contained in the claims shall not be constructed as limiting the scope.

20060222

20090811

20070104

93052.0

H04B708

TRAN, KHAI

VIRTUAL-ANTENNA RECEIVER

UNDISCOUNTED

ACCEPTED

H04B

ACCEPTED

Circuit arrangement and method for supporting and monitoring a microcontroller

A circuit arrangement for supporting and monitoring a microcontroller, which is constructed externally of the microcontroller, comprises a watchdog circuit for monitoring the microcontroller, which circuit outputs an error signal if not reset by the microcontroller within a watchdog period, and an interrupt circuit, which feeds important system messages to the microcontroller as interrupt events for processing. In order correctly to combine interrupt processing and watchdog operation, the watchdog circuit is connected to the interrupt circuit and cooperates therewith in such a way that the interrupt circuit feeds at most a predetermined number of interrupt events to the microcontroller within a watchdog period.

1. A circuit arrangement (100) for supporting and monitoring a microcontroller, which is constructed externally of the microcontroller (10), having a watchdog circuit for monitoring the microcontroller (10), which circuit outputs an error signal if not reset (14) by the microcontroller (10) within a watchdog period, and an interrupt circuit, which feeds (12) important system messages to the microcontroller (10) as interrupt events for processing, characterized in that the watchdog circuit is connected to the interrupt circuit and cooperates therewith in such a way that the interrupt circuit feeds at most a predetermined number of interrupt events to the microcontroller (10) within a watchdog period. 2. A circuit arrangement (100) for supporting and monitoring a microcontroller, which is constructed externally of the microcontroller (10), having a watchdog circuit for monitoring the microcontroller (10), which circuit outputs an error signal if not reset (14) by the microcontroller (10) within a watchdog period, and an interrupt circuit with various interrupt sources, which feeds (12) important system messages to the microcontroller (10) as interrupt events for processing, characterized in that the interrupt sources are assigned to priority classes, and a predetermined maximum number of interrupt events per watchdog period is set for at least one priority class, and the watchdog circuit is connected to the interrupt circuit and cooperates therewith in such a way that the interrupt circuit for priority classes with a set maximum number, feeds at most this maximum number of interrupt events of the associated interrupt sources to the microcontroller (10) within a watchdog period and, for priority classes without a set maximum number, feeds all the interrupt events of the associated interrupt sources to the microcontroller (10). 3. A circuit arrangement (100) as claimed in claim 2, characterized in that the priority classes comprise one maximum priority class, for which no maximum number is set. 4. A circuit arrangement (100) as claimed in claim 3, characterized in that each interrupt source is assigned either to the maximum priority class or to a second, lower priority class, for which a predetermined maximum number is set. 5. A circuit arrangement (100) as claimed in claim 1, characterized in that the circuit arrangement (100) is a transceiver, which comprises all the peripheral components to constitute a bus node. 6. A circuit arrangement (100) as claimed in claim 1, characterized in that the circuit arrangement (100) comprises the voltage supply for the microcontroller. 7. A circuit arrangement (100) as claimed in claim 3, characterized in that failure of the supply voltage constitutes an interrupt source in the maximum priority class. 8. A circuit arrangement (100) as claimed in claim 7, characterized in that a non-volatile memory (16) is provided, in which the microcontroller (10) saves important data in the event of failure of the supply voltage. 9. A method of supporting and monitoring a microcontroller, in which the microcontroller is monitored by a watchdog circuit, which outputs an error signal if not reset by the microcontroller within a watchdog period, and important system messages are fed to the microcontroller by an interrupt circuit as interrupt events for processing, characterized in that the watchdog circuit and the interrupt circuit cooperate in such a way that the interrupt circuit feeds at most a predetermined number of interrupt events to the microcontroller within a watchdog period. 10. A method of supporting and monitoring a microcontroller, in which the microcontroller is monitored by a watchdog circuit, which outputs an error signal if not reset by the microcontroller within a watchdog period, and important system messages are fed to the microcontroller by an interrupt circuit with various interrupt sources as interrupt events for processing, characterized in that the interrupt sources are assigned to priority classes, and a predetermined maximum number of interrupt events per watchdog period is set for at least one priority class, and the watchdog circuit and the interrupt circuit cooperate in such a way that the microcontroller for priority classes with a set maximum number, is fed by the interrupt circuit with at most this maximum number of interrupt events within a watchdog period, and for priority classes without a set maximum number, is fed by the interrupt circuit with all the interrupt events of the associated interrupt sources.

The invention relates to a circuit arrangement and a method for supporting and monitoring a microcontroller. The circuit arrangement is constructed externally of the microcontroller and comprises a watchdog circuit for monitoring the microcontroller, which circuit outputs an error signal if not reset by the microcontroller within a watchdog period, and an interrupt circuit, which feeds important system messages to the microcontroller as interrupt events for processing. These days, the software in modern control devices or microcontrollers, especially in the automotive industry, is monitored as a rule by a so-called watchdog circuit or reset circuit. In error-free operation, the watchdog circuit is regularly reset within a given time window, the watchdog period, by the control device or the microcontroller. If this does not happen, an error is detected and the watchdog circuit outputs a corresponding error signal. The error signal may, for example, trigger a restart of the control device or of the microcontroller. Consequently, the software of the control device must not exceed a given maximum running time within the watchdog period. In this respect, the processing of unforeseeable events, such as those involving interrupts for example, is problematic. In order to ensure that the maximum running time is complied with, the software designer may for example limit the number of interrupts which are handled per watchdog period. If a plurality of interrupts occur within one watchdog period, it may be the case that the last interrupts have to wait until the beginning of the next watchdog period. Direct processing of the interrupts is not possible, due to the unforeseeable nature of the events. The risk therefore arises of very urgent interrupt events, such as for example the impending loss of supply voltage, no longer being handled in time, so meaning that important system information or data may be lost. In principle, there are two different methods for a microprocessor to process incoming messages. With the so-called polling method, the messages directed to the microprocessor are stored in a buffer and the processor regularly checks to see whether a message has arrived which needs processing. This method has the disadvantage that, if the processor checks the buffer relatively seldom, a long time may pass between the arrival of a message and the processing thereof. If, on the other hand, the processor checks relatively frequently, the response time to the message is shortened, but heavy demands are made on the processor's computing time by the frequent checking, such that less time remains for other tasks. In a second method, the incoming messages trigger an interrupt, which interrupts the program the processor is running in order to process the message which has been received. This method has the advantage that the response time to a message is very short, and that the processor is only occupied with processing a message when a message is actually present. A disadvantage, however, is that the program which is running is constantly interrupted if messages arrive relatively frequently. In order to be able to exchange messages efficiently in a multiprocessor environment, the article “Polling Watchdog: Combining Polling and Interrupts for Efficient Message Handling”, O. Maquelin, G. R. Gao, H. H. J. Hum, K. B. Theobald, and X. Tian, 23rd Annual International Symposium on Computer Architecture, pages 179-188, Philadelphia, Pa., U.S.A., May 1996, proposes to eliminate the disadvantages of the two methods described above by reading out incoming messages regularly according to the polling method and starting a watchdog at the same time as each message arrives, which watchdog ensures that the response time to a message which has been received does not exceed a set amount. If the message is processed in good time, the watchdog is stopped. Otherwise, the watchdog triggers an interrupt, which forces the processor to process the message immediately. In this way, the processor workload is kept low and at the same time it is ensured that the response time to a message does not exceed a given amount. U.S. Pat. No. 6,505,298 B1 discloses a device which makes it possible to monitor an operating system by means of a watchdog. The watchdog periodically starts an interrupt routine, which may establish by access to a particular register whether the operating system is still operating properly. If this is not the case, the computer is reset. Special interrupt control is not proposed in this patent specification. It is an object of the invention to provide an improved control circuit of the above-stated type with which interrupt processing and watchdog operation may be correctly combined. This object is achieved by the control circuit having the features indicated in claim 1 or claim 2 and the method having the method steps indicated in claim 9 or claim 10. According thereto, the invention consists, in a first aspect, in the fact that, in a control circuit of the type discussed above, the watchdog circuit is connected to the interrupt circuit and cooperates therewith in such a way that the interrupt circuit feeds at most a predetermined number of interrupt events to the microcontroller within a watchdog period. The number of interrupts per watchdog period is thereby limited by hardware means. According to a second aspect, in which the interrupt circuit comprises various interrupt sources, the invention builds on the prior art in that the interrupt sources are assigned to priority classes and in that, for at least one priority class, a predetermined maximum number of interrupt events per watchdog period is set. The watchdog circuit is connected to the interrupt circuit and cooperates therewith in such a way that, for priority classes with a set maximum number, the interrupt circuit feeds at most this maximum number of interrupt events of the associated interrupt sources to the microcontroller within a watchdog period and, for priority classes without a set maximum number, feeds all the interrupt events of the associated interrupt sources to the microcontroller. The number of interrupts per watchdog period is thus limited by hardware means at least for one of the priority classes. Only a given limited quota of interrupts is thus available to the priority classes with a fixed maximum number. By adding up the maximum number for each class, the software designer may reliably estimate the total number of interrupts per watchdog period. The occurrence of interrupt events is thereby calculable to a considerable extent, so enabling rapid and direct processing of the interrupts. Assignment of the interrupt sources to different priority classes has the additional advantage that different interrupt groups may be separated from one another, so preventing an individual interrupt source from blocking the entire interrupt system. Advantageous developments and further embodiments of the invention are revealed by dependent claims 3 to 8. According to the preferred development of claim 3, the priority classes comprise a maximum priority class, for which no maximum number is set. Particularly urgent interrupts may be assigned to this class, which are still processed quickly enough even when the interrupt quota of all the other classes has already been exhausted. According to the advantageous measure of claim 4, each interrupt source is assigned either to the maximum priority class or to a second, lower priority class, for which a predetermined maximum number is set. In particular, the maximum number of the second class may be one, such that only a single one of the relatively unimportant interrupts may be triggered per watchdog period. This ensures that the microcontroller may always respond rapidly to the important interrupts of the maximum priority class and is not blocked by the handling of less important interrupts. According to the advantageous further embodiment of claim 5, the circuit arrangement is a transceiver, which comprises all the peripheral components to constitute a bus node. In particular, the circuit arrangement may comprise the voltage supply for the microcontroller, as indicated in claim 6. According to the advantageous further embodiment as claimed in claim 7, failure of the supply voltage constitutes an interrupt source in the maximum priority class. This measure ensures that the microcontroller may respond to such a failure in good time, even when the maximum number of interrupts from other interrupt sources has already been reached. According to the expedient development of claim 8, a non-volatile memory is provided in which the microcontroller saves important data in the event of failure of the supply voltage. Since the microcontroller supply is generally buffered by capacitors, if a corresponding interrupt command is processed in good time there is sufficient time available to perform such data saving. Claims 9 and 10 are directed towards methods of supporting and monitoring a microcontroller according to the first and second aspects of the invention respectively. The invention will be further described with reference to examples of embodiment shown in the drawings to which, however, the invention is not restricted. The single FIGURE shows a schematic block diagram of a microcontroller, which is supported and monitored by a base chip according to an example of embodiment of the invention. The single FIGURE is a block diagram of a base chip 100, which supports and monitors a microcontroller 10. The base chip 100 is a transceiver, which comprises all the peripheral components to constitute a bus node, such as watchdog, reset logic and voltage supply for the microcontroller 10. The base chip 100 monitors the software with the watchdog and informs the microcontroller 10, via a data line 12 with the assistance of the interrupts, about important processes in the system. The watchdog of the base chip 100 is reset by the microcontroller 10 via a connecting line 14 after every watchdog period. If resetting does not occur on time, the watchdog circuit detects an error and outputs a corresponding error signal. The hardware which may produce interrupts is coupled to the watchdog. The different interrupt sources of this hardware are subdivided into priority classes, in accordance with the invention, each priority class having available to it a given quota of interrupts per watchdog period. Only one maximum priority class, to which the most important interrupt sources are assigned, has an unlimited quota available to it. In this way, the software designer may reliably estimate the total number of interrupts per watchdog period. An important system message would be failure of the battery voltage, for example. The battery error interrupt is therefore assigned to the maximum priority class and may thus be processed sufficiently quickly even if the interrupt quota of all the other priority classes has already been exhausted. Since the supply of the microcontroller 10 is buffered by capacitors, not shown, important data may in this case still be quickly saved in a non-volatile memory 16. While the invention has been illustrated and described with particular reference to preferred examples of embodiment, it will be clear to the person skilled in the art that modifications may be made to form and detail without going beyond the concept and scope of the invention. Accordingly, the disclosure of the present invention is not intended to be limiting, but instead to illustrate the scope of the invention as set out below in the claims. LIST OF REFERENCE NUMERALS 10 Microcontroller 12 Data line to microcontroller 14 Connecting line for resetting watchdog 16 Non-volatile memory 100 Base chip

20060222

20090505

20070104

98104.0

G06F1100

WILSON, YOLANDA L

CIRCUIT ARRANGEMENT AND METHOD FOR SUPPORTING AND MONITORING A MICROCONTROLLER

UNDISCOUNTED

ACCEPTED

G06F

ACCEPTED

Slurry tolerant pilot operated relief valve

Cartridge-style fluid control devices are provided that are static pressure independent and capable of repeatable, reliable, particulate insensitive performance in service conditions typical of downhole intervention environments.

1. A pressure-actuated valve comprising: (a) a valve body with a cavity formed therein, said cavity being defined by a retaining cap at one end of the valve body and extending from there for a length until an annular wall is encountered, said annular wall separating the cavity for the remainder thereof into a central bore and an outer annular region, said valve body having two passages from outside the valve body into the bore serving interchangeably for inlet and outlet of fluids (possibly containing small solids) whose flow is to be controlled by the valve, and an annular valve seat disposed in said bore between said inlet and said outlet, said inlet and outlet being disposed in the bore remote from the retaining cap, said retaining cap having a passage through it providing communication between outside the valve body and the valve body cavity; (b) a plunger with a head and a sealing end, said plunger being movably disposed within said bore with said head end extending out of the bore into the valve body cavity, said head being larger than the outer diameter of said annular wall enclosing said bore, said sealing end being adapted for operative engagement with said valve seat thus preventing fluid flow between the inlet and the outlet and constituting the off position for the valve, said plunger having a range of travel in the bore to a valve-open position at which the plunger head contacts the retaining cap, said plunger's length being determined such that fluid passage between the inlet and the outlet is substantially unobstructed by the plunger in the valve-open position; (c) a spring disposed in said outer annular region surrounding said bore such that the plunger head contacts the spring requiring compression of the spring in order for the plunger's sealing end to contact the valve seat wherein, in operation, a high-pressure actuating fluid entering the valve body cavity through the passage in the retaining cap exerts pressure on the plunger head tending to force the plunger toward the valve seat and closing the valve when the fluid pressure overcomes the spring's resistance; and (d) a seal between the plunger and the bore disposed between (i) the fluid inlet and outlet and (ii) the end of the bore nearer to the retaining cap, said seal isolating the high-pressure actuating fluid from the fluid flowing between said valve body inlet and outlet. 2. The valve of claim 1, further comprising a bushing movably disposed between said spring and said plunger head, said bushing serving as a shim adjustment to the valve operation, thereby determining the bushing's thickness. 3. The valve of claim 1, wherein one of said two passages into the core for valve-controlled fluids is disposed such that it enters the bore non-axially into the side of the bore at a location between the valve seat and the plunger head, thereby enabling no more than negligible fluid pressure on the plunger in a direction tending to force the valve open from a closed position. 4. The valve of claim 3, wherein the other passage into the core for valve-controlled fluids is a continuation of said bore through the valve body at the end of the valve body remote from the retaining cap. 5. The valve of claim 1 wherein the clearance tolerance between the plunger and the core is between 0.13 mm and 0.25 mm. 6. The valve of claim 1 where the valve seat is designed with a chamfer of approximately 45 degrees. 7. The valve of claim 1, wherein said annular valve seat has a radial dimension of approximately 0.25 mm. 8. The valve of claim 1, wherein said valve body is formed for cartridge-style deployment. 9. The valve of claim 1, wherein said spring is designed to be in a state of partial compression with said plunger head in contact with said retaining cap. 10. The valve of claim 1, wherein said spring comprises a plurality of stacked Belleville (disc) springs.

FIELD OF THE INVENTION This invention pertains to fluid control devices for metering, maintaining, and isolating fluid pressure and flow between two or more sources. BACKGROUND OF THE INVENTION Fluid control is routinely practiced within a wide variety of industries. Control is typically achieved using devices that are specifically designed to perform a unique control operation. Examples of such control devices are pressure relief valves, pressure regulators, back-pressure regulators, velocity fuses, mass flow controllers, pilot operated valves, check valves, and shuttle valves. Pressure is typically communicated from one source to another via the flow of gas or liquid. Operational challenges arise when the flow used to communicate pressure is laden with particulates. These particulates introduce the potential for a device to lose functionality as a result of solids becoming lodged in a device's moving parts, as well as damage resulting from the cutting capacity of high velocity, particle-laden fluid streams passing over a device's sealing components. The use of rigid seal materials such as metal or thermoplastics enhance the durability of a device, but compromise the sealability of the device. For example, a steel ball could never seal a circular steel aperture if a sand grain was wedged between the steel ball and the edge of the aperture (or if the edge of the aperture was slightly nicked). If the ball was made of a pliable material such as rubber, the ball could seal the circular aperture because the sand grain could imbed in the ball and the ball could then fully contact the perimeter of aperture. While the rubber ball is a superior sealing material, it is also highly susceptible to damage from the cutting action of high velocity fluid streams. Many valving designs directly, or indirectly, involve three pressures: 1.) inline high pressure source; 2.) inline low pressure source; and 3.) a static pressure source, e.g., ambient pressure in a spring cavity. Valve designs that involve an isolated, or sealed, static pressure exhibit limited functionality in a downhole environment. The primary reason is that most downhole operations are performed in a well that is filled with liquid, thus the static pressure increases as a function of depth. This change in static pressure results in a change in valve performance as a function of depth. Valve designs that provide free static pressure communication to all actuating parts within the system enable depth (or static pressure) independence. This is because fluid based valve actuation forces result from differential pressures acting upon an area. Since the actuation forces are based on the difference between pressure sources, the reference pressure (or static pressure) that is common to all sources is canceled out, and the performance of the valve becomes depth independent. An additional criteria required of downhole fluid control operations is related to size. Wellbores of various diameters are created in an effort to optimize the economic impact of a field development; and valves must be smaller than the wellbore diameter in which they are deployed. As a result, valves with small external dimensions possess a larger portfolio of accessible intervention wells than larger valves of similar function. In addition, when valves are deployed downhole they are not readily accessible for servicing; thus significant expense is typically incurred if valve failures occur during an intervention program. This emphasizes the need for downhole valves to be highly reliable. For various applications, certain advantages can be realized by designing a control valve device in the form of a cartridge valve. A cartridge style control valve offers the following benefits: 1.) the ability to interchangeably deploy the same valve in multiple tools that require the given valve's control function; 2.) the ability to incorporate the valve into cartridge valve based logic systems; 3.) the ability to verify functionality before deployment by performing bench-top surface testing of the valve; 4.) simplified valve replacement and servicing; and 5.) cartridge valves are well suited for deployment in parallel, or series (e.g., for the purpose of redundancy in safety critical applications). Most downhole fluid control devices are deployed as a single unit or connected in series with other downhole components. The systems are generally comprised of a combination of annular based components, springs, and/or balls. Annular based components are defined as parts that are symmetric about the centerline of the valve. The valves tend to have rigid seal materials and are designed in a fashion that are susceptible to compromised functionality due to particulate bridging between the rigid seal materials. Current technology does not provide a suitable physical design, or design concept for the problem. A need exists for small cartridge-style fluid control devices that are static pressure independent and capable of repeatable, reliable, particulate insensitive performance in service conditions typical of downhole intervention environments. An object of this invention is to provide such fluid control devices. Other objects will become apparent through consideration of the following specification together with the accompanying drawings. SUMMARY OF THE INVENTION In one embodiment, the present invention is a pressure-actuated valve comprising: (a) a valve body with a cavity formed therein, said cavity being defined by a retaining cap at one end of the valve body and extending from there for a length until an annular wall is encountered, said annular wall separating the cavity for the remainder thereof into a central bore and an outer annular region, said valve body having two passages from outside the valve body into the bore serving interchangeably for inlet and outlet of fluids (possibly containing small solids) whose flow is to be controlled by the valve, and an annular valve seat disposed in said bore between said inlet and said outlet, said inlet and outlet being disposed in the bore remote from the retaining cap, said retaining cap having a passage through it providing communication between outside the valve body and the valve body cavity; (b) a plunger with a head and a sealing end, said plunger being movably disposed within said bore with said head end extending out of the bore into the valve body cavity, said head being larger than the outer diameter of said annular wall enclosing said bore, said sealing end being adapted for operative engagement with said valve seat thus preventing fluid flow between the inlet and the outlet and constituting the off position for the valve, said plunger having a range of travel in the bore to a valve-open position at which the plunger head contacts the retaining cap, said plunger's length being determined such that fluid passage between the inlet and the outlet is substantially unobstructed by the plunger in the valve-open position; (c) a spring disposed in said outer annular region surrounding said bore such that the plunger head contacts the spring requiring compression of the spring in order for the plunger's sealing end to contact the valve seat wherein, in operation, a high-pressure actuating fluid entering the valve body cavity through the passage in the retaining cap exerts pressure on the plunger head tending to force the plunger toward the valve seat and closing the valve when the fluid pressure overcomes the spring's resistance; and (d) a seal between the plunger and the bore disposed between (i) the fluid inlet and outlet and (ii) the end of the bore nearer to the retaining cap, said seal isolating the high-pressure actuating fluid from the fluid flowing between said valve body inlet and outlet. In some embodiments of the present invention, the valve further comprises a bushing movably disposed between the spring and the plunger head, with inner diameter large enough to fit movably around the annular wall defining the central bore. The bushing can serve as a shim adjustment for the valve's operation, thereby determining the thickness of the bushing. In some embodiments of the invention, the valve body is formed for cartridge-style deployment. In some embodiments of the invention, the spring is installed under compression, i.e., it is in a state of partial compression even when the plunger head is fully up against the retaining cap. DESCRIPTION OF THE DRAWINGS The advantages of the present invention will be better understood by referring to the following detailed description and the attached drawings in which: FIG. 1A illustrates a valve according to this invention in the open position; and FIG. 1B illustrates a valve according to this invention in the closed position. While the invention will be described in connection with its preferred embodiments, it will be understood that the invention is not limited thereto. To the extent that the following description is specific to a particular embodiment or a particular use of the invention, this is intended to be illustrative only, and is not to be construed as limiting the scope of the invention. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the spirit and scope of the present disclosure, as defined by the appended claims. DETAILED DESCRIPTION OF THE INVENTION The following discussion describes the invention within the context of oilfield downhole intervention technology, although the invention is not limited to such use. An application in which a valve according to this invention is particularly useful is fracture stimulation, especially when used with a coiled tubing deployed intervention tool that comprises an inflatable packer, slips, and a circuit of cartridge valves that perform tasks as a function of applied pressure. In wellbores with multiple zones open (multiple sets of reservoir intervals in communication with the wellbore at different depths), the possibility exists that flow will exit one reservoir interval and travel through the wellbore into another reservoir interval. This phenomenon is called cross-flow and it is driven by a pressure imbalance between reservoirs. If a bottom hole assembly (i.e., BHA or intervention tool) is located between two zones that are cross-flowing, the potential exists for the BHA to be pushed uphole and buckle the coiled tubing, pulled downhole and pull part the BHA or coiled tubing, or damage the BHA as debris passes by the tool at high rates. This phenomenon can be particularly significant while an inflatable packer is being inflated and deflated. This is because during the inflation and deflation process the packer reaches a point where the packer has effectively shut-off the cross-flow fluid passing between the casing and the packer but has not yet contacted the casing with enough force to anchor it in place. At this time, the differential pressure that exists between the cross-flowing reservoir intervals is applied to the full cross-sectional area of the un-anchored BHA. Depending on the specific application, the resulting forces could be significant and promote the aforementioned results. In an effort to avoid the potential results of operating an inflatable packer in the presence of cross-flow, the pressure across the packer is preferably equalized through the center of the packer until it is firmly anchored to the wall. To achieve this goal, a pilot operated relief valve according to this invention is incorporated into the BHA design. The valve equalizes wellbore pressure across the inflatable packer while it is inflating and then closes the equalization path after the packer has fully contacted the casing walls. During packer deflation the valve opens prior to release of the packer from the casing wall and remains open during the deflation process. The valve is designed to be pressure actuated using a pilot pressure from the coiled tubing. The use of coiled tubing pressure to control the valve's operation enables the valve to actuate at the proper time relative to the packer inflation and deflation cycle. An application in which the intervention tool is particularly useful is reservoir fracture stimulation using sand or proppant. Thus, the fluid environment in which the valve is expected to operate reliably is one in which sand and proppant may pass through the valve under normal operating conditions or under upset operating conditions. Since wellbore fluids are typically laden with various particles, the valve design must be robust with respect to actuation and sealing in the presence of particulate debris. The general function of a Pilot Operated Relief Valve (PORV) according to this invention is described below. The valve is designed to remain fully open when the actuating pressure remains below a pre-set value. When the actuating pressure surpasses this pre-set pressure, the closing process is initiated. When the valve is closed, the fluid pressure acting on the valve plunger does not have an effective area to act upon, thus the valve's function is independent of this pressure. This feature is particularly important if the intervention application involves applying significant pressure to the fluid in this passage (e.g., fracture stimulation operations). Operation of the valve is described in connection with a packer, as described above. The packer is not shown in the drawings. Referring to the drawings, the primary moving parts of a valve 10 according to this invention are: (i) spring assembly 12 that preferably comprises a plurality of springs or discs 12a; (ii) a plunger 14 having a head 14a and a sealing end 14b; and (iii) bushing 16. A valve 10 according to this invention also comprises valve body 17 having a hollow spring support portion 17a and a connector portion 17b, valve body sleeve 19, seat 26, seat housing 27, and retaining cap 18. A fluid pressure force acts at cross-sectional area 11 to move plunger 14 toward seat 26; i.e., high pressure fluid 13 above cross-sectional area 11 acts on cross-sectional area 11 to push plunger 14 in the direction of seat 26. Plunger 14 moves axially and its motion is governed by a force balance between the force of springs 12 pushing plunger 14 away from seat 26 and the fluid pressure force acting at cross-sectional area 11 pushing plunger 14 toward seat 26. When valve 10 is in the open position, the force of springs 12 is greater than the pressure force at cross-sectional area 11 and it pushes plunger 14 away from seat 26 and holds it against retaining cap 18. Flow is free to communicate in either direction between passage 20, for fluid from uphole of the packer, and passage 22, for fluid from downhole of the packer. High pressure actuating fluid 13 is isolated from fluid 23 flowing between passages 20 and 22 by seals 15 in plunger 14 at cross-sectional area 11 and seals 28 on valve body 17. As the pressure of actuating fluid 13 is increased above the pre-set close value of valve 10, the pressure force at cross-sectional area 11 overcomes the force of springs 12 (plus any breakaway friction force from seals or O-rings 15 in plunger 14 at cross-sectional area 11) and begins to push plunger 14 toward seat 26. As plunger 14 moves toward seat 26, flow begins to be restricted through the region between the bottom of plunger 14 and location 21. As bottom edge 24 of plunger 14 reaches location 21, flow is significantly reduced. This reduction in flow, in combination with the vertical and inclined passage geometry leading up to location 21, allows particles to tumble away from location 21 before plunger 14 enters the orifice of passage 22. This reduction in flow rate results in a reduction in particle delivery rate and particle delivery size to the pinch point at location 21, thus the likelihood of particles becoming lodged between plunger 14 and location 21 is diminished. In addition, the curved geometry of the sharp location 21 edge insures that only a small number of particles could reside at the pinch point. The large plunger force attainable via the actuating fluid pressure acting on cross-sectional area 11 provides sufficient force to shear through a small number of particulate grains. Referring now to FIG. 1B, as plunger 14 continues its downward stoke it enters the orifice of passage 22. The diameter tolerance between plunger 14 and the orifice is preferably small in an effort to significantly reduce the flow rate through valve 10 (e.g., about 0.13 mm to 0.25 mm, (0.005 in to 0.010 in)). If the flow direction is from passage 22 to passage 20, the significantly reduced flow rate limits the size of particles that can be carried against gravity to seat 26 of passage 22. If the flow direction is from passage 20 to passage 22, then the gap between plunger 14 and the orifice of passage 22 acts as a screen that filters all particles greater than the gap width. As a result, regardless of the flow direction between passages 20 and 22, there is a physical mechanism that acts to minimize the size and delivery rate of particles to seat 26. Seat 26 is preferably designed with a 45° chamfer to allow particles to fall from seat 26 under the influence of gravity, or to be squeezed off during the seating process. In addition, seat 26 is preferably designed with a relatively small diameter decrease from the diameter of passage 22. The size of the small lip that comprises the plunger contact portion of seat 26 (e.g., about 0.25 mm (0.010 in)) provides an upper bound on the particle diameter that could fit on the lip, assuming that it was possible for the particle to maintain a stable position on the 45° chamfer. In addition, the low-profile nature of seat 26 provides minimal restriction to flow when valve 10 is fully open. Valve 10 is re-opened by reducing the actuating pressure and allowing the spring force to push plunger 14 back to retaining cap 18. The pressure at which valve 10 becomes fully open is nominally similar to the pre-set pressure that initiated the valve closing process. After valve 10 is opened, fluid is able to freely exchange between passages 20 and 22. EXAMPLES The following discussion provides a paper example that is based on deployment of a pilot operated relief valve (PORV) according to this invention in a fracture stimulation application. For this example a coiled tubing deployed bottom-hole-assembly (BHA) is assumed and this BHA is comprised of an inflatable packer and a circuit of cartridge valves that perform tasks as a function of applied pressure. It is also assumed that packer inflation occurs via applied coiled tubing pressure, and the PORV port for actuation fluid (fluid 13 in the drawings) is in communication with the coiled tubing. Additionally, it is assumed that an independent flow passage exists through the center of the packer with one passage in the PORV (passage 20 in the drawings) in communication with the annular fluid uphole of the packer and another passage (passage 22 in the drawings) being in communication with the fluid downhole of the packer. It is also assumed that the fracture stimulation is pumped between the casing and the coiled tubing into an interval uphole of the inflated packer. It is also assumed that the fracture stimulation process occurs in a wellbore with several pre-existing reservoir intervals in communication with the wellbore below the location of the BHA. It is assumed that the PORV is configured to remain open up to an actuating pressure of 13.8 MPa (2000 psi) and with a close pressure of 34.5 MPa (5000 psi). With the BHA positioned between reservoir intervals that are in communication with the wellbore, the possibility exists that the two intervals are in cross-flow communication. The application of pressure to the coiled tubing initiates the packer inflation process. As the inflatable packer increases in diameter and begins to touch the casing wall, the fraction of the cross-flow that was originally passing between the outside diameter of the packer and the inside diameter of the casing diverts into the equalization passage running through the center of the packer. Increasing the coiled tubing pressure to approximately 13.8 MPa (2000 psi) anchors the packer to casing walls and initiates the closing process for the pilot operated relief valve. As the coiled tubing pressure is increased the PORV begins to close, the packer anchoring pressure increases, and the cross-flow induced differential pressure begins to build across the packer. Increasing the coiled tubing pressure to 34.5 MPa (5000 psi) closes the PORV and places 34.5 MPa (5000 psi) of anchoring pressure into the packer. The simulation program is initiated after the packer is firmly anchored to the casing wall. Since the packer is sealed against the casing walls and the PORV is closed, all stimulation fluids pumped down the annulus between the casing and coiled tubing are injected into the desired reservoir interval. Since passage 20 (see the drawings) of the PORV is in direct communication with the fluid above the packer, the stimulation pressures applied to the annulus are directly applied to the plunger in the PORV via passage 20. However, since the PORV is designed such that there is essentially no effective area for this stimulation pressure to act, the valve remains closed. Following the stimulation, the coiled tubing pressure is decreased. When the coiled tubing pressure and packer pressure reach approximately 13.8 MPa (2000 psi) the PORV has completely re-opened and pressure equalization is fully enabled. Decreasing the coiled tubing pressure to zero allows the packer to release from the casing walls and deflate. The stimulation is then complete and the BHA is free to move uphole. Although this invention is well suited for use in oilfield downhole intervention technology, it is not limited thereto; rather, this invention is suitable for any application where fluid control is required. Additionally, while the present invention has been described in terms of one or more preferred embodiments, it is to be understood that other modifications may be made without departing from the scope of the invention, which is set forth in the claims below.

<SOH> BACKGROUND OF THE INVENTION <EOH>Fluid control is routinely practiced within a wide variety of industries. Control is typically achieved using devices that are specifically designed to perform a unique control operation. Examples of such control devices are pressure relief valves, pressure regulators, back-pressure regulators, velocity fuses, mass flow controllers, pilot operated valves, check valves, and shuttle valves. Pressure is typically communicated from one source to another via the flow of gas or liquid. Operational challenges arise when the flow used to communicate pressure is laden with particulates. These particulates introduce the potential for a device to lose functionality as a result of solids becoming lodged in a device's moving parts, as well as damage resulting from the cutting capacity of high velocity, particle-laden fluid streams passing over a device's sealing components. The use of rigid seal materials such as metal or thermoplastics enhance the durability of a device, but compromise the sealability of the device. For example, a steel ball could never seal a circular steel aperture if a sand grain was wedged between the steel ball and the edge of the aperture (or if the edge of the aperture was slightly nicked). If the ball was made of a pliable material such as rubber, the ball could seal the circular aperture because the sand grain could imbed in the ball and the ball could then fully contact the perimeter of aperture. While the rubber ball is a superior sealing material, it is also highly susceptible to damage from the cutting action of high velocity fluid streams. Many valving designs directly, or indirectly, involve three pressures: 1.) inline high pressure source; 2.) inline low pressure source; and 3.) a static pressure source, e.g., ambient pressure in a spring cavity. Valve designs that involve an isolated, or sealed, static pressure exhibit limited functionality in a downhole environment. The primary reason is that most downhole operations are performed in a well that is filled with liquid, thus the static pressure increases as a function of depth. This change in static pressure results in a change in valve performance as a function of depth. Valve designs that provide free static pressure communication to all actuating parts within the system enable depth (or static pressure) independence. This is because fluid based valve actuation forces result from differential pressures acting upon an area. Since the actuation forces are based on the difference between pressure sources, the reference pressure (or static pressure) that is common to all sources is canceled out, and the performance of the valve becomes depth independent. An additional criteria required of downhole fluid control operations is related to size. Wellbores of various diameters are created in an effort to optimize the economic impact of a field development; and valves must be smaller than the wellbore diameter in which they are deployed. As a result, valves with small external dimensions possess a larger portfolio of accessible intervention wells than larger valves of similar function. In addition, when valves are deployed downhole they are not readily accessible for servicing; thus significant expense is typically incurred if valve failures occur during an intervention program. This emphasizes the need for downhole valves to be highly reliable. For various applications, certain advantages can be realized by designing a control valve device in the form of a cartridge valve. A cartridge style control valve offers the following benefits: 1.) the ability to interchangeably deploy the same valve in multiple tools that require the given valve's control function; 2.) the ability to incorporate the valve into cartridge valve based logic systems; 3.) the ability to verify functionality before deployment by performing bench-top surface testing of the valve; 4.) simplified valve replacement and servicing; and 5.) cartridge valves are well suited for deployment in parallel, or series (e.g., for the purpose of redundancy in safety critical applications). Most downhole fluid control devices are deployed as a single unit or connected in series with other downhole components. The systems are generally comprised of a combination of annular based components, springs, and/or balls. Annular based components are defined as parts that are symmetric about the centerline of the valve. The valves tend to have rigid seal materials and are designed in a fashion that are susceptible to compromised functionality due to particulate bridging between the rigid seal materials. Current technology does not provide a suitable physical design, or design concept for the problem. A need exists for small cartridge-style fluid control devices that are static pressure independent and capable of repeatable, reliable, particulate insensitive performance in service conditions typical of downhole intervention environments. An object of this invention is to provide such fluid control devices. Other objects will become apparent through consideration of the following specification together with the accompanying drawings.

<SOH> SUMMARY OF THE INVENTION <EOH>In one embodiment, the present invention is a pressure-actuated valve comprising: (a) a valve body with a cavity formed therein, said cavity being defined by a retaining cap at one end of the valve body and extending from there for a length until an annular wall is encountered, said annular wall separating the cavity for the remainder thereof into a central bore and an outer annular region, said valve body having two passages from outside the valve body into the bore serving interchangeably for inlet and outlet of fluids (possibly containing small solids) whose flow is to be controlled by the valve, and an annular valve seat disposed in said bore between said inlet and said outlet, said inlet and outlet being disposed in the bore remote from the retaining cap, said retaining cap having a passage through it providing communication between outside the valve body and the valve body cavity; (b) a plunger with a head and a sealing end, said plunger being movably disposed within said bore with said head end extending out of the bore into the valve body cavity, said head being larger than the outer diameter of said annular wall enclosing said bore, said sealing end being adapted for operative engagement with said valve seat thus preventing fluid flow between the inlet and the outlet and constituting the off position for the valve, said plunger having a range of travel in the bore to a valve-open position at which the plunger head contacts the retaining cap, said plunger's length being determined such that fluid passage between the inlet and the outlet is substantially unobstructed by the plunger in the valve-open position; (c) a spring disposed in said outer annular region surrounding said bore such that the plunger head contacts the spring requiring compression of the spring in order for the plunger's sealing end to contact the valve seat wherein, in operation, a high-pressure actuating fluid entering the valve body cavity through the passage in the retaining cap exerts pressure on the plunger head tending to force the plunger toward the valve seat and closing the valve when the fluid pressure overcomes the spring's resistance; and (d) a seal between the plunger and the bore disposed between (i) the fluid inlet and outlet and (ii) the end of the bore nearer to the retaining cap, said seal isolating the high-pressure actuating fluid from the fluid flowing between said valve body inlet and outlet. In some embodiments of the present invention, the valve further comprises a bushing movably disposed between the spring and the plunger head, with inner diameter large enough to fit movably around the annular wall defining the central bore. The bushing can serve as a shim adjustment for the valve's operation, thereby determining the thickness of the bushing. In some embodiments of the invention, the valve body is formed for cartridge-style deployment. In some embodiments of the invention, the spring is installed under compression, i.e., it is in a state of partial compression even when the plunger head is fully up against the retaining cap.

20060227

20081223

20070104

66703.0

F16K3100

FRISTOE JR, JOHN K

SLURRY TOLERANT PILOT OPERATED RELIEF VALVE

UNDISCOUNTED

ACCEPTED

F16K

ACCEPTED

Method to make single-layer pet bottles with high barrier and improved clarity

The present invention comprises a blend of polyester and a partially aromatic polyamide with an ionic compatibilizer and a cobalt salt. This blend can be processed into a container that has both active and passive oxygen barrier and carbon dioxide barrier properties at an improved color and clarity than containers known in the art. The partially aromatic polyamide is preferably meta-xylylene adipamide. The ionic compatibilizer is preferably 5-sodiumsulfoisophthalic acid or 5-zincsulfoisophthalic acid, or their dialkyl esters such as the dimethyl ester (SIM) and glycol ester (SIPEG). The cobalt salt is selected form the class of cobalt acetate, cobalt carbonate, cobalt chloride, cobalt hydroxide, cobalt naphthenate, cobalt oleate, cobalt linoleate, cobalt octoate, cobalt stearate, cobalt nitrate, cobalt phosphate, cobalt sulfate, cobalt (ethylene glycolate), or mixtures of two or more of these. The partially aromatic polyamide is present in a range from about 1 to about 10 wt. % of said composition. The ionic compatibilizer is present in a range from about 0.1 to about 2.0 mol-% of said composition. The cobalt salt is present in a range from about 20 to about 500 ppm of said composition.

1) A composition for containers comprising: polyester, partially aromatic polyamide, ionic compatibilizer, and a cobalt salt. 2) The composition of claim 1, wherein said partially aromatic polyamide is present in a range from about 1 to about 10 wt. % of said composition. 3) The composition of claim 1, wherein said ionic compatibilizer is present in a range from about 0.1 to about 2.0 mol-% of said composition 4) The composition of claim 1, wherein said cobalt salt is present in a range from about 20 to about 500 ppm of said composition. 5) The composition of claim 1, wherein said partially aromatic polyamide contains meta-xylylene. 6) The composition of claim 5, wherein said meta- xylylene polyamide is meta-xylylene adipamide. 7) The composition of claim 1, wherein said partially aromatic polyamide is selected from the group of poly(hexamethylene isophthalamide), poly(hexamethylene adipamide-co-isophthalamide), poly(hexamethylene adipamide-co-terephthalamide), poly(hexamethylene isophthalamide-co-terephthalamide), or mixtures of two or more of these. 8) The composition of claim 1, wherein said cobalt salt is selected form the class of cobalt acetate, cobalt carbonate, cobalt chloride, cobalt hydroxide, cobalt naphthenate, cobalt oleate, cobalt linoleate, cobalt octoate, cobalt stearate, cobalt nitrate, cobalt phosphate, cobalt sulfate, cobalt (ethylene glycolate), or mixtures of two or more of these. 9) The composition of claim 1, wherein said ionic compatibilizer is preferably a copolyester containing a metal sulfonate salt. 10) The composition of claim 9, wherein said metal ion of the sulfonate salt may be Na+, Li+, K+, Zn++, Mn++, Ca++ and the like. 11) The composition of claim 10, wherein said sulfonate salt group is attached to an aromatic acid nucleus or the ester equivalent selected from the group of benzene, naphthalene, diphenyl, oxydiphenyl, sulfonyldiphenyl, or methylenediphenyl nucleus. 12) The composition of claim 11, wherein said aromatic acid nucleus or the ester equivalent is sulfophthalic acid, sulfoterephthalic acid, sulfoisophthalic acid, 4-sulfonaphthalene-2,7-dicarboxylic acid, and their esters. 13) The composition of claim 12, wherein said ionic compatibilizer is 5-sodiumsulfoisophthalic acid or 5-zincsulfoisophthalic acid, or their dialkyl esters such as the dimethyl ester (SIM) and glycol ester (SIPEG). 14) A perform or container comprising: a composition of polyester, partially aromatic polyamide, ionic compatibilizer, and a cobalt salt. 15) The perform or container of claim 14, wherein said partially aromatic polyamide is present in a range from about 1 to about 10 wt. % of said composition. 16) The perform or container of claim 14, wherein said ionic compatibilizer is present in a range from about 0.1 to about 2.0 mole-% of said composition. 17) The perform or container of claim 14, wherein said cobalt salt is present in a range from about 20 to about 500 ppm of said composition. 18) The perform or container of claim 14, wherein said partially aromatic polyamide contains meta-xylylene. 19) The perform or container of claim 18, wherein said meta-xylylene polyamide is meta-xylylene adipamide. 20) The perform or container of claim 14, wherein said partially aromatic polyamide is selected from the group of poly(hexamethylene isophthalamide), poly(hexamethylene adipamide-co-isophthalamide), poly(hexamethylene adipamide-co-terephthalamide), poly(hexamethylene isophthalamide-co-terephthalamide), or mixtures of two or more of these. 21) The perform or container of claim 14, wherein said cobalt salt is selected form the class of cobalt acetate, cobalt carbonate, cobalt chloride, cobalt hydroxide, cobalt naphthenate, cobalt oleate, cobalt linoleate, cobalt octoate, cobalt stearate, cobalt nitrate, cobalt phosphate, cobalt sulfate, cobalt (ethylene glycolate), or mixtures of two or more of these. 22) The perform or container of claim 14, wherein said ionic compatibilizer is preferably a copolyester containing a metal sulfonate salt. 23) The perform or container of claim 22, wherein said metal ion of the sulfonate salt may be Na+, Li+, K+, Zn++, Mn++, Ca++ and the like. 24) The perform or container of claim 23, wherein said sulfonate salt group is attached to an aromatic acid nucleus or the ester equivalent selected from the group of benzene, naphthalene, diphenyl, oxydiphenyl, sulfonyldiphenyl, or methylenediphenyl nucleus. 25) The perform or container of claim 24, wherein said aromatic acid nucleus or the ester equivalent is sulfophthalic acid, sulfoterephthalic acid, sulfoisophthalic acid, 4-sulfonaphthalene-2,7-dicarboxylic acid, and their esters. 26) The perform or container of claim 25, wherein said ionic compatibilizer is 5-sodiumsulfoisophthalic acid or 5-zincsulfoisophthalic acid, or their dialkyl esters such as the dimethyl ester (SIM) and glycol ester (SIPEG). 27) A polyester container having an oxygen permeation rate of <0.01 cc(STP)-cm/m2-atm-day after 100 hours in oxygen. 28) The container of claim 27, comprising: a composition of polyester, partially aromatic polyamide, ionic compatibilizer, and a cobalt salt. 29) The container of claim 27, having a wall b* of less than 2.5. 30) A polyester container that has a carbon dioxide transmission rate of less than 7 cc/bottle/day, based on a 0.59 liter bottle.

BACKGROUND OF THE INVENTION 1) Field of the Invention The invention relates to compatibilized blends of polyamides in polyesters, a method for forming such compositions, and to containers made from such compositions. Specifically the compositions have less yellowness than previous blends. The blends can be used as passive gas barriers, or active oxygen scavengers with the addition of a transition metal catalyst. 2) Prior Art Plastic materials have been replacing glass and metal packaging materials due to their lighter weight, decreased breakage compared to glass, and potentially lower cost. One major deficiency with polyesters is its relatively high gas permeability. This restricts the shelf life of carbonated soft drinks and oxygen sensitive materials such as beer and fruit juices. Multilayer bottles containing a low gas permeable polymer as an inner layer, with polyesters as the other layers, have been commercialized. Blends of these low gas permeable polymers into polyester have not been successful due to haze formed by the domains in the two-phase system. The preferred polyamide is a partially aromatic polyamide containing meta-xylylene groups, especially poly (m-xylylene adipamide), MXD6. The MXD6 bulletin (TR No. 0009-E) from Mitsubishi Gas Chemical Company, Inc., Tokyo Japan, clearly shows that the haze of a multilayer bottle containing a layer of 5 wt-% MXD6 is ˜1% compared to 15% for a blend of the same 5 wt-%. However, the use of partially aromatic polyamides as the low gas permeable polymer gives an increase in the yellowness of the resultant container. U.S. Pat. No. 4,501,781 to Kushida et al. discloses a hollow blow-molded biaxially oriented bottle shaped container comprising a mixture of polyethylene terephthalate (PET) resin and a xylylene group-containing polyamide resin. Both monolayer and multilayer containers are disclosed, but there is no information on the color of the bottles. U.S. Pat. No. 5,650,469 to Long et al. discloses the use of a terephthalic acid based polyester blended with low levels (0.05 to 2.0 wt-%) of a polyamide to reduce the acetaldehyde level of the container. These blends produced lower yellowness containers than a corresponding blend made from a dimethyl terephthalate based polyester, but are still unsatisfactory for the higher levels required to significantly lower (decrease) the gas permeability. U.S. Pat. Nos. 5,258,233, 5,266,413 and 5,340,884 to Mills et al. discloses a polyester composition comprising 0.05 to 2.0 wt-% of low molecular weight polyamide. At a 0.5 wt-% blend of MXD6 the haze of the bottle increased from 0.7 to 1.2%. No gas permeation or color data is given. U.S. Pat. No. 4,837115 to Igarashi et al. discloses a blend of amino terminated polyamides with PET to reduce acetaldehyde levels. There was no increase in haze with the addition of 0.5 wt-% MXD6, but at 2 wt-% the haze increased from 1.7 to 2.4%. No gas permeation or color data is given. U.S. Pat. No. 6,239,233 to Bell et al. discloses a blend of acid terminated polyamides with PET that has reduced yellowness compared to amino terminated polyamides. No gas permeation data is given. U.S. Pat. No. 6,346,307 to A1 Ghatta et al. discloses the use of a dianhydride of a tetracarboxylic acid to reduce the dispersed domain size of a blend of MXD6 in PET. The examples did not give color data, but at a 10 wt-% MXD6 blend level the oxygen permeability was reduced from 0.53 to 0.12 ml/bottle/day/atm and the carbon dioxide permeability was reduced from 18.2 to 7.02 ml/bottle/day/atm. U.S. Pat. No. 6,444,283 to Turner et al. discloses that low molecular weight MXD6 polyamides have lower haze than higher molecular weight MXD6 when blended with PET. The examples did not give color data, but at a 2 wt-% MXD6 (Mitsubishi Chemical Company grade 6007) the oxygen permeability of an oriented film was reduced from 8.1 to 5.7 cc-mil/100 in2-atm-day compared to 6.1 for the low molecular weight MXD6. U.S. Pat. No. 4,957,980 to Koyayashi et al. discloses the use of maleic anhydride grafted copolyesters to compatibilize polyester-MXD6 blends. U.S. Pat. No. 4,499,262 to Fagerburg et al. discloses sulfo-modified polyesters that give an improved rate of acetaldehyde generation and a lower critical planar stretch ratio. Blends with polyamides were not discussed. Japanese Pat. No. 2663578 B2 to Katsumasa et al. discloses the use of 0.5 to 10 mole % 5-sulfoisophthalte copolymers as compatibilizer of polyester-MXD6 blends. No color data was given. The use of a transition metal catalyst to promote oxygen scavenging in polyamide multilayer containers, and blends with PET, has been disclosed in the following patents, for example. U.S. Pat. Nos. 5,021,515, 5,639,815 and 5,955,527 to Cochran et al. disclose the use of a cobalt salt as the preferred transition metal catalyst and MXD6 as the preferred polyamide. There is no data on the color or haze of the polyamide blends. U.S. Pat. Nos. 5,281,360 and 5,866,649 to Hong, and U.S. Pat. No. 6,288,161 to Kim discloses blends of MXD6 with PET and a cobalt salt catalyst. There is no data on the color or haze of the polyamide blends. U.S. Pat. No. 5,623,047 to You et al. discloses the use of a catalyst composition containing an alkali metal acetate, preferably 30 ppm cobalt acetate to mask the yellowness in polyesters polymerized from terephthalic acid. US Pat. Application 2003/0134966 A1 to Kim et al. discloses the use of cobalt octoate and xylene group-containing polyamides for use in multi-layer extrusion blow-molding for improved clarity. Extrusion blow-molding minimizes the orientation of the polyamide domain size compared to injection stretch blow molding containers. No color data is given. There is a need for an improved gas barrier polyester composition that can be injection stretch blow molded as a monolayer container that has reduced yellowness and adequate haze. This is particularly required for containers that require a long shelf life, such as beer and other oxygen sensitive materials. None of these patents disclose how this balance of properties can be achieved. SUMMARY OF THE INVENTION The present invention is an improvement over polyester/polyamide blends known in the art in that these compositions have reduced yellowness. In the broadest sense the present invention comprises a compatibilized blend of polyester and a partially aromatic polyamide with an ionic compatibilizer and a cobalt salt. The broadest scope of the present invention also comprises a container that has both active and passive oxygen barrier and carbon dioxide barrier properties at an improved color and clarity than containers known in the art. In the broadest sense the present invention also comprises a container in which the balance of gas barrier properties and color can be independently balanced. In the broadest sense the present invention is a method to blend polyester and polyamides with an ionic compatibilizer and a cobalt salt. BRIEF DESCRIPTION OF THE DRAWING The drawing is to aid those skilled in the art in understanding the invention and is not meant to limit the scope of the invention in any manner beyond the scope of the claims. FIG. 1 shows a graph of the oxygen permeation rate of selected runs of Example 3. FIG. 2 shows a graph of the oxygen permeation rate of the runs of Example 4. DETAILED DESCRIPTION OF THE INVENTION Compositions of the present invention comprise: polyester, partially aromatic polyamide, ionic compatibilizer, and a cobalt salt. Generally polyesters can be prepared by one of two processes, namely: (1) the ester process and (2) the acid process. The ester process is where a dicarboxylic ester (such as dimethyl terephthalate) is reacted with ethylene glycol or other diol in an ester interchange reaction. Because the reaction is reversible, it is generally necessary to remove the alcohol (methanol when dimethyl terephthalate is employed) to completely convert the raw materials into monomers. Certain catalysts are well known for use in the ester interchange reaction. In the past, catalytic activity was then sequestered by introducing a phosphorus compound, for example polyphosphoric acid, at the end of the ester interchange reaction. Primarily the ester interchange catalyst was sequestered to prevent yellowness from occurring in the polymer. Then the monomer undergoes polycondensation and the catalyst employed in this reaction is generally an antimony, germanium or titanium compound, or a mixture of these. In the second method for making polyester, an acid (such as terephthalic acid) is reacted with a diol (such as ethylene glycol) by a direct esterification reaction producing monomer and water. This reaction is also reversible like the ester process and thus to drive the reaction to completion one must remove the water. The direct esterification step does not require a catalyst. The monomer then undergoes polycondensation to form polyester just as in the ester process, and the catalyst and conditions employed are generally the same as those for the ester process. For most container applications this melt phase polyester is further polymerized to a higher molecular weight by a solid state polymerization. In summary, in the ester process there are two steps, namely: (1) an ester interchange, and (2) polycondensation. In the acid process there are also two steps, namely: (1) direct esterification, and (2) polycondensation. Suitable polyesters are produced from the reaction of a diacid or diester component comprising at least 65 mol-% terephthalic acid or C1-C4 dialkylterephthalate, preferably at least 70 mol-%, more preferably at least 75 mol-%, even more preferably, at least 95 mol-%, and a diol component comprising at least 65% mol-% ethylene glycol, preferably at least 70 mol-%, more preferably at least 75 mol-%, even more preferably at least 95 mol-%. It is also preferable that the diacid component is terephthalic acid and the diol component is ethylene glycol, thereby forming polyethylene terephthalate (PET). The mole percent for all the diacid component totals 100 mol-%, and the mole percentage for all the diol component totals 100 mol-%. Where the polyester components are modified by one or more diol components other than ethylene glycol, suitable diol components of the described polyester may be selected from 1,4-cyclohexandedimethanol, 1,2-propanediol, 1,4-butanediol, 2,2-dimethyl-1,3-propanediol, 2-methyl-1,3-propanediol (2MPDO) 1,6-hexanediol, 1,2-cyclohexanediol, 1,4-cyclohexanediol, 1,2-cyclohexanedimethanol, 1,3-cyclohexanedimethanol, and diols containing one or more oxygen atoms in the chain, e.g., diethylene glycol, triethylene glycol, dipropylene glycol, tripropylene glycol or mixtures of these, and the like. In general, these diols contain 2 to 18, preferably 2 to 8 carbon atoms. Cycloaliphatic diols can be employed in their cis or trans configuration or as mixture of both forms. Preferred modifying diol components are 1,4-cyclohexanedimethanol or diethylene glycol, or a mixture of these. Where the polyester components are modified by one or more acid components other than terephthalic acid, the suitable acid components (aliphatic, alicyclic, or aromatic dicarboxylic acids) of the linear polyester may be selected, for example, from isophthalic acid, 1,4-cyclohexanedicarboxylic acid, 1,3-cyclohexanedicarboxylic acid, succinic acid, glutaric acid, adipic acid, sebacic acid, 1,12-dodecanedioic acid, 2,6-naphthalenedicarboxylic acid, bibenzoic acid, or mixtures of these and the like. In the polymer preparation, it is often preferable to use a functional acid derivative thereof such as the dimethyl, diethyl, or dipropyl ester of the dicarboxylic acid. The anhydrides or acid halides of these acids also may be employed where practical. These acid modifiers generally retard the crystallization rate compared to terephthalic acid. Also particularly contemplated by the present invention is a modified polyester made by reacting at least 85 mol-% terephthalate from either terephthalic acid or dimethyl-terephthalate with any of the above comonomers. In addition to polyester made from terephthalic acid (or dimethyl terephthalate) and ethylene glycol, or a modified polyester as stated above, the present invention also includes the use of 100% of an aromatic diacid such as 2,6-naphthalene dicarboxylic acid or bibenzoic acid, or their diesters, and a modified polyester made by reacting at least 85 mol-% of the dicarboxylate from these aromatic diacids/diesters with any of the above comonomers. Preferably the polyamide used as the gas barrier component of the blend is selected from the group of partially aromatic polyamides is which the amide linkage contains at least one aromatic ring and a non-aromatic species. Preferred partially aromatic polyamides include: poly(m-xylylene adipamide); poly(hexamethylene isophthalamide); poly(hexamethylene adipamide-co-isophthalamide); poly(hexamethylene adipamide-co-terephthalamide); poly(hexamethylene isophthalamide-co-terephthalamide); or mixtures of two or more of these. The most preferred is poly(m-xylylene adipamide). The preferred range of polyamide is 1 to 10% by weight of the composition depending on the required gas barrier required for the container. The ionic compatibilizer is preferably a copolyester containing a metal sulfonate salt group. The metal ion of the sulfonate salt may be Na+, Li+, K+, Zn++, Mn++, Ca++ and the like. The sulfonate salt group is attached to an aromatic acid nucleus such as a benzene, naphthalene, diphenyl, oxydiphenyl, sulfonyldiphenyl, or methylenediphenyl nucleus. Preferably, the aromatic acid nucleus is sulfophthalic acid, sulfoterephthalic acid, sulfoisophthalic acid, 4-sulfonaphthalene-2,7-dicarboxylic acid, and their esters. Most preferably, the sulfomonomer is 5-sodiumsulfoisophthalic acid or 5-zincsulfoisophthalic acid and most preferably their dialkyl esters such as the dimethyl ester (SIM) and glycol ester (SIPEG). The preferred range of 5-sodiumsulfoisophthalic or 5-zincsulfoisophthalic acid to reduce the haze of the container is 0.1 to 2.0 mol-%. Suitable cobalt compounds for use with the present invention include cobalt acetate, cobalt carbonate, cobalt chloride, cobalt hydroxide, cobalt naphthenate, cobalt oleate, cobalt linoleate, cobalt octoate, cobalt stearate, cobalt nitrate, cobalt phosphate, cobalt sulfate, cobalt (ethylene glycolate), and mixtures of two or more of these, among others. As a transition metal catalyst for active oxygen scavenging, a salt of a long chain fatty acid is preferred, cobalt octoate or stearate being the most preferred. For color control of passive gas barrier blends any cobalt compound can be used, with cobalt acetate being preferred. It has surprisingly been found that the ionic compatibilizer, in addition to improving gas barrier properties and improving haze, in combination with a cobalt salt significantly reduces the yellowness of the resin, preform and container. The preferred range of Co for blends containing 1 to 10 wt-% partially aromatic polyamide and 0.1 to 2.0 mol-% of an ionic compatibilizer is 20 to 500 ppm. Although not required, additives may be used in the polyester/polyamide blend. Conventional known additives include, but are not limited to an additive of a dye, pigment, filler, branching agent, reheat agent, anti-blocking agent, antioxidant, anti-static agent, biocide, blowing agent, coupling agent, flame retardant, heat stabilizer, impact modifier, UV and visible light stabilizer, crystallization aid, lubricant, plasticizer, processing aid, acetaldehyde and other scavengers, and slip agent, or a mixture thereof. The blend of polyester, ionic compatibilizer, cobalt salt and partially aromatic polyamide is conveniently prepared by adding the components are the throat of the injection molding machine that produces a preform that can be stretch blow molded into the shape of the container. If a conventional polyester base resin designed for polyester containers is used, then one method is to prepare a master batch of a polyester containing the ionic compatibilizer, and optionally a transition metal catalyst for active scavenging, together with the partially aromatic polyamide using a gravimetric feeder for the three components. Alternatively the polyester resin can be polymerized with the ionic compatibilizer, and optionally a transition metal catalyst for active scavenging, to form a copolymer. This copolymer can be mixed at the injection molding machine with the partially aromatic nylon. Alternative all the blend components can be blended together, or as a blend of master batches, and fed as a single material to the extruder. The mixing section of the extruder should be of a design to produce a homogeneous blend. This can be determined by measuring the thermal properties of the preform and observing a single glass transition temperature in contrast to two separate glass transition temperatures of the partially aromatic polyamide and polyester. These process steps work well for forming carbonated soft drink, water or beer bottles, and containers for hot fill applications, for example. The present invention can be employed in any of the conventional known processes for producing a polyester container. Testing Procedures 1. Oxygen and Carbon Dioxide Permeability of Films, Passive Oxygen flux of film samples, at zero percent relative humidity, at one atmosphere pressure, and at 25° C. was measured with a Mocon Ox-Tran model 2/20 (MOCON Minneapolis, Minn.). A mixture of 98% nitrogen with 2% hydrogen was used as the carrier gas, and 100% oxygen was used as the test gas. Prior to testing, specimens were conditioned in nitrogen inside the unit for a minimum of twenty-four hours to remove traces of atmospheric oxygen dissolved in the PET matrix. The conditioning was continued until a steady base line was obtained where the oxygen flux changed by less than one percent for a thirty-minute cycle. Subsequently, oxygen was introduced to the test cell. The test ended when the flux reached a steady state where the oxygen flux changed by less than 1% during a 30 minute test cycle. Calculation of the oxygen permeability was done according to a literature method for permeation coefficients for PET copolymers, from Fick's second law of diffusion with appropriate boundary conditions. The literature documents are: Sekelik et al., Journal of polymer Science Part B: Polymer Physics, 1999, Volume 37, Pages 847-857. The second literature document is Qureshi et al., Journal of Polymer Science Part B: Polymer Physics, 2000, Volume 38, Pages 1679-1686. The third literature document is Polyakova, et al., Journal of Polymer Science Part B: Polymer Physics, 2001, Volume 39, Pages 1889-1899. The carbon dioxide permeability of films was measured in the same manner, replacing the oxygen gas with carbon dioxide and using the Mocon Permatran-C 4/40 instrument. All film permeability values are reported in units of (cc(STP).cm)/(m2.atm.day)). 2. Oxygen Permeability of Films, Active Scavenger. The same method was used as for passive oxygen permeability above with the exception that the oxygen flux did not necessarily equilibrate to a steady state. After the introduction of the oxygen into the cell, the reduction in the amount of oxygen was measured from 0 to at least 350 hours. Treatment of the data generated an Apparent Permeation Coefficient (APC), as a function of time with oxygen exposure (cc(STP).cm)/(m2.atm.day). The generated APC data is not a steady state value in normal permeation coefficients. APC is data generated that describes oxygen permeation at a fixed point in time, even though this coefficient is changing slowly with time. These changes are too small to be detected during the time necessary for measuring their value at any fixed point in time. Calculation of the APC was done according to a literature method for permeation coefficients for PET copolymers, from Fick's second law of diffusion with appropriate boundary conditions, in the same manner as described for passive barrier permeability. 3. Carbon Dioxide Permeability of Bottles. Carbon dioxide permeability of bottles was measured using a MOCON Permatran C-200 CO2 Permeation System. Tests were conducted at 22° C. The bottles were purged with nitrogen and then pressurized with CO2 at a pressure of 60 psi (4.01 MPa). The bottles were left in ambient conditions for 3 days and the pressure measured. Bottles in which the pressure had dropped below 56 psi (3.75 Mpa) were rejected, otherwise the bottles were repressurized to 60 psi (4.01 MPa) and placed in the testing chamber, which has been purged with nitrogen for at least 5 hours. After a day, measurements of the CO2 in the test chamber were taken over a 30 minute time frame, over an eight hour time period. The nitrogen flow rate to the sensor was 100 cm3/min, and to the carrier stream was 460 cm3/min. Results are reported as cm3/bottle/day. 4. Intrinsic Viscosity (IV) Intrinsic viscosity (IV) is determined by dissolving 0.2 grams of an amorphous polymer composition in 20 milliliters of dichloroacetic acid at a temperature of 25° C. and using an Ubbelhode viscometer to determine the relative viscosity (RV). RV is converted to IV using the equation: IV=[(RV−1)×0.691]+0.063. 5. Color The haze of the preform and bottle walls was measured with a Hunter Lab ColorQuest II instrument. D65 illuminant was used with a CIE 1964 10° standard observer. The haze is defined as the percent of the CIE Y diffuse transmittance to the CIE Y total transmission. The color of the preform and bottle walls was measured with the same instrument and is reported using the CIELAB color scale, L* is a measure of brightness, a* is a measure of redness (+) or greenness (−) and b* is a measure of yellowness (+) or blueness (−). 6. Diethylene Glycol (DEG) The DEG (diethylene glycol) content of the polymer is determined by hydrolyzing the polymer with an aqueous solution of ammonium hydroxide in a sealed reaction vessel at 220±5° C. for approximately two hours. The liquid portion of the hydrolyzed product is then analyzed by gas chromatography. The gas chromatography apparatus is a FID Detector (HP5890, HP7673A) from Hewlett Packard. The ammonium hydroxide is 28 to 30% by weight ammonium hydroxide from Fisher Scientific and is reagent grade. 7. Isophthalic and Naphthalene Dicarboxylic Acid The percent isophthalic acid and naphthalene dicarboxylic acid present in the amorphous polymer was determined at 285 nanometers using a Hewlett Packard Liquid Chromatograph (HPLC) with an ultraviolet detector. An amorphous polymer sample was hydrolyzed in diluted sulfuric acid (10 ml acid in 1 liter deionized water) in a stainless steel bomb at 230° C. for 3 hours. After cooling, an aqueous solution from the bomb was mixed with three volumes of methanol (HPLC grade) and an internal standard solution. The mixed solution was introduced into the HPLC for analysis. 8. Metal Content The metal content of the ground polymer samples was measured with an Atom Scan 16 ICP Emission Spectrograph. The sample was dissolved by heating in ethanolamine, and on cooling, distilled water was added to crystallize out the terephthalic acid. The solution was centrifuged, and the supernatant liquid analyzed. Comparison of atomic emissions from the samples under analysis with those of solutions of known metal ion concentrations was used to determine the experimental values of metals retained in the polymer samples. 9. Preform and Bottle Process After solid state polymerization, the resin of the present invention is typically, dried for 4-6 hours at 170-180° C., melted and extruded into preforms. Each preform for a 0.59 liter soft drink bottle, for example, employs about 24 grams of the resin. The preform is then heated to about 100-120° C. and blown-molded into a 0.59 liter contour bottle at a stretch ratio of about 12.5. The stretch ratio is the stretch in the radial direction times the stretch in the length (axial) direction. Thus if a preform is blown into a bottle, it may be stretched about two times its length and stretched about six times is diameter giving a stretch ratio of twelve (2×6). Since the bottle size is fixed, different preform sizes can be used for obtaining different stretch ratios. 10. Scanning Electron Micrograph Films were prepared by compression molding by heating at 275° C. in a press for 3 minutes without pressure, then the pressure was cycled several times between 0 and 300 psi and then held at 300 psi for 4 minutes. The film was quenched in ice water. These films were notched with a razor blade on the film surface to facilitate a brittle failure, immersed in liquid nitrogen for 15 minutes, removed and fractured by hand perpendicular to the thickness direction. Fracture surfaces were coated with 100 angstrom of gold and were observed using a JEOL 840A scanning electron microscope. The following examples are given to illustrate the present invention, and it shall be understood that these examples are for the purposes of illustration and are not intended to limit the scope of the invention. EXAMPLES Various polyester (PET) resins reflecting typical commercial recipes were produced. Comonomers included isophthalic acid (or its dimethyl ester) (IPA) and diethylene glycol (DEG) as crystallization retardants and naphthalene dicarboxylic acid (or its dimethyl ester) (NDC) to improve the temperature at which a container can be filled. Amorphous polyester was first produced with an IV of about 0.6, this was then solid phase polymerized to the final resin IV. The additives used were, manganese acetate, zinc acetate, cobalt acetate, antimony trioxide and poly-phosphoric acid. The analyses of these resins are set forth in Table 1. TABLE 1 Resin Identification A B C D Process TA DMT DMT DMT IV 0.83 0.82 0.84 0.81 IPA, wt-% 2.5 3.1 0 0 NDC, wt-% 0 0 5 5 DEG, wt-% 1.5 0.7 0.6 0.6 Cobalt, ppm 30 40 100 0 A series of copolyesters were made containing various amounts of 5-sulfoisophthalic acid (SIPA), either the ester or the gylcolate of SIPA was used. The melt phase polymerization was conducted in the normal way, but the amorphous resin was not solid state polymerized for resin S3. In the case of Resin S1, zinc acetate was used in place of manganese acetate as the ester-interchange catalyst. The analyses of these resins are set forth in Table 2. TABLE 2 Resin Identification S1 S2 S3 Process DMT DMT DMT IV 0.84 0.82 0.56 SIPA, mol-% 0.11 1.3 1.7 Cobalt, ppm 0 0 40 A master batch of the cobalt salt to be used as the transition metal catalyst for active oxygen scavenging was made by late addition of 2 wt-% cobalt octoate to a polyester prepared using 75 ppm Zn (as zinc acetate), 250 ppm Sb (as antimony trioxide, 60 ppm P (as poly-phosphoric acid) and 2.5 wt-% IPA. This material had an IV of 0.35-0.40. Unless otherwise stated the partially aromatic nylon used in the blend was Type 6007 from Mitsubishi Gas Chemical, Tokyo Japan. Type 6007 has a number average molecular weight of 25,900 and its melt viscosity at 271° C. and 1000 sec−1 is 280 Pa.s. Unless otherwise stated the preforms were prepared on an Arburg injection molding machine using 24 g of material, and blown into a 0.59 liter contour bottle on a Sidel SBO2 stretch blow molding machine. The bottle sidewall thickness is about 0.25 mm. Example 1 The effect of the interaction of SIPA with Co on the yellowness of preforms and bottles was studied by blending either polyester resin D or S1 with the cobalt master batch and MXD6. The yellowness value (b*) of the preforms and bottle sidewalls are set forth in Table 3 (lower or negative b* values correspond to less yellowness). TABLE 3 Pre- Bot- Run Co, MXD6, SIPA, form tle No. Resin ppm wt-% mol-% b* Delta1 b* Delta2 1 D 0 0 0 11 Control 3.6 Control 2 D 0 5 0 19.3 8.3 7.1 3.5 3 D 100 0 0 0.7 −10.3 1 −2.6 4 D 200 5 0 4.2 −6.8 3.5 −0.1 5 S1 0 0 0.11 16.3 Control 4.6 Control 6 S1 0 5 0.11 17.5 1.2 5.5 0.9 7 S1 100 0 0.11 −0.8 −17.1 1.1 −3.5 8 S1 200 5 0.11 −6.6 −22.9 2 −2.6 1Difference in b* of the preform compared to the control. 2Difference in b* of the bottle compared to the control. This table shows that the cobalt salt, at a 200 ppm level, will more than offset the yellowness due to a blend with 5 wt-% MXD6, but more importantly, in the presence of 0.11 mol-% SIPA, there is a synergistic effect and the Co salt is markedly more effective in offsetting the yellowness. Example 2 A similar trial was conducted using resin C as the control and the results set forth in Table 4. TABLE 4 Run Co, MXD6, SIPA, Preform Bottle No. Resin ppm wt-% mol-% b* b* 9 C 100 0 0 −0.1 1.2 10 C 200 5 0 3.6 5.7 11 S1 200 5 0.11 −3.5 3.6 The haze of these preforms and bottle sidewalls are set forth in Table 5. TABLE 5 Run Co, MXD6, SIPA, Preform Bottle No. Resin ppm wt-% mol-% haze, % haze, % 9 C 100 0 0 9.5 1.3 10 C 200 5 0 16.4 13.9 11 S1 200 5 0.11 14.3 8.2 The results again show the synergistic effect of the ionic compatibilizer on the cobalt salt as a means to reduce yellowness, in addition the ionic compatibilizer reduced the haze of the bottle sidewall containing 5 wt-% MXD6. Example 3 Another trial was conducted in which the amount of MXD6 was varied at a constant SIPA level of 0.11 mol-%, and the results set forth in Table 6 TABLE 6 Run MXD6, SIPA, Preform Bottle No. Resin Co, ppm wt-% mol-% b* b* 12 C 100 0 0 0.4 0.8 13 S1 100 0 0.11 −1.8 1.1 14 C 200 3 0 1.4 2.4 15 S1 200 3 0.11 −7.4 1.9 16 C 200 4 0 1.0 2.8 17 S1 200 4 0.11 −7.8 2.0 18 C 200 5 0 3.2 3.2 19 S1 200 5 0.11 −6.1 2.6 At all levels of MXD6 the incorporation of an ionic compatibilizer reduced the yellowness. The oxygen permeability of the bottle sidewalls was measured and the results plotted in FIG. 1. This shows that the ionic compatibilizer decreases the permeability at each MXD6 concentration. Surprisingly there is a non-linear relationship of oxygen permeability with MXD6 concentration with extremely low values at 5 wt-% MXD6. Example 4 In order to better define the oxygen permeability as a function of MXD6 concentration a series of blends were prepared using polyester A as the base resin. The concentration of MXD6 used was 1, 2, 3, 4, 4.5 and 5 wt-%, each containing 100 ppm cobalt octoate. The oxygen permeability of the bottle sidewalls was measured and the results shown in FIG. 2. This illustrates that there is a surprising reduction in oxygen permeability between 4.5 and 5 wt-% MXD6. Example 5 Another trial was run in which the level of MXD6 was held constant at 5 wt-% and the concentration of SIPA changed, the results are set forth in Table 7. In these runs the base polyester resin was A and the master batch of SIPA polymer S2 was used. TABLE 7 Run Co, MXD6, Preform Bottle No. Resins ppm wt-% SIPA, mol-% b* b* 20 A 30 0 0 3.8 1.0 21 A 130 5 0 0.5 4.1 22 A/S2 130 5 0.13 −2.5 3.6 23 A/S2 130 5 0.26 −2.9 3.7 24 A/S2 130 5 0.65 −3.6 3.3 25 S2 100 5 1.3 −9.1 2.8 These results show that the ionic compatibilizer can be used as a master batch to obtain the synergistic reduction of yellowness with cobalt, as well as a copolymer that was used in the previous Examples 1-3. Example 6 Instead of using sodium as the SIPA salt, a copolyester using the divalent zinc ester was made using the process that was used for copolymer S1. Since this Zn copolyester was more yellow than S1 no comparison of the relative difference between Na-SIPA and Zn-SIPA can be given. However the haze of bottle sidewalls made with PET resin A as the control, using 0.11 mol-% SIPA (the runs containing MXD6 contained 100 ppm Co) are compared in Table 8 below. TABLE 8 Run No. MXD6, wt-% SIPA type Haze, % 26 0 none 5.5 27 5 none 14.2 28 5 Na 12.0 29 5 Zn 9.6 It would appear that the divalent ionic compatibilizer is more effective than the monovalent in reducing the bottle sidewall haze. Example 7 A low molecular weight MXD6 was prepared. A mixture of 438 g of adipic acid, 428.4 g of m-xylylenediamine and 500 g of deionized water were charged in a 2-liter autoclave under nitrogen atmosphere. The mixture was stirred for 15 minutes then heated to reflux for 30 minutes. Water was distilled off and the temperature was increased to 275° C. over a period of 60-90 minutes. The mixture was stirred at 275° C. for 30 minutes before extrusion. This polymer had a viscosity of 9.5 Pa.s at 1000 sec−1 and 271° C. (compared to 280 Pa.s for the commercial 6007). The procedure of Example 3 was followed, using this low molecular weight MXD6 (LMW) compared to the commercial 6007. The results are set forth in Table 9. TABLE 9 Run MXD6 MXD6, SIPA, Preform Bottle No. Resin Co, ppm type wt-% mol-% b* b* 32 C 200 6007 3 0 2.0 2.5 33 C 200 LMW 3 0 3.4 2.1 34 C 200 6007 5 0 4.2 3.5 35 C 200 LMW 5 0 1.1 3.6 36 S1 200 6007 5 0.11 −6.1 2.6 37 S1 200 LMW 5 0.11 −6.6 2.0 This illustrates that the color is better (less yellow) with the low molecular weight MXD6 than 6007. The haze of these runs was also measured and the results set forth in Table 10 below. TABLE 10 Run Co, MXD6 MXD6, SIPA, Preform Bottle No. Resin ppm Type wt-% mol-% Haze, % Haze, % 32 C 200 6007 3 0 50.3 10.9 33 C 200 LMW 3 0 48.3 7.7 34 C 200 6007 5 0 50.1 14.0 35 C 200 LMW 5 0 49.9 11.8 36 S1 200 6007 5 0.11 49.3 11.1 37 S1 200 LMW 5 0.11 45.4 7.4 The use of the lower molecular MXD6 in conjunction with SIPA markedly reduces the haze of the bottle sidewalls. Example 7 In order to determine the effect of the ionic compatibilizer on MXD6 domain size, a series of films were prepared and fractured. PET resin B was used together with blends with the S3 SIPA copolyester and 6007 MXD6. The domain size was measured and the results set forth in Table 11. TABLE 11 MXD6, wt-% SIPA, mol-% Domain size, μm 10 0 0.8-1.5 20 0 2.2-4.5 20 1.35 0.2-0.5 10 0.03 0.5-1.5 10 0.08 0.5-1.5 10 0.16 0.2-0.5 This shows that at a low level of SIPA, less than 0.2 mol-%, the domain size of a blend containing 10 wt-% MXD6 is reduced to less than 0.5 μm. Example 8 A series of bottles were produced using C as the base PET resin, the S3 SIPA copolyester and 6007 MXD6. The passive oxygen permeability, at 0% Relative Humidity, of the bottle sidewalls was measured and the results set forth in Table 12. TABLE 12 MXD6, SIPA, O2 Permeability Run No. wt-% mol-% (cc(STP) · cm)/(m2 · atm · day) 38 0 0 0.180 39 2.5 0 0.181 40 2.5 0.3 0.164 41 5 0 0.138 42 5 0.3 0.131 43 5 0.6 0.145 44 10 0 0.079 45 10 0.3 0.054 46 10 0.6 0.051 This shows that the ionic compatibilizer is improving the oxygen gas barrier at a given MXD6 level, possibly due to the reduction in domain size, which increases the number of domains, as shown in Example 7. Example 9 Following the procedure of Example 7 a polyamide was produced in which 12% of the adipic acid was replaced with isophthalic acid. The melt viscosity of this polyamide at 171° C. and 1000 sec−1 was 237 Pa.s. This polyamide was blended at a 5 wt-% level with PET resin C and ionic compatibilizer S3 to give a level of SIPA of 0.6 mol-% in the blend. Bottles were prepared from this blend and the oxygen permeation rate measures at 0.155 (cc(STP).cm)/(m2.atm.day). This can be compared with a lower oxygen permeation rate of 0.145 measured on run 43 achieved with 5 wt-% MXD6. Example 10 The carbon dioxide transmission rate of 0.5 liter bottles made from PET resin A were measured to be 8.6 cc/bottle/day. The addition of 5 wt-% MXD6 decreased this rate to 4.5 cc/bottle/day. Example 11 Master batches using cobalt stearate and cobalt naphthenate in place of cobalt octoate were prepared using the same method as described above for cobalt octoate. Using PET base resin D, bottles were prepared using different amounts of MXD6 and different concentrations of cobalt octoate, cobalt stearate and cobalt naphthenate. The bottle wall oxygen permeability was measured and the value after 100 hours (at this time the rate is at equilibrium, see FIG. 1) is set forth in Table 13. Table 13 TABLE 13 Oxygen Permeability @ MXD6, Co, 100 hours, Run No. wt-% Cobalt salt ppm (cc(STP)·cm)/(m2·atm·day) 47 0 — — 0.150 48 1.75 Octoate 200 0.098 49 1.75 Octoate 400 0.120 50 1.75 Stearate 100 0.098 51 1.75 Stearate 200 0.122 52 3.0 Octoate 400 0.120 53 3.0 Octoate 60 0.048 54 5.0 Octoate 100 0.005 55 5.0 Stearate 30 0.005 56 5.0 Stearate 50 <0.005 57 5.0 Naphthenate 50 <0.005 An excess of the transition metal catalyst can in fact act as an anti-oxidant and increase the oxygen permeability, compare runs 48 and 49, runs 52 and 53. Although particular embodiments of the invention have been described in detail, it will be understood that the invention is not limited correspondingly in scope, but include all changes and modifications coming within the spirit and terms of the claims appended hereto.

<SOH> BACKGROUND OF THE INVENTION <EOH>1) Field of the Invention The invention relates to compatibilized blends of polyamides in polyesters, a method for forming such compositions, and to containers made from such compositions. Specifically the compositions have less yellowness than previous blends. The blends can be used as passive gas barriers, or active oxygen scavengers with the addition of a transition metal catalyst. 2) Prior Art Plastic materials have been replacing glass and metal packaging materials due to their lighter weight, decreased breakage compared to glass, and potentially lower cost. One major deficiency with polyesters is its relatively high gas permeability. This restricts the shelf life of carbonated soft drinks and oxygen sensitive materials such as beer and fruit juices. Multilayer bottles containing a low gas permeable polymer as an inner layer, with polyesters as the other layers, have been commercialized. Blends of these low gas permeable polymers into polyester have not been successful due to haze formed by the domains in the two-phase system. The preferred polyamide is a partially aromatic polyamide containing meta-xylylene groups, especially poly (m-xylylene adipamide), MXD6. The MXD6 bulletin (TR No. 0009-E) from Mitsubishi Gas Chemical Company, Inc., Tokyo Japan, clearly shows that the haze of a multilayer bottle containing a layer of 5 wt-% MXD6 is ˜1% compared to 15% for a blend of the same 5 wt-%. However, the use of partially aromatic polyamides as the low gas permeable polymer gives an increase in the yellowness of the resultant container. U.S. Pat. No. 4,501,781 to Kushida et al. discloses a hollow blow-molded biaxially oriented bottle shaped container comprising a mixture of polyethylene terephthalate (PET) resin and a xylylene group-containing polyamide resin. Both monolayer and multilayer containers are disclosed, but there is no information on the color of the bottles. U.S. Pat. No. 5,650,469 to Long et al. discloses the use of a terephthalic acid based polyester blended with low levels (0.05 to 2.0 wt-%) of a polyamide to reduce the acetaldehyde level of the container. These blends produced lower yellowness containers than a corresponding blend made from a dimethyl terephthalate based polyester, but are still unsatisfactory for the higher levels required to significantly lower (decrease) the gas permeability. U.S. Pat. Nos. 5,258,233, 5,266,413 and 5,340,884 to Mills et al. discloses a polyester composition comprising 0.05 to 2.0 wt-% of low molecular weight polyamide. At a 0.5 wt-% blend of MXD6 the haze of the bottle increased from 0.7 to 1.2%. No gas permeation or color data is given. U.S. Pat. No. 4,837115 to Igarashi et al. discloses a blend of amino terminated polyamides with PET to reduce acetaldehyde levels. There was no increase in haze with the addition of 0.5 wt-% MXD6, but at 2 wt-% the haze increased from 1.7 to 2.4%. No gas permeation or color data is given. U.S. Pat. No. 6,239,233 to Bell et al. discloses a blend of acid terminated polyamides with PET that has reduced yellowness compared to amino terminated polyamides. No gas permeation data is given. U.S. Pat. No. 6,346,307 to A1 Ghatta et al. discloses the use of a dianhydride of a tetracarboxylic acid to reduce the dispersed domain size of a blend of MXD6 in PET. The examples did not give color data, but at a 10 wt-% MXD6 blend level the oxygen permeability was reduced from 0.53 to 0.12 ml/bottle/day/atm and the carbon dioxide permeability was reduced from 18.2 to 7.02 ml/bottle/day/atm. U.S. Pat. No. 6,444,283 to Turner et al. discloses that low molecular weight MXD6 polyamides have lower haze than higher molecular weight MXD6 when blended with PET. The examples did not give color data, but at a 2 wt-% MXD6 (Mitsubishi Chemical Company grade 6007) the oxygen permeability of an oriented film was reduced from 8.1 to 5.7 cc-mil/100 in 2 -atm-day compared to 6.1 for the low molecular weight MXD6. U.S. Pat. No. 4,957,980 to Koyayashi et al. discloses the use of maleic anhydride grafted copolyesters to compatibilize polyester-MXD6 blends. U.S. Pat. No. 4,499,262 to Fagerburg et al. discloses sulfo-modified polyesters that give an improved rate of acetaldehyde generation and a lower critical planar stretch ratio. Blends with polyamides were not discussed. Japanese Pat. No. 2663578 B2 to Katsumasa et al. discloses the use of 0.5 to 10 mole % 5-sulfoisophthalte copolymers as compatibilizer of polyester-MXD6 blends. No color data was given. The use of a transition metal catalyst to promote oxygen scavenging in polyamide multilayer containers, and blends with PET, has been disclosed in the following patents, for example. U.S. Pat. Nos. 5,021,515, 5,639,815 and 5,955,527 to Cochran et al. disclose the use of a cobalt salt as the preferred transition metal catalyst and MXD6 as the preferred polyamide. There is no data on the color or haze of the polyamide blends. U.S. Pat. Nos. 5,281,360 and 5,866,649 to Hong, and U.S. Pat. No. 6,288,161 to Kim discloses blends of MXD6 with PET and a cobalt salt catalyst. There is no data on the color or haze of the polyamide blends. U.S. Pat. No. 5,623,047 to You et al. discloses the use of a catalyst composition containing an alkali metal acetate, preferably 30 ppm cobalt acetate to mask the yellowness in polyesters polymerized from terephthalic acid. US Pat. Application 2003/0134966 A1 to Kim et al. discloses the use of cobalt octoate and xylene group-containing polyamides for use in multi-layer extrusion blow-molding for improved clarity. Extrusion blow-molding minimizes the orientation of the polyamide domain size compared to injection stretch blow molding containers. No color data is given. There is a need for an improved gas barrier polyester composition that can be injection stretch blow molded as a monolayer container that has reduced yellowness and adequate haze. This is particularly required for containers that require a long shelf life, such as beer and other oxygen sensitive materials. None of these patents disclose how this balance of properties can be achieved.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is an improvement over polyester/polyamide blends known in the art in that these compositions have reduced yellowness. In the broadest sense the present invention comprises a compatibilized blend of polyester and a partially aromatic polyamide with an ionic compatibilizer and a cobalt salt. The broadest scope of the present invention also comprises a container that has both active and passive oxygen barrier and carbon dioxide barrier properties at an improved color and clarity than containers known in the art. In the broadest sense the present invention also comprises a container in which the balance of gas barrier properties and color can be independently balanced. In the broadest sense the present invention is a method to blend polyester and polyamides with an ionic compatibilizer and a cobalt salt.

20060224

20110405

20061102

58897.0

B65D102

WOODWARD, ANA LUCRECIA

METHOD TO MAKE SINGLE-LAYER PET BOTTLES WITH HIGH BARRIER AND IMPROVED CLARITY

UNDISCOUNTED

ACCEPTED

B65D

ACCEPTED

Immunogenic agent and pharmaceutical composition for use against homologous and heterologous pathogens

The present invention relates to an immunogenic agent comprising a low dose of an antigenic component from one or more pathogens and an agent capable of increasing an amount of IL-12 in animal, and use thereof for reducing infection or improving recovery from an infection from the pathogen. The immunogenic agent preferably comprises CpG nucleic acid, IL-12 protein and/or IL-12 nucleic acid. The pathogen is preferably an intracellular pathogen comprising one or more species and strains, such as Plasmodium spp. The invention also relates to a pharmaceutical composition comprising the immunogenic agent. The pharmaceutical composition is preferably an immunotherapeutic composition. The immunotherapeutic composition, is preferably a vaccine capable of providing protection against or treating Plasmodium spp infection, the causative agent of malaria in humans.

1. An immunogenic agent comprising: a low dose of an antigenic component obtainable from at least one Plasmodium spp; and an agent capable of increasing an amount of IL-12 in an animal. 2. The immunogenic agent of claim 1 wherein the antigenic component is selected from the group consisting of: live whole Plasmodium spp, inactivated whole Plasmodium spp, killed whole Plasmodium spp, an extract from Plasmodium spp, purified proteins derived from Plasmodium spp, one or more recombinantly expressed nucleic acid encoding Plasmodium spp proteins and a pool of recombinant expressed Plasmodium spp proteins. 3. The immunogenic agent of claim 2 wherein the antigenic component comprises an extract from one or more different species of killed Plasmodium spp. 4. The immunogenic agent of claim 3 wherein the extract comprises an equivalent of less than 106 whole Plasmodium spp. 5. The immunogenic agent of claim 4 wherein the extract comprises an equivalent of less than 105 whole Plasmodium spp. 6. The immunogenic agent of claim 5 wherein the extract comprises an equivalent of less than 103 whole Plasmodium spp. 7. The immunogenic agent of claim 1 wherein the Plasmodium spp is selected from the group consisting of: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi, Plasmodium berghei, Plasmodium yoelii, Plasmodium chabaudi and Plasmodium vinckei. 8. The immunogenic agent of claim 7 wherein the Plasmodium spp is selected from the group consisting of: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. 9. The immunogenic agent of claim 8 wherein the Plasmodium spp is selected from the group consisting of: Plasmodium falciparum. 10. The immunogenic agent of claim 1 wherein the agent capable of increasing an amount of IL-12 in the animal is capable of stimulating endogenous IL-12 expression in the animal. 11. The immunogenic agent of claim 10 wherein the agent comprises a CpG nucleic acid. 12. The immunogenic agent of claim 11 wherein the CpG nucleic acid comprises a nucleotide sequence selected from the group consisting of: TCGTCGTTTTGTCGTTTTGTC, (SEQ ID NO: 1) TCCATGACGTTCCTGACGTT (SEQ ID NO: 2) and TCCAGGACTTCTCTCAGGTT. (SEQ ID NO: 3) 13. The immunogenic agent claim 1 wherein the agent capable of increasing an amount of IL-12 in the animal is IL-12 protein or biologically active fragment thereof. 14. The immunogenic agent claim 13 wherein the IL-12 protein or biologically active fragment thereof is human IL-12. 15. The immunogenic agent claim 14 wherein the IL-12 protein or biologically active fragment thereof is recombinant the IL-12 protein or biologically active fragment thereof. 16. The immunogenic agent of claim 14 wherein the IL-12 protein or biologically active fragment thereof is isolated wild type IL-12 protein or biologically active fragment thereof. 17. The immunogenic agent claim 1 wherein the agent capable of increasing an amount of IL-12 in the animal is a nucleic acid comprising a nucleotide sequence encoding IL-12 protein or biologically active fragment thereof. 18. The immunogenic agent claim 17 wherein the nucleic acid is operably linked to a promoter capable of expressing the nucleic acid in the animal. 19. The immunogenic agent of claim 1 further comprising an adjuvant. 20. The immunogenic agent of claim 19 wherein the adjuvant is selected from the group consisting of: aluminum hydroxide (alum), IL-12, CpG-ODN, SBAS2, SBAS4, QS21 and ISCOM. 21. The immunogenic agent of claim 20 wherein the adjuvant is aluminum hydroxide. 22. The immunogenic agent of claim 1 wherein the animal is a mammal. 23. The immunogenic agent of claim 22 wherein the mammal is human. 24. A pharmaceutical composition comprising the immunogenic agent of claim 1 and a pharmaceutically-acceptable carrier. 25. The pharmaceutical composition of claim 24 wherein said pharmaceutical composition is an immunotherapeutic composition. 26. The pharmaceutical composition of claim 25 wherein the immunotherapeutic composition is a vaccine. 27. The pharmaceutical composition of claim 24, which when administered to the animal is capable of reducing severity of or improving recovery from infection by one or more different Plasmodium spp. 28. The pharmaceutical composition of claim 27 wherein the one or more different Plasmodium spp comprises one or more different respective stains thereof. 29. The pharmaceutical composition of claim 26 wherein said vaccine is capable of providing protective immunity in a mammal against one or more different Plasmodium spp. 30. The pharmaceutical composition of claim 29 wherein the one or more Plasmodium spp comprises one or more respective stains thereof. 31. A method for inducing an immune response in an animal, including the step of administering the pharmaceutical composition of claim 24 to a mammal. 32. The method of claim 31 wherein the pharmaceutical composition is an immunotherapeutic composition capable of reducing severity of infection by or improving recovery from infection by Plasmodium spp in the mammal. 33. The method of claim 32 wherein the immunotherapeutic composition is a vaccine capable of providing protective immunity or treating the mammal against one or more Plasmodium spp. 34. The method of claim 31 wherein the mammal is human. 35. Use of the pharmaceutical composition of claim 24 to reduce severity of infection by or improve recovery from infection by Plasmodium spp in the animal. 36. Use of the pharmaceutical composition of claim 35 to prevent or treat Plasmodium spp infection in the animal. 37. Use of the pharmaceutical composition of claim 36 wherein the animal is a mammal. 38. Use of the pharmaceutical composition of claim 35 wherein the mammal is human. 39. Use of the pharmaceutical composition of claim 38 to reduce severity of by or improve recovery from malaria. 40. Use of the pharmaceutical composition of claim 39 to prevent or treat malaria.

FIELD OF THE INVENTION THIS INVENTION relates to an immunogenic agent and pharmaceutical composition, in particular an immunotherapeutic composition, preferably a vaccine against one or more different strains or species of pathogen. The immunotherapeutic composition is particularly useful for stimulating a cellular immune response for reducing severity of infection and/or improving treatment and recovery from infection from a pathogen such as Plasmodium spp. BACKGROUND OF THE INVENTION Diseases have plagued animals, including humans, for centuries. Modern medicine has successfully developed vaccines for some diseases, for example polio, thereby providing protection against infection by some disease causing pathogens. Such vaccines have improved human health and potentially save millions of lives annually. However, developing vaccines to protect against infection by some pathogens has proven to be challenging and remains elusive. For example, malaria vaccines against Plasmodium species and different strains thereof are yet to be successful. Early attempts to develop a malaria vaccine include irradiated sporozoites that are live, but inactived or attenuated, (i.e. are capable of infecting, but not replicating in a host), Clyde 1975, Am J Trop Med Hyg 24 397. Delivery of this type of vaccine commonly relied on the attenuated live sporozoites being inoculated through mosquito bites, see Herrington et al, 1990, Bull World Health Organ. 68 Suppl 33. This type of vaccine is difficult to implement and has not resulted in a successful malaria vaccine. Recently, a common approach in developing a vaccine is identification of a pathogen antigen, cloning of the nucleic acid encoding the antigen and protein expression of recombinant nucleic acid. This approach for developing a malaria vaccine has resulted in a number of blood-stage derived recombinant antigens for inclusion in subunit vaccines, including MSP1, MSP2, MSP3, MSP4, MSP5, AMA1, PfEMP1, RESA, RAP1, and RAP2 (Carvalhuo et al, 2002, Scand J. Immol 56 327). However, a subunit vaccine for malaria is yet to be successful. Although subunit vaccines are the most common form of a malaria vaccine currently in development, a subunit vaccine has a number of limitations, in particular in relation to developing a vaccine against a pathogen characterised by multiple strains, for example Plasmodium. An important inadequacy of subunit vaccines is their aim to mimic natural immunity, a process that in itself may be entirely inadequate. This is illustrated, for example, from a study conducted in Kenya (Hoffman et al, 1987, Science 237 639). The researchers treated adult Kenyan volunteers who had lived their entire lives in a malaria endemic area with anti-malaria drugs and then monitored each volunteer for appearance of Plasmodium parasites in their blood over the ensuing three months. By three months, 80% of the volunteers had become infected with Plasmodium parasites although antibody levels against the pathogen circumsporozoite protein were indistinguishable between individuals who developed parasitemia and those who did not. Thus, immunity to sporozoites (the form of the parasite inoculated by the mosquito) was inadequate, immunity to liver stage parasites (the next stage in the life cycle) was inadequate and immunity to blood forms (the stage of exponential growth after the liver stage) was also inadequate. Subunit vaccines that aim to mimic natural immune responses by inducing antibodies to the sporozoite coat, by inducing T cells which secrete INF-γ (gamma interferon) and which are potentially cytolytic for infected liver cells or inducing antibodies to merozoite surface proteins to block the invasion of red blood cells have not provided protection against malaria. There are three main possibilities why naturally occurring immune responses induced by subunits are not protective: (i) small molecules lack sufficient immunological determinants (or epitopes) to be widely immunogenic; (ii) many malaria proteins, and all major vaccine candidates, are polymorphic and these polymorphisms can be discriminated by antibodies or T cells raised against any one particular polymorphism; and (iii) malaria infection suppresses the induction of immunity by blocking dendritic cell maturation (Urban et al, 1999, Nature 400 73) and killing parasite-specific T cells by apoptosis (Xu et al, 2002, J Exp Med 195 881) and thus prevents the development of antibody-independent immunity as well as T cell-dependent antibody responses and subsequent memory responses. It was recently shown that it was possible to immunize humans against a single strain of Plasmodium using an ultra-low dose of live P. faiciparum infected red blood cells (Pombo et al, 2002, Lancet 360 610). In this study, naive volunteers were repeatedly infected with parasites and drug treated to stop the infection. They did not develop any symptoms of malaria during the eight days during which parasite numbers increased as determined by a very sensitive Polymerase Chain Reaction (PCR). Parasites could not be detected by microscopy. Although immunisation with ultra-low dosages of live parasite may provide some protection against subsequent infection by the same parasite, it is difficult to cultivate large numbers of live parasite for use in a vaccine. Transport of live parasites to areas requiring administration of the vaccine, maintaining the parasites viability and a requirement for blood products to propagate live parasite for the vaccine is not practical and is prohibitive for general application. Areas affected by malaria are typically remote with limited facilities. Also, inoculation with live pathogen is cumbersome and requires repeated infection/treatment cycles to prevent full infection. Rhee etal, 2002, J Exper Med 195 1565 describes vaccination of mice with heat killed Leishmania major and either IL-12 or CpG oligonucleotide (CpG-ODN). This publication relates to a specific pathogen, Leishmania major, which is the causative agent of cutaneous leishmaniasis and a vaccine for the same pathogen. There is a need for a pharmaceutical composition capable of stimulating an immune response in an animal and reducing a risk of infection or improving recovery from an infection by one or more pathogen, namely Plasmodium spp or strain. SUMMARY OF THE INVENTION The inventors have developed a pharmaceutical composition that is suitable for inducing immunity against homologous and heterologous forms of a pathogen, e.g. one or more of a same or different species or strain of species. In a preferred form, the invention relates to a surprising discovery that administering an animal with a low dose of an antigenic component derived from a pathogen was capable of reducing an occurrence of pathogen infection in a same and different strain of pathogen. In particular, a preferred form of the invention relates to a composition and administration of the composition comprising a low dose of an antigenic component derived from at least one species of killed Plasmodium, which is capable of inducing an immune response for one or more strains of Plasmodium. Malaria is caused by one or more species of Plasmodium and each species of Plasmodium comprises potentially hundreds, if not thousands of identified and unidentified strains, making development of a successful pharmaceutical composition for preventing or treating malaria difficult. The present discovery provides a means for practically developing a pharmaceutical composition that when administered is preferably capable of inducing an immune response in an animal against one or more strains of Plasmodium spp. The background art does not describe this surprising discovery and a pharmaceutical composition comprising this preferred characteristic is only now possible or contemplated by the present invention. As will be described herein in more detail, the low dose of an antigenic component from a pathogen may be administered in combination with other agents, including an agent capable of increasing IL-12 in an animal, such as a CpG nucleic acid, and an adjuvant such as alum. In a first aspect, the invention provides an immunogenic agent comprising: a low dose of an antigenic component obtainable from at least one Plasmodium spp; and an agent capable of increasing an amount of IL-12 in an animal. Preferably, the antigenic component is selected from the group consisting of: live whole Plasmodium spp, inactivated whole Plasmodium spp, killed whole Plasmodium spp, an extract from Plasmodium spp, purified proteins derived from Plasmodium spp, one or more recombinantly expressed nucleic acid encoding Plasmodium spp proteins and a pool of recombinant expressed Plasmodium spp proteins. More preferably, the antigenic component comprises an extract from one or more different species of killed Plasmodium spp. Preferably, the extract comprises an equivalent of less than 106 whole Plasmodium spp. More preferably, the extract comprises an equivalent of less than 105 whole Plasmodium spp. Even more preferably, the extract comprises an equivalent of less than 103 whole Plasmodium spp. In one form, the extract may comprise an equivalent of less than 102 and even less than 10 whole Plasmodium spp. Plasmodium spp is preferably selected from the group consisting of: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi, Plasmodium berghei, Plasmodium yoelii, Plasmodium chabaudi and Plasmodium vinckei. Preferably, the at least one Plasmodium spp is selected from the group consisting of: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. Preferably, the Plasmodium spp is Plasmodium falciparum. In one form of the first aspect, the agent capable of increasing an amount of IL-12 in the animal is capable of stimulating endogenous IL-12 expression in the animal. More preferably, the agent comprises a CpG nucleic acid. Preferably, the CpG nucleic acid comprises a nucleotide sequence selected from the group consisting of: TCGTCGTTTTGTCGTTTTGTC, (SEQ ID NO: 1) TCCATGACGTTCCTGACGTT (SEQ ID NO: 2) and TCCAGGACTTCTCTCAGGTT. (SEQ ID NO: 3) In another form of the first aspect, the agent capable of increasing an amount of IL-12 in the animal is IL-12 protein or biologically active fragment thereof. Preferably, the IL-12 protein or biologically active fragment thereof is human IL-12. In one form, the IL-12 protein or biologically active fragment thereof is recombinant the IL-12 protein or biologically active fragment thereof. In another form, the IL-12 protein or biologically active fragment thereof is isolated wild type IL-12 protein or biologically active fragment thereof. In another form of the first aspect, the agent capable of increasing an amount of IL-12 in the animal is a nucleic acid comprising a nucleotide sequence encoding IL-12 protein or biologically active fragment thereof. Preferably, the nucleic acid is operably linked to a promoter capable of expressing the nucleic acid in the animal. The immunogenic agent preferably further comprises an adjuvant. Preferably, the adjuvant is selected from the group consisting of: aluminum hydroxide (alum), IL-12, CpG-oligonucleotide (ODN), SBAS2, SBAS4, QS21 and ISCOMs In a more preferred form, the adjuvant is aluminum hydroxide. Preferably, the animal is a mammal. More preferably, the mammal is human. In a second aspect, the invention provides a pharmaceutical composition comprising the immunogenic agent of the first aspect and a pharmaceutically-acceptable carrier. Preferably, the pharmaceutical composition is an immunotherapeutic composition. More preferably, the immunotherapeutic composition is a vaccine. Preferably, the pharmaceutical composition, which when administered to the animal is capable of reducing severity of or improving recovery from infection by one or more different Plasmodium spp. Preferably, the one or more different Plasmodium spp comprises one or more respective stains thereof. Preferably, the vaccine is capable of providing protective immunity in a mammal against one or more different Plasmodium spp. Preferably, the one or more different Plasmodium spp comprises one or more respective stains thereof. In a third aspect, the invention provides a method for inducing an immune response in an animal, including the step of administering the pharmaceutical composition of the second aspect to a mammal. Preferably, the pharmaceutical composition is an immunotherapeutic composition capable of reducing severity of infection by or improving recovery from infection by Plasmodium spp in the mammal. Preferably, the immunotherapeutic composition is a vaccine capable of providing protective immunity or treating the mammal against one or more Plasmodium spp. The mammal is preferably human. In a fourth aspect, the invention relates to use of the pharmaceutical composition of the second aspect to reduce severity of infection by or improve recovery from infection by Plasmodium spp in the animal. Preferably, use of the pharmaceutical composition prevents or treats Plasmodium spp infection in the animal. Preferably, the animal is a mammal. More preferably, the mammal is human. Preferably, use of the pharmaceutical composition reduces severity of by or improves recovery from malaria. More preferably, use of the pharmaceutical composition of prevents or treats malaria. It will be appreciated that the present invention provides a pharmaceutical composition and method capable of reducing a risk of infection and/or improving recovery from an infection from a pathogen. In a preferred form of the invention, the pharmaceutical composition is an immunotherapeutic composition capable of inducing an immune response in an animal administered with the immunotherapeutic composition. In an even more preferred form, the invention is a vaccine capable of providing protection against a pathogen, in particular intracellular pathogens comprising a plurality of strains or variants characterized by heterogeneous antigens. More particularly, the present invention is preferably capable of inducing and maintaining a cellular immune response in an animal, namely a human, against one or more strains of Plasmodium spp, the causative agent of malaria. Accordingly, preferred forms of the invention relate to a pharmaceutical composition comprising an antigenic component from at least one species of Plasmodium spp capable of infecting a human, e.g. P. falciparum, P. vivax, P. malariae and P. ovale, and use of the pharmaceutical composition to prevent malaria in a human. Throughout this specification unless the context requires otherwise, the word “comprise”, and variations such as “comprises” or “comprising”, will be understood to imply the inclusion of the stated integers or group of integers or steps but not the exclusion of any other integer or group of integers. BRIEF DESCRIPTION OF THE FIGURES AND TABLES In order that the invention may be readily understood and put into practical effect, preferred embodiments will now be described by way of example with reference to the accompanying figures and tables. FIG. 1: Levels of malaria-specific antibodies in the sera of A/J mice immunized s.c. with antigen alone, antigen in alum, antigen plus IL-12 or antigen plus IL-12 in alum and boosted 3 weeks later by i.p. injection with antigen. Two weeks later, sera were collected from immunized mice and the levels of total malaria-specific antibody, IgG1, and IgG2a were determined by ELISA. Data represent OD values for individual mice and are pooled from 2 experiments. FIG. 2: Course of parasitemia and survival in A/J mice immunized s.c. with antigen alone, antigen in alum, antigen plus IL-12, or antigen plus IL-12 in alum and boosted 3 weeks later by i.p. injection with antigen. Two weeks later, immunized and untreated, control mice were challenged i.p. with 1×106 P. chabaudi AS parasitized red blood cells (PRBC). The percentage of PRBC in peripheral blood (A and B) was determined for each group of 5 mice. Data of one of two replicate experiments are presented. Mice were examined twice daily for the duration of the experiment for survival (C). Cumulative data from 6 experiments are shown. FIG. 3: Course of parasitemia and survival in immunized CD4+T cell depleted A/J mice or in wildtype or IFN-γ deficient (GKO) C57BL/6 mice. To deplete CD4+in vivo, A/J mice were treated i.p. with GK1.5 monoclonal antibody or with an equivalent amount of rat IgG as control 3 days prior to challenge infection and three times per week during infection. Two weeks after boosting, mice were challenged i.p. with 1×106 P. chabaudi AS PRBC and the course of parasitemia was determined (A). Female wildtype (B) and GKO (C) C57BL/6 mice were immunized with antigen plus IL-12 in alum and two weeks after boosting, mice were challenged i.p. with 1×106 P. chabaudi AS PRBC and the course of parasitemia was determined. Similar results were obtained in a replicate experiment using male wildtype and GKO mice. In panel A, *, p<0.001, for control vs. CD4+T cell depleted mice. In panel B, *, p<0.0001, for untreated vs. immunized C57BL/6 mice. FIG. 4: Course of parasitemia in immunized B cell-deficient μ-MT (BKO) and wildtype (WT) C57BL/10 mice. Groups of BKO (male, n=6; female, n=8) and WT (male and female, n=10) mice were immunized s.c. with antigen plus IL-12 in alum and boosted i.p. with antigen three weeks later. Two weeks later, mice were challenged i.p. with 1×106 P. chabaudi AS PRBC and the course of parasitemia was determined in male (A, B) and female (C, D) BKO (A, C) and wildtype (B, D) mice. *, p<0.001, #, P<0.05 for unimmunized vs. immunized mice. FIG. 5: Course of parasitemia in A/J mice immunized with antigen plus IL-12 in alum or antigen plus CpG-ODN in alum. Groups of 5 A/J mice were immunized s.c. with either antigen plus IL-12 in alum (IL-12), antigen plus CpG-ODN in alum (CpG-ODN), or antigen plus ODN in alum (Control ODN) and boosted i.p. with antigen three weeks later. Two weeks later, mice were challenged i.p. with 1×106 P. chabaudi AS PRBC and the course of parasitemia was determined. *, p<0.001 for day 9 parasitemia between antigen plus ODN in alum versus antigen plus CpG-ODN in alum. p=0.114 for antigen plus CpG-ODN in alum versus antigen plus IL-12 in alum. FIG. 6: A single low dose infection primes antigen-specific splenic lymphocytes without inducing lymphocyte apoptosis. Mice were infected with 1×105 P. c.chabaudi AS PRBC i.v. at day 0. On day 2, a first group of infected mice was killed along with naïve controls (n=4). Low dose mice were drug-cured on day 2, while high dose mice were allowed to develop detectable parasitaemia. Naïve, high dose and low dose mice were killed at day 8 (n=4). Apoptosis of splenic lymphocyte sub-sets was assessed by staining with Annexin V and antigen-specific proliferation of lymphocytes was examined. Means+SEM are shown. This is representative of two experiments. FIG. 7: Low dose infection induced significant protection against challenge with homologous and heterologous parasites. Low dose mice (lower panels) were administered three i.v. injections at 3-4 week intervals with 1×105 P. c.chabaudi AS primary variant PRBC. Naïve mice (upper panels) were injected with PBS at the same time points. All mice were administered Malarone by oral gavage for four consecutive days, commencing 48 hours after each injection. Six weeks after a third injection mice were challenged i.v. with either (A) 1×106 P. c.chabaudi AS primary variant PRBC, 1×106 P. c.chabaudi CB PRBC or (B) 1×106 P. c.chabaudi AS recrudescent variant PRBC. Parasitaemia was monitored by blood smears for 4 weeks post-challenge. Each line represents an individual mouse. FIG. 8: Splenic lymphocytes from low dose mice showed significant proliferation in vitro to homologous and heterologous parasite antigen. Low dose mice were given three i.v. injections at 3-4 week intervals with 1×105 P. c.chabaudi AS primary variant PRBC. Naïve mice were injected with PBS at the same time points. All mice were administered Malarone by oral gavage for four consecutive days, commencing 48 hours after each injection. Spleens were removed 6 weeks after the third injection and single spleen cell suspensions cultured in vitro with nmRBC, Concanavalin A or different doses of homologous (P. c.chabaudi AS) or heterologous (P. c.chabaudi CB) PRBC. Results show an average stimulation index +/− standard error of 4 mice. The stimulation index is a ratio of proliferation in the presence of stimulant to proliferation in the presence of nmRBC. Values over three are typically regarded as significant. Data from one of three replicate experiments are presented. FIG. 9: Serum from low dose mice had significantly lower levels of IgG that bound strain-specific antigens on the surface of homologous PRBC compared to hyper-immune serum. Low dose mice were given three i.v. injections at 3-4 week intervals with 1×105 P. c.chabaudi AS primary variant PRBC. Naïve mice were injected with PBS at the same time points. All mice were given Malarone by oral gavage for four consecutive days, commencing 48 hours after each injection. Hyper-immune serum was generated by giving mice three i.v. injections at 3-4 week intervals with 1×105 P. c.chabaudi AS PRBC and allowing the mice to self cure, exposing the mice to high doses of live parasite. Serum was collected from all mice 3 weeks after the third injection. P. c.chabaudi AS (homologous) or P. c.chabaudi CB (heterologous) late stage PRBC were stained with serum indirectly conjugated to FITC to detect red cell surface antigens and the parasite DNA counterstained with ethidium bromide, which binds directly to the DNA. Cells were analysed by flow cytometry. Data show a representative mouse from each group of 10 from one of two replicate experiments. Numbers indicate percentage of cells in each quadrant. FIG. 10 shows a low dose (1×103)), killed plasmodium parasite, in combination with CpG plus alum, induces significant protection against challenge with homologous parasite in A/J mice. Animals were first immunized subcutaneously with either CpG (Group A), alum (Group B), combined CpG plus alum, or combined CpG, alum and dead parasite (1×103 (Group F), 1×105 (Group E) or 1×107 (Group D) P. c.chabaudi parasites (ip) that had been killed by multiple freeze/thaw cycles) at Day 0. At Day 21, animals were boosted with same amount of parasite or PBS alone (ip). At Day 42, mice were given a further boost with the same amount of dead parasite (ip). On Day 56, all animals were challenged with live 1×105 P. c.chabaudi parasites administered intraveneously. Parasitaemia was monitored by blood smears for 30 days post-challenge. Each line represents percent parasitaemia in an individual mouse (n=5 per group). FIG. 11 shows low dose (1×103 and 1×105) of heat-killed plasmodium parasite combined with CpG and alum, prevents recrudescence in C57BL/6 mice. Animals were immunized subcutaneously with either CpG (Group F), combined CpG plus alum (Group B, C, D, E), control (inactive CpG) plus alum (Group A), or combined CpG, alum and dead parasite (1×103 (Group F), 1×105 (Group E), or 1×107 (Group D) P. c.chabaudi parasites) at Day 0. At Day 21, animals were boosted the same amount of dead parasite or vehicle alone. At Day 42, all animals were challenged with live 1×105 P. c.chabaudi parasites administered intraveneously. Parasitaemia was monitored by blood smears for 30 days post-challenge. Each data point represents % parasitaemia in an individual mouse (n=5 per group). Straight bars represent the mean data of n=5 animals per group. A=Control CpG+Alum+107 p. Ch. Chabaudi; B=CpG+Alum+107 p. Ch. Chabaudi; C=CpG+Alum+105 p. Ch. Chabaudi; D=CpG+Alum+103 p. Ch. Chabaudi; E=CpG+Alum+PBS; F=CpG+PBS TABLE 1: Antigen-Specific Spleen Cell Proliferation and Cytokine Responses in Immunized Mice Prior to P. chabaudi AS Challenge Infection. TABLE 2: Long Term Protection Against Blood-Stage Malaria Induced by Immunization With Malaria Antigen Plus IL-12 in Alum. DETAILED DESCRIPTION OF THE INVENTION Unless defined otherwise, all technical and scientific terms used herein have a meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any method and material similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purpose of the present invention, the following terms are defined below. The present invention relates to a pharmaceutical composition that is preferably capable of inducing heterologous immunity against a pathogen. Accordingly, the pharmaceutical composition preferably comprises an immunotherapeutic agent capable of inducing an immune response in an animal. The immunotherapeutic agent is preferably capable is of reducing infection and/or improving recoverfrom infection by Plasmodium species. The invention in a preferred form may be useful for protection against different, but preferably related, pathogens. A preferred pathogen described herein is Plasmodium, which is known to comprise different species and strains or variants. In a preferred form, the pharmaceutical composition of the invention comprises a low dose of an antigenic component obtainable from at least one strain of Plasmodium and a CpG nucleic acid, IL-12 protein and/or nucleic acid encoding IL-12, and an adjuvant such as alum. Preferably, the antigenic component is obtained from at least one species of Plasmodium capable of infecting a human that has been inactivated by killing. Administration of a low dose respectively of live and killed parasite was investigated in the resistant mouse C57BI/6 strain. The blood stage infection was restricted to levels undetectable on a blood smear by curative drug treatment 48 hours after infection in relation to administration of live Plasmodium. The investigators first determined that such a low dose infection was sufficient to prime lymphocytes whilst avoiding or minimising apoptotic death observed with a fulminant infection. The investigators then assessed an ability of multiple low dose infections to induce protective immunity following challenge infection with a high dose of either a homologous parasite or a heterologous parasite strain or variant. Initial investigations into the mechanism of protection found high levels of lymphocyte proliferation to both homolgous and heterologous parasite antigen and an absence of antibodies recognising antigens on the surface of PRBC. The present invention also relates to the use of a low dose of an antigenic component from one or more Plasmodium spp in combination with an agent capable of increasing IL-12 in an animal, for example an agent capable of stimulating endogenous IL-12 expression in the animal and/or exogenous IL-12 in a pharmaceutical composition, immunotherapeutic composition or vaccine against Plasmodium spp. CpG-oligonucleotides are referred to herein as an agent capable of increasing IL-12 in an animal by stimulating endogenous IL-12 expression in the animal. It will be appreciated that any suitable biologically active IL-12 may be used, for example a biologically active fragment of IL-12, IL-12 derived from any suitable source (including human and human orthologues, homologues, recombinant IL-12), nucleic acids and nucleic acid homologs encoding IL-12 (including nucleic acids encoding human IL-12, human IL-12 homologues and orthologues and homologous having one or more codon sequence altered by taking advantage of codon sequence redundancy). Preferably, the IL-12 administered to an animal is IL-12 protein or nucleic acid encoding IL-12 of the species of the animal. Accordingly, use of IL-12 in humans is preferably human IL-12 or biologically active fragment thereof. Antigens and Pathogens For the purposes of this invention, by “isolated” is meant material that has been removed from its natural state or otherwise been subjected to human manipulation. Isolated material may be substantially or essentially free from components that normally accompany it in its natural state, or may be manipulated so as to be in an artificial state together with components that normally accompany it in its natural state. Isolated material includes material in native and recombinant form. For example, isolated whole pathogen, extracts of a pathogen, purified proteins, recombinantly expressed proteins, including IL-12. An “antigenic component” is meant a component derived from an organism capable of stimulating an immune response in an animal, preferably a mammal including mouse and human. An antigenic component may be an immunogenic agent. The antigenic component may comprise sub-cellular components including, organelles, membranes, proteins, lipids, glycoproteins and other components derived from the organism. The antigenic component may be derived from a whole organism, for example a whole parasite, or a part of an organism, for example a cell or tissue of an organism. The antigenic component may also include isolated sub-cellular components recombined, for example, respective membranes, proteins, lipids and glycoproteins may be purified and recombined. Also, a sub-set of proteins may be purified, for example by size fractionation or affinity purification, and recombined. Further, the antigenic component may comprise one or more recombinantly expressed antigens. For example, an expression library, such as a cDNA library, may be prepared from an organism and encoded proteins recombinantly expressed. Suitable methods for preparing such an expression library are well known in the art and described for example in CURRENT PROTOCOLS IN MOLECULAR BIOLOGY Eds. Ausubel et al., (John Wiley & Sons, Inc. 1995-1999), in particular chapters 5 and 6, incorporated herein by reference. It will be appreciated that the antigenic component preferably comprises a plurality of antigens expressed by the organism, more preferably a majority of the antigens expressed by the organism, including greater than 50%, greater than 60%, greater than 75%, greater than 90%, greater than 95% and even greater than 99% and even 100% (for example whole extract or whole intact organism). It will be appreciated that in one form of the invention, the antigenic component need not be fully characterized and specific antigens of the antigenic component may not be defined. This has advantages in that time and effort is not required to isolate and purify specific and defined antigens. In one form of the invention, a crude extract of the pathogen may be used. In a preferred form, the antigenic component comprises live Plasmodium spp, inactivated Plasmodium spp, killed Plasmodium spp, extract derived from the Plasmodium spp, purified proteins derived from the Plasmodium spp, recombinantly expressed nucleic acids encoding proteins derived from the Plasmodium spp and a pool of recombinant expressed proteins derived from the Plasmodium spp. In a preferred form, the antigenic component is a Plasmodium spp that has been killed, for example by freezing and thawing, and is not able to infect a host. In contrast, an inactivated Plasmodium spp comprises attenuated Plasmodium spp that are capable of infecting, but not replicating, in a host. A preferred species of Plasmodium is one that is capable of infecting humans, for example Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae or Plasmodium ovale. An antigenic component preferably comprises one or more antigens derived from one or more different pathogens, however, in one form of the invention, the antigenic component may comprise antigens derived from a single pathogen, for example, a single species of Plasmodium or a single strain of a single species of Plasmodium. The pathogen preferably comprises one or more different Plasmodium spp, including for example P. falciparum, P. vivax, P. malariae, P. ovale, P. knowlesi, P. berghei, P. yoelii, P. chabaudi and/or P. vinckei. In a preferred form, the antigenic component comprises all Plasmodium spp known to infect humans, namely one or more Plasmodium spp selected from the group consisting of: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae or Plasmodium ovale. The antigenic component may also comprise one or more strains of any one or more of the different Plasmodium spp. In a preferred form of the invention, the antigenic component comprises at least one strain of Plasmodium for each species capable of infecting a human, whereby heterologous immunity is provided for each strain of human Plasmodium spp when administered to a human. This is particularly advantageous as it will be appreciated there is potentially hundreds if not thousands of strains of Plasmodium capable of infecting humans, both known and unknown. The antigenic component may comprise Plasmodium in any developmental form or combination thereof, including: sporozoites, merozoites, gametocytes and/or ookinetes. In a preferred form of the invention, the antigenic component is obtained from Plasmodium spp in the form of at least a merozoite. In a more preferred form, the Plasmodium spp is in the form of a merozoite. It will also be appreciated that the antigenic component of the invention, when administered to a subject preferably reduces infection or improves recover from infection from one or more species and strains of Plasmodium. Accordingly, in a preferred form of the invention, administering to a human a pharmaceutical composition comprising an antigenic component from one or more different Plasmodium spp capable of infecting a human is capable of reducing or preventing malaria or improves recovery therefrom. An antigenic component is suitably an immunogenic agent and included as an active in a pharmaceutical composition. In one preferred form of the invention, the antigenic component is included as part of an immunotherapeutic composition. In more preferred form of the invention, the antigenic component forms part of a vaccine. An ability of the antigenic component to stimulate an immune response preferably encompasses stimulation of at least a T-cell response. Stimulating an immune response in an animal may also be referred to a “biological activity” of the antigenic component. In one preferred form, the antigenic component may stimulate a T-cell response without stimulating B-cells to produce antibodies capable of binding the antigenic component. In one form, a B-cell is not stimulated to produce antibodies, but may be activated to perform other known B-cell functions such as secreting cytokines. “Extract” as used herein comprises the contents of a whole organism, fractions and sub-fraction of an extract, antigenic component of the organism and isolated component thereof. By “endogenous” substance or compound is meant a substance or compound that may be found in a native cell, tissue or animal in isolation or otherwise. For example, endogenous IL-12 may be induced by CpG nucleic acid. By “heterologous” pathogens means related pathogens that may be different strains or variants of a same or related species. An example of different strains of a same species is P. c. chabaudi AS and P. c. chabaudi CB. Heterologous may also refer to related species for example, P. falciparum and P. vivax. A “pathogen” as used herein refers to an agent capable of causing disease, for example a virus, bacteria, fungus or parasite. Parasite includes intracellular parasites such as Mycobacterium spp, Plasmodium spp and Leishmania spp. “Plasmodium spp” as used herein comprises all Plasmodium species, strains and variants, including: P. falciparum, P. vivax, P. malariae, P. ovale, P. knowlesi, P. berghei, P. yoelii, P. chabaudi, P. c. chabaudi AS, P. c. chabaudi CB and P. vinckei. A strain of Plasmodium spp includes variants within a same species, for example P. c. chabaudi AS, P. c. chabaudi CB. A variant is referred to in FIG. 7. The term “low dose” is used herein to refer to a dose wherein an individual is infected or administered with a live (including inactivated and attenuated) or killed (e.g. dead) parasite, but the parasite density is preferably sufficiently low that the parasite cannot be substantially detected on a blood smear, more preferably no parasite can be detected. In relation to malaria, low dose is typically referred to as a sub-patent infection. A low dose in a preferred form is capable of inducing a T-cell response when administered to an animal. Preferably, the low dose does not stimulate production of detectable antibodies from B-cells that are capable of binding to the antigenic component of the low dose. A low dose of an antigenic component in a preferred form is derived from killed whole pathogen (for example killed whole Plasmodium spp), wherein the dose is equivalent to less than 107 whole pathogens/mL of blood from the animal, more preferably less than an equivalent of 106, 105, 104, 103, 102 or 10 pathogens/mL of blood from the animal. An example of a low dose includes about 1000 to 3000 PRBC/mL of blood obtained from live PRBC, which have been treated to inactivate them, preferably by killing so that infection and replication in a host is not possible. Preferably, an equivalent of inactivated pathogen or antigenic component is prepared by calculating a number of parasite infected red blood cells (PRBC) in a sample and treating the PRBC to inactivate or kill the parasite and adjusting the concentration to achieve a desired blood concentration. For example, if a mouse is bled and 5×108 red blood cells are isolated at 20% parasitaemia, there is a total of 1×108 PRBC. The PRBC are lysed, sonicated and/or irradiated, which results in an amount of antigen equivalent to 1×108 PRBC. The sample comprising the parasite antigen(s) is diluted in an appropriate volume so that each recipient may be administered a dose of antigen equivalent to about preferably 1000-3000 PRBC/mL blood. An approximate volume of blood in a mouse is around 1 mL. A person skilled in the art will appreciate that a low dose for administration in a human may be determined by administering an approximate low dose of antigenic component to a human and assessing an immune response in the human. Preferably, the immune response is characterised by inducing a T-cell response and preferably not inducing B-cells to produce detectable levels, or only low levels, of antibodies capable of binding to the antigenic component. A low level of antibody production preferably refers to a level not sufficient to protect an animal against a pathogen. A low dose is preferably less than an equivalent of 107, 106, 105, 104, 103, 102 or even less than 10 whole parasites. Accordingly, a low dose may comprise as few as an equivalent of 10, 50, 100, 200, 250, 500 or 750 whole parasite. In one form of the invention, a preferred low dose for an antigenic component comprising one or more different species of Plasmodium spp is less than an amount equivalent to 106 parasite equivalents per mL of blood in the mouse. More preferably, less than an equivalent to 105, 104, 103, 102 or 10 parasite equivalents per mL of blood in the mouse. A preferred range is between an equivalent to 103-106 parasite equivalents per mL of blood in the mouse. More preferably, the low dose is in a range between 10-105, more preferably in a range between 102-105, even more preferably in a range between 103-104. Preferably, the low dose is 1×103, 3×103, 5×103, 1×104, 5×104, 1×105, 5×105, 1×106, 5×106, 1×107 or 5×107 pathogens per mL of blood. Also, an amount of the antigenic component of a low dose may be determined by a person skilled in the art by assessing an ability of the administered dose to provide partial or complete protection or recovery from a pathogen infection as describe herein. For example, providing partial or complete protection against malaria. Also, a low dose may be assessed by determining an ability of administration of the low dose of antigenic component to protect the animal against one or more different species or strains of pathogen, such as different species or strains of Plasmodium. Proteins and Peptides By “protein” is also meant “polypeptide”, either term referring to an amino acid polymer, comprising natural and/or non-natural amino acids, D- or L-amino acids, as are well understood in the art. For example, IL-12 may be referred to as both a protein or polypeptide. “Protein” may refer to a peptide, polypeptide, or fragments thereof, inclusive of complexes with other moieties such as biotin, fluorochromes and nucleic acids. As described herein, proteins may be recombinantly expressed or isolated from a native source. Such proteins include pathogen proteins used in accordance with the present invention. For example, an extract in one form may comprise one or more proteins derived from one or more species of Plasmodium spp. In one embodiment, a “fragment” includes an amino acid sequence which constitutes less than 100%, but at least 20%, preferably at least 30%, more preferably at least 80% or even more preferably at least 90%, 95%, 98% or 99% of said polypeptide. The fragment may also include a “biologically active fragment” which retains the biological activity of a given polypeptide or peptide. For example, a biologically active fragment of IL-12 or a biologically active fragment of one or more pathogen derived protein(s). The biologically active fragment constitutes at least greater than 1% of the biological activity of the entire polypeptide or peptide, preferably at least greater than 10% biological activity, more preferably at least greater than 25% biological activity and even more preferably at least greater than 50%, 60%, 70%, 80%, 90%, 95%, 98% and even 99% biological activity. As generally used herein, a “homolog” shares a definable nucleotide or amino acid sequence relationship with a nucleic acid or polypeptide as the case may be. Included within the scope of homologs are “orthologs”, which are functionally-related polypeptides and their encoding nucleic acids, isolated from other organisms. For example, homologs of mouse and human IL-12. Nucleic Acids The term “nucleic acid” as used herein designates single or double stranded mRNA, RNA, cRNA and DNA, said DNA inclusive of cDNA and genomic DNA. Nucleic acid includes primers, probes and oligonucleotides, such as oligodexoynucleotides (ODN). A nucleic acid may be native or recombinant and may comprise one or more artificial nucleotides, e.g. nucleotides not normally found in nature. Nucleic acid encompasses modified purines (for example, inosine, methylinosine and methyladenosine) and modified pyrimidines (thiouridine and methylcytosine). Nucleic acid includes CpG nucleic acids. CpG nucleic acids include any suitable CpG nucleic acid, for example, CpG motif-containing oligodeoxynucleotide immunostimulatory sequences: (1) uniformly modified phosphorothioate (PS) oligodeoxyribonucleotides (ODNs), which appear to initiate B cell functions, but poorly activate dendritic cells (DCs) to make interferon (IFN)-alpha, and (2) chimeric PS/phosphodiester (PO) ODNs containing runs of six contiguous guanosines, which induce very high levels of plasmacytoid DC (PDC)-derived IFN-alpha, but poorly stimulate B cells as described in Marshall et al, 2003, J Leukoc Biol 73 781. The CpG oligonucleotides described herein are merely examples of suitable CpG oligonucleotides and it will be appreciated that a person skilled in the art will be able to select other suitable CpG oligonucleotides having a similar or different nucleotide sequence, or fragments of same or similar CpG oligonucleotides and CpG oligonucleotides of different lengths and comprising any suitable combination of nature or unnatural nucleotide bases. As described in WO 00/31540, the CpG dinucleotide may form a core motif common to immunostimulatory DNA (Krieg et al., 1995, Nature 374 546). However, it is also clear that flanking sequence can be important, in that CpG sequences flanked by a cytosine (C) or guanine (G) nucleotide are less immunostimulatory (Krieg et al., 1995, supra). CpG sequences are relatively common in bacterial DNA, and are generally unmethylated. In contrast, CpG sequences occur less commonly in vertebrate DNA (about 25% of what would be expected based on random base utilization) and are generally methylated (Bird, 1987, Trends Genet. 3 342; Bird, 1993, Cold Spring Harbor Symp. Quant. Biol. 58 281). Thus, by virtue of the presence of unmethylated CpG sequences, bacterial DNA can be distinguished by the immune system as being non-self, whereas ACpG suppressed@ vertebrate sequences are treated as self. It should also be noted that unmethylated vertebrate CpG sequences tend to be flanked by C or G nucleotides, rendering them less immunostimulatory. Accordingly, the nucleotide sequence comprising CpG and the amount of methylation may be selected by a skilled person to appropriately stimulate an immune response in accordance with the invention. An “expression vector” may be either a self-replicating extra-chromosomal vector such as a plasmid, or a vector that integrates into a host genome. Expression vectors are well known in the art and a suitable expression vector may be selected for expression in humans. Such an expression vector may be suitable of expressing IL-12 in an animal. An expression vector may also be used to express a pathogen protein(s). By “operably linked” is meant that said regulatory nucleotide sequence(s) is/are positioned relative to the recombinant nucleic acid to initiate, regulate or otherwise control transcription. For example, IL-12 nucleic acid and/or a pathogen nucleic acid(s) may be operably linked to a regulatory nucleotide sequence(s). Regulatory nucleotide sequences will generally be appropriate for the host cell used for expression. Numerous types of appropriate expression vectors and suitable regulatory sequences are known in the art for a variety of hosts, including eukaryotes such as humans. Pharmaceutical Compositions, Immunotherapeutic Compositions and Vaccines A pharmaceutical composition comprises actives that may be “immunogenic agents” capable of eliciting an immune response in an animal. An immunogenic agent may comprise an antigenic component. It will be appreciated that an immunogenic agent in one embodiment when administered to a subject, such as a human, may reduce infection by a pathogen and/or may improve recovery from an infection by a pathogen. Accordingly, a pharmaceutical composition or an immunogenic agent may provide partial protection or recovery and need not provide complete protective immunity against a pathogen. Partial protection against a pathogen may be useful, for example, by reducing severity of infection or improving survival or recovery of the subject from an infection by a pathogen. Partial protection preferably prevents clinical diagnosis of malaria or symptoms of malaria, including prevention of death of the infected subject. In addition to administration of the immunogenic agent, one or more other agents may be administered to treat or prevent the infection or other ailment. For example, a pharmaceutical composition for preventing or treating malaria may be administered to a same subject as the immunogenic agent. This may be preferred in a situation where the immunogenic agent provides partial protection against Plasmodium spp infection and the disease malaria. In one embodiment, an anti-malaria pharmaceutical, such as chloroquine, atovaquone and/or proguanil is administered to a same subject being administered the immunogenic agent. In one embodiment, an anti-malaria pharmaceutical composition may be administered to improve protection and/or recovery from infection by a range of unknown Plasmodium spp or unknown strains. The anti-malaria pharmaceutical may be administered before, concurrently and/or after administration of the pharmaceutical composition of the invention. A “vaccine” is capable of providing protective immunity against an organism. The vaccine may provide protection against a same (i.e. homologous) or different (i.e. heterologous) strain of an organism. The vaccine of the invention preferably is capable of providing protection against homologous and heterologous species, variants or strains. In a preferred embodiment, the vaccine is capable of protecting or treating a human from infection from one or more heterologous strains of Plasmodium, for example, one, two, three, four, fix, six, seven, eight, nine, ten, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 and even more than 1000 different strains of Plasmodium. Preferably, the Plasmodium spp is selected from a species capable of infecting a human, for example Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. The vaccine is preferably capable of protecting or treating a human from one or more different strains of one or more different species of Plasmodium. Immunogenic agents used as actives in a pharmaceutical composition may be suitable for immuno-therapy or vaccination of humans. An immunogenic agent when administered to an animal, for example a human, is capable of eliciting an immune response in said animal against the immunogenic agent. A pharmaceutical composition includes an immunotherapeutic composition. An immunotherapeutic composition includes a vaccine. Suitably, the pharmaceutical composition comprises a pharmaceutically-acceptable carrier. By “pharmaceutically-acceptable carrier, diluent or excipient” is meant a solid or liquid filler, diluent or encapsulating substance that may be safely used in systemic administration. Depending upon the particular route of administration, a variety of carriers, well known in the art may be used. These carriers may be selected from a group including sugars, starches, cellulose and its derivatives, malt, gelatine, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, and pyrogen-free water. Any suitable route of administration may be employed for providing a patient with the pharmaceutical composition of the invention. For example, oral, rectal, parenteral, sublingual, buccal, intravenous, intraarticular, intramuscular, intradermal, subcutaneous, inhalational, intraocular, intraperitoneal, intracerebroventricular, transdermal and the like may be employed. Intramuscular and subcutaneous injection is appropriate for administration of immunogenic agents of the present invention. Dosage forms include tablets, dispersions, suspensions, injections, solutions, syrups, troches, capsules, suppositories, aerosols, transdermal patches and the like. These dosage forms may also include injecting or implanting controlled releasing devices designed specifically for this purpose or other forms of implants modified to act additionally in this fashion. Controlled release of the therapeutic agent may be effected by coating the same, for example, with hydrophobic polymers including acrylic resins, waxes, higher aliphatic alcohols, polylactic and polyglycolic acids and certain cellulose derivatives such as hydroxypropylmethyl cellulose. In addition, the controlled release may be effected by using other polymer matrices, liposomes and/or microspheres. Pharmaceutical compositions of the present invention suitable for administration may be presented as discrete units such as vials, sachets, syringes and the like, each containing a pre-determined amount of one or more immunogenic agent, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more immunogenic agents as described above with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the agents of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. The above compositions may be used as a therapeutic or prophylactic composition comprising a protein and/or nucleic acid of a pathogen, preferably a plurality of pathogen proteins, more preferably a majority of pathogen proteins, even more preferably an extract derived from the pathogen. In one embodiment, the vaccine comprises an immunogenic agent as described above. Preferably, the vaccine prevents or treats infection by a parasite, more preferably infection by one or more different species of Plasmodium spp or one or more strains thereof. Accordingly, in a preferred form, the vaccine protects against both homologous and heterologous strains of Plasmodium spp, preferably one or more different strains of one or more different species capable of infecting humans, in particular, a Plasmodium spp selected from the group consisting of: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovate. Accordingly, the invention extends to the production of vaccines comprising as actives an antigenic component of the invention. Any suitable procedure is contemplated for producing such vaccines. Exemplary procedures include, for example, those described in NEW GENERATION VACCINES (1997, Levine et al., Marcel Dekker, Inc. New York, Basel Hong Kong) which is incorporated herein by reference. An immunogenic agent according to the invention can be mixed, conjugated or fused with other antigens, including B and/or T cell epitopes of other antigens. In addition, it can be conjugated to a carrier as described below. When a haptenic peptide is used (i.e., a peptide which reacts with cognate antibodies, but cannot itself elicit an immune response), it can be conjugated with an immunogenic carrier. Useful carriers are well known in the art and include for example: thyroglobulin; albumins such as human serum albumin; toxins, toxoids or any mutant cross reactive material (CRM) is of the toxin from tetanus, diptheria, pertussis, Pseudomonas, E. coil, Staphylococcus, and Streptococcus; polyamino acids such as poly(lysine:glutamic acid); influenza; Rotavirus VP6, Parvovirus VP1 and VP2; hepatitis B virus core protein; hepatitis B virus recombinant vaccine and the like. Alternatively, a fragment or epitope of a carrier protein or other immunogenic polypeptide may be used. For example, a haptenic peptide can be coupled to a T cell epitope of a bacterial toxin, toxoid or CRM. In this regard, reference may be made to U.S. Pat. No 5,785,973 which is incorporated herein by reference. The vaccines can also contain a physiologically-acceptable carrier, diluent or excipient such as water, phosphate buffered saline or saline. The vaccines and immunogenic agents may include an adjuvant as is well known in the art. Suitable adjuvants include, but are not limited to adjuvants for use in human for example: aluminum hydroxide (alum), IL-12, CpG-ODN, SBAS2, SBAS4, QS21, or ISCOMs. Preferably, the adjuvant is alum. Immunotherapeutic Agent and Vaccine Development Heterologous Antigens Malaria is a disease characterized by several species and strains of pathogenic organisms, i.e. Plasmodium spp as described herein. Accordingly, malaria is used as an example of a suitable disease that may be controlled by reducing severity of infection and improving recovery, or preventing and/or treating by the pharmaceutical composition of the present invention. In relation to preparation of a malaria immunotherapeutic agent and vaccine, an antigenic component derived from whole Plasmodium spp, for example P. falciparum, or extract thereof, would comprise every parasite antigen, thus minimizing the consequences of limited immunological recognition of any one antigen and the consequences of antigenic polymorphisms. Further, the antigenic component may comprise antigens derived from one or more different species of Plasmodium, including for example a combination of two or more different species of Plasmodium spp or a combination of two or more different strains of one or more different species of Plasmodium. For example, the antigenic component may comprise one or more antigens derived or obtained from one or more Plasmodium spp selected from the group consisting of: P. falciparum, P. vivax, P. malariae, P. ovale, P. knowlesi, P. berghei, P. yoelii, P. chabaudi and P. vinckei. In a preferred form, the one or more Plasmodium spp is selected from those capable of infecting human, including those selected from the group consisting of: P. falciparum, P. vivax, P. malariae, P. ovale, Not being bound by theory, a combination of a very low dose of antigenic component together with an IL-12 inducing adjuvant such as CpG is thought to lead to a potent T cell response (cell mediated immunity; CMI). Such responses are not induced by natural infection, possibly because of apoptosis of parasite-specific T cells at high parasite density. Consequently, the antigens that might have been recognized by T cells are not under immune pressure and are likely to be conserved (Makobongo et al., 2003). Inducing such CMI using a pharmaceutical composition of the present invention may result in immunity against one or more Plasmodium spp or one or more strains of Plasmodium spp, preferably a plurality of Plasmodium strains, more preferably all Plasmodium strains. For example, one, two, three, four, five, six, seven, eight, nine, ten or more strains of a Plasmodium spp. A skilled person would be aware of Plasmodium strains, in particular those strains capable of infecting humans and causing malaria. As new and unknown strains may cause malaria, including different strains in different regions of the world, the present invention in a preferred form is particularly useful in being capable of reducing infection or improving recovery from infection by one or more strains of Plasmodium spp. In a preferred embodiment, administration of the pharmaceutical composition results in immunity against one or more Plasmodium spp, preferably a plurality of species, more preferably all Plasmodium spp. For example, one, two, three, four, five, six, seven, eight or more species. In a preferred form of the invention, the Plasmodium spp is selected from the group consisting of: P. falciparum, P. vivax, P. malariae, P. ovale, P. knowlesi, P. berghei, P. yoelii, P. chabaudi and P. vinckei. In a more preferred form, the one or more Plasmodium spp is selected from those capable of infecting human, including those selected from the group consisting of: P. falciparum, P. vivax, P. malariae and P. ovale, While it is presently less practical to develop a low dose live (including attenuated) pathogen pharmaceutical composition for widespread human use, a low dose of Adead” or killed pathogen or extract therefrom as described herein could be practically administered and widely distributed. Not being bound by theory, it will be appreciated that an extract from killed whole organism may present pathogen antigens differently to immune cells, e.g. T-cells, antigen presenting cells, B-cells, than live pathogen (including attenuated pathogen), which may provide an improved immune response or heterologous protection. Also, in a preferred embodiment, the pharmaceutical composition comprises CpG-oligonucleotides, which are inexpensive and have been safely administered in humans. Accordingly, a preferred form of an immunotherapeutic agent and vaccine comprises a low dose of an antigenic component comprising an inactivated Plasmodium spp in combination with CpG-oligonucleotide. Not being bound by theory, it will also be appreciated that in the preferred form comprising CpG-oligonucleotide, IL-12 will be produced by dendritic cells stimulated by binding CpG-oligonucleotide. IL-12 will activate T-cells within a localised area where an immune response is required and not systemically, as would be the case if IL-12 was injected into the animal. Accordingly, non-specific effects are minimised. An estimate of the amount of parasite antigen required to stimulate an appropriate immune response may be approximated based on the example herein and also as about an equivalent amount of antigen present in naive volunteers described as above in Pombo et al, 2002, supra, eight days after being administered 30 parasites, i.e. about 1000-3000 parasites/ml blood equivalents. Using modern proteomics and protein chemistry it is entirely feasible to purify an antigenic component of Plasmodium spp from red cell antigens (primarily red cell membranes and hemoglobin). Any slight chance that potentially deleterious anti-red cell immune responses might result would be further greatly reduced by growing the P. falciparum parasites in O NEG (Auniversal donor@) blood. It may also be feasible to recombinantly express a pool of pathogen proteins, for example Plasmodium spp proteins, that represent a majority of Plasmodium spp proteins. This may mimic an extract derived from Plasmodium spp by providing a broad range of antigens, which may be suitable for protecting against heterologous challenge. The feasibility of the above approach rests with the extremely low dose of antigen required for protection and an ability of new adjuvants, such as CpG (already known to be efficacious in humans) to promote strong immune responses. If large doses of parasites (107-109 equivalents) were required, this approach would be far more commercially difficult and impractical due to logistic reasons; however, the examples herein provide evidence that not only can low dose immunization be effective, but it will be more effective than high dose. Discussion Complete protective immunity to malaria requires the immune system to be capable of recognising and eliminating different variants, strains and species of Plasmodium, each expressing a wide range of polymorphic antigens. The development of natural immunity to P. falciparum appears to rely predominantly on exposure a wide repertoire of different pathogens, eg parasite strains and variants, although a small component of non-strain-specific immunity may also be involved. To further complicate the development of natural immunity, the parasite induces immunosuppression and apoptosis of immune cells, which impairs immune responses, particularly to cryptic or poorly immunogenic eptiopes/antigens. When considering the development of a vaccine against malaria, imitating the mechanism of natural immunity is impractical and to a certain degree undesirable. The apoptosis of immune cells and the suppression of proliferative T cell responses seen with a fulminant malaria infection did not occur when a single low dose infection of parasite was administered, and proliferative responses to both homologous and heterologous parasite antigen were maintained after three low dose infections. This would allow the development of a potentially novel immune response, possibly targeting conserved epitopes that could produce a strain- and variant-transcending immunity. Challenge infections demonstrate that three low dose infections can induce protective immunity capable of controlling infection with a homologous parasite and with a heterologous parasite strain and variant. It is likely that immune responses are predominantly targeting conserved epitopes, and this is supported by flow cytometric analysis of PRBC stained with prechallenge sera from low dose mice and from mice given three full infections with live parasite (representative of a natural infection). Whilst full infections induce the production of antibodies that strongly recognise antigens on the surface of homolgous PRBC, low dose infections produced antibodies that only poorly recognised homologous PRBC. An important aspect of vaccine development against infectious diseases, including malaria, is the identification of an appropriate adjuvant that is both capable of stimulating a protective immune response and safe for use in humans. Aluminum hydroxide (alum) is not always the most appropriate adjuvant given its potential to stimulate a Th2 type immune response characterized by IgG1 and IgE production and the lack of induction of cytotoxic T cell responses (5). This is particularly problematic in the development of vaccines against diseases caused by intracellular pathogens such as protozoan parasites, including intraerythrocytic Plasmodium parasites, the causative agent of malaria. Protective immunity against intracellular pathogens is generally dependent on Th1 type immune responses. However, protective immunity against blood-stage malaria is particularly complex and requires a concerted effort by a Th1 type cellular immune response and humoral immunity possibly involving a Th2 type response (24,29). Co-adsorption of antigen and IL-12 to alum promotes both Type 1 cytokine and antibody responses (19,21). Since both cellular and humoral responses have been implicated in protective immunity to malaria, the inventors hypothesised that immunization with the combination of malaria antigen and IL-12 co-adsorbed to alum may enhance protective immunity to blood-stage malaria. To investigate this possibility, the inventors examined the feasibility of using crude malaria antigen co-adsorbed with IL-12 to alum as a vaccine against blood-stage malaria in the mouse model of P. chabaudi AS. Cellular and humoral immune responses were compared in A/J mice immunized with antigen plus IL-12 in alum as well as antigen alone, antigen in alum, or antigen plus IL-12 and boosted three weeks later with antigen alone prior to challenge infection. A/J mice are susceptible to primary P. chabaudi AS infection and experience fulminant and lethal parasitemia by 10-13 days post-infection (36). During the first week of infection, spleen cells from these mice produce high levels of IL-4 and low levels of IFN-γ in vitro in response to parasite antigen (38). Determination of proliferation and cytokine production in vitro by spleen cells from A/J mice immunized with the various vaccine combinations revealed that spleen cells from mice immunized with malaria antigen plus IL-12 in alum had the highest levels of proliferation as well as of IFN-γ production in response to specific antigen. Spleen cells from these mice also produced lower levels of the Th2 cytokine IL-4 as well as the Th1 cytokine, TNF-γ and low levels of IL-10. The present results indicate that vaccination with the combination of malaria antigen plus IL-12 co-adsorbed to alum induced a Th1 immune response in vaccinated mice. The induction of a Th1 immune response by administration of malaria antigen plus IL-12 co-adsorbed to alum is relevant given the important role of Type 1 cell-mediated and humoral immune responses in mediating naturally-induced immunity against blood-stage malaria in mice infected with blood-stage P. chabaudi AS, and possibly humans (24,29,39,40). Importantly, immunization with the combination of malaria antigen plus IL-12 in alum induced strong protective immunity against challenge infection with blood-stage P. chabaudi AS in both susceptible A/J and resistant C57BL/6 mice. In contrast to control A/J mice which experience a severe course of parasitemia and 100% mortality (36), immunization with either antigen plus IL-12 or antigen plus IL-12 co-adsorbed to alum resulted in less severe courses of infection and significant decreases in peak parasitemia level. However, only mice immunized with antigen plus IL-12 in alum experienced 100% survival. Moreover, the protection induced by this formulation was long-lasting since mice challenged 3 months after boosting were still completely protected against P. chabaudi AS. This group of animals had significant decreases in peak parasitemia levels and time to parasite clearance comparable to mice challenged 2 weeks after boosting. In both instances, there was 100% survival of vaccinated mice. Although CD4+ T cells are known to play an important role in immunity to primary blood-stage P. chabaudi AS (24,29), little is known about the role of these cells in vaccine-induced immunity to blood-stage malaria. Earlier studies by Langhorne and colleagues (25) demonstrated that depletion of CD4+ T cells from immune C57BL/6 mice results in a low, transient parasitemia following challenge with P. chabaudi AS which is eventually cleared. In contrast, the present results in CD4+ T cell depleted, immunized mice indicate that CD4+ T cells play a critical role in immunity induced by vaccination with malaria antigen and IL-12 in alum. The inventors observed that immunized CD4+ T cell depleted mice experienced severe and lethal infections when challenged with P. chabaudi AS. It is likely that CD4+ T cells participate in immunity induced by immunization with malaria antigen and IL-12 co-adsorbed to alum by producing IFN-γ. NK cells may be a source of IFN-γ in mice immunized with malaria antigen and IL-12 in alum. NK cells have been found to produce IFN-γ early in infection with various species of mouse malaria parasites, including P. chabaudi AS (9,28). Recent studies in humans demonstrated that P. falciparum infected red blood cells induce IFN-γ production by NK cells from individuals infected with P. falciparum and non-exposed donors (3). IFN-γ is considered to be a major component of innate and acquired immunity to primary blood-stage P. chabaudi infections (11,24,40,42). The inability to protect GKO compared to wildtype C57BL/6 mice against challenge infection as shown here indicates that IFN-γ is also a critical cytokine in vaccine-induced immunity following immunization with malaria antigen and IL-12 co-adsorbed to alum. In humans, IFN-γ production has been found to correlate with resistance to reinfection with Plasmodium falciparum as well as with protection from clinical attacks of malaria (6,8,26). Based on these observations, it has been concluded that IFN-γ production should be considered as an important hallmark of effector T cell function for development of an effective malaria vaccine (14,32). Our results in the present report support this contention. During primary P. chabaudi AS infection, mice rendered B cell deficient by treatment from birth with anti-IgM antibodies or μ-MT mice with targeted disruption of the membrane exon of the immunoglobin μ-chain gene can control acute parasitemias similar to intact mice (41,44). However, B cell-deficient mice maintain a chronic low level of parasitemia indicating that effective parasite clearance at the later, chronic stage of infection requires the presence of B cells. (41,44). In addition to their ability to produce antibody, B cells may also play a role via production of IL-10 (41) in the switch from Th1 cells producing IFN-γ, which mediates control of acute parasitemia, to Th2 cells which provide help for antibody production leading to clearance of primary blood-stage P. chabaudi AS infection. Studies in μ-MT mice also showed that B cell-deficient animals are unable to control a challenge infection and develop parasitemia levels similar in magnitude to a primary infection (44). These findings suggest that B cell-dependent mechanisms may be important for an effective memory response to P. chabaudi AS infection (44). In the present study, we observed that immunization of B cell-deficient μ-MT mice with malaria antigen and IL-12 co-adsorbed to alum is ineffective in providing enhanced protection against challenge infection with P. chabaudi AS suggesting a role for a B cell-dependent mechanism(s) in vaccine induced immunity. The investigators also examined the possibility of replacing IL-12 with immunostimulatory CpG-ODN. Because of its ability to induce a Type 1 pattern of cytokine production dominated by IL-12 and IFN-γ with little secretion of Type 2 cytokines, CpG-ODN have been found to be useful as adjuvants for vaccines, including peptide vaccines, against a variety of pathogens (4,5,7,15,23,30,35,45). Near and colleagues (30) recently demonstrated that vaccination with the combination of CpG-ODN and a defined single P. yoelii antigen, MSP119, in alum resulted in a dramatic elevation in IFN-γ production as well as elevated production of IL-10 by MSP119-stimulated splenocytes suggesting induction of a mixed Th1/Th2 response. In mice vaccinated with this formulation, IgG1 was found to be the predominant antibody isotype in sera although increased levels of MSP119-specific IgG2a, IgG2b, and IgG3 isotype antibodies were also observed. Furthermore, increased antibody levels were found to correlate with protection against challenge infection with a high dose of P. yoelii PRBC. The present experimental results demonstrate that inclusion of immunostimulatory CpG-ODN instead of IL-12 in the vaccine formulation provides strong protection against blood-stage P. chabaudi AS infection in A/J mice. Also, immunization with CpG-ODN and crude malaria antigen in alum induces high levels of malaria-specific IgG2a in A/J mice before challenge infection in comparison to immunization with control ODN and antigen in alum (data not shown). Murine models are commonly used to study host parasite interactions and mechanisms of immunity to malaria in humans and the murine model often closely predicts the outcome in humans as discussed in Doolan and Hoffman, 2000, J. Immunol. 165 1453, incorporated herein by reference. For example, it is well known that in the murine P. Ch. Chabaudi model, parasites undergo recrudescence. An immune response to P. Ch. Chabaudi is the most well characterized model. Parasitaemia in this mouse model most closely resembles P. faiciparum in humans, which is the most important type of malaria in humans. In conclusion, it is possible to enhance the potency of a crude malaria antigen in alum vaccine formulation by inclusion of agents with immunostimulatory properties, such as IL-12 or CpG-ODN. Immunity induced by immunization with malaria antigen and IL-12 co-adsorbed to alum induced a long-lasting, Th1 immune response required for protection against challenge infection with P. chabaudi AS infection. In order that the invention may be readily understood and put into practical effect, particular preferred embodiments will now be described by way of the following non-limiting examples. EXAMPLE 1 Vaccination Against Blood-Stage Malaria Using Th1 Immunostimulatory Adjuvants Materials and Methods Mice Age- and sex-matched mice, 6-8 wk old, were used in all experiments. A/J mice were purchased from The Jackson Laboratory (Bar Harbor, Me.) and C57BL/6 mice from Charles River Laboratories (St. Constant, Quebec). Interferon-γ knockout (GKO) mice on the C57BL/6 background were bred in the animal facility of the Montreal General Hospital Research Institute from breeding pairs of GKO mice, which were originally from Genentech, Inc. (South San Francisco, Calif.) and backcrossed onto the C57BL/6 strain for eight generations, by Dr. F. P. Heinzel (Case Western Reserve University School of Medicine, Cleveland, Ohio) (16). B cell-deficient μ-MT with targeted disruption of the membrane exon of the immunoglobin μ-chain gene or B cell knockout (BKO) mice were originally derived on a 129 X C57BL/6 background and backcrossed to the C57BL/10 background for 12 generations (20,22). B cell-deficient μ-MT and wild type C57BL/10SgSnAi mice were obtained from Taconic Farms, Inc. (Germantown, N.Y.). CD4+ T Cell Depletion Monoclonal anti-CD4 antibody from the hybridoma clone GK1.5 was raised as ascites fluid in BALB/c mice as previously described (33) and incorporated herein by reference. The ascites fluid was delipified, dialyzed, and quantitated for concentration of rat IgG. Mice were treated with the first dose of 500 μg anti-CD4 antibody intraperitoneally (i.p.) 3 days prior to infection. Following infection, 200 μg was administered i.p. 3 times per week until the end of the experiment. Control mice received purified rat IgG at similar dosages and timing. Treatment with GK1.5 monoclonal antibody consistently depletes >98% of CD4+ T cells based on fluorocytometric analysis (33,37) and functional studies (33). P. chabaudi AS Infection and Antigen Preparation P. chabaudi AS was maintained as previously described (33). Naive and immunized mice were infected i.p. with 1×106 PRBC. The course and outcome of infection were monitored by previously described procedures (33). For determination of cytokine and antibody levels in sera, mice were sacrificed at the indicated times and blood was obtained by cardiac puncture, allowed to clot for 30 min at 4° C., and centrifuged at 3,000×g for 3 min. Sera were collected and stored at 4° C. for measurement of IL-12 p70 or at −20° C. for determination of the levels of other cytokines and malaria-specific antibodies. Antigen was prepared by modification of a freeze-thaw protocol described by Amante and Good (2). Briefly, blood from A/J mice with parasitemias of 40-45% was collected, pooled and centrifuged at 300×g for 10 minutes. The red blood cell pellet was subjected to 2 rounds of lysis with distilled H2O and centrifugation at 10,000×g for 25 minutes. After 2 washes with PBS, the parasite pellet was resuspended in PBS and subjected to 3 cycles of freeze-thaw at −70° C. and 37° C. The suspension, containing both soluble and particulate antigens, was further disrupted by passage 2-3 times through a syringe with a 25 g needle. Immunization Protocol Malaria antigen equivalent to 1-1.5×107 PRBC was mixed with 1 μg of mrIL-12 (a kind gift from Wyeth, Genetics Institute Cambridge, Mass.) to a volume of 50 μl with PBS. An equal volume of alum (Imject® Alum, Pierce Chemical Co, Rockford, Ill.) was added and the suspension was mixed thoroughly. Mice were immunized with 0.1 ml subcutaneously (s.c.) on the nape. Other groups of mice were also immunized in a similar manner with the following vaccine combinations: antigen suspended in PBS, antigen admixed in alum, and antigen admixed with 1 μg of mrIL-12 in PBS. Three weeks later, the antigen treated groups were boosted with the same amount of antigen in 0.1 ml PBS injected i.p. Mice were challenged i.p. with 1×106 PRBC two weeks later. CpG DNA Oligodeoxynucleotids (ODN) comprising CpG motifs (CpG-ODN No. 1826) and control ODN (No. 1982) were provided by Coley Pharmaceuticals Canada (Ottawa, ON, Canada). 100 μg of CpG-ODN or control ODN was admixed with antigen and alum and used according to the standard immunization protocol described above. The nucleotide sequences of CpG nucleic acids used herein are as follows: ODN No. 1826 = TCCATGACGTTCCTGAGTT; (SEQ ID NO: 1) ODN No. 1982 = TCCAGGACTTCTCTCAGGTT (SEQ ID NO: 2) Spleen Cell Culture and Proliferation Assay Spleens from immunized mice were removed aseptically and pressed through a sterile fine wire mesh with 10 ml RPMI 1640 (Gibco-Invitrogen, Burlington, ON, Canada) supplemented with 5% heat-inactivated FCS (Hyclone Laboratories, Logan, UT), 25 mM HEPES (Gibco-lnvitrogen), 0.12% gentamicin (Schering, Montreal, QC, Canada), and 2 mM glutamine (Gibco-lnvitrogen). Cell suspensions were centrifuged at 350×g for 10 minutes. Red blood cells were lysed with 0.175 M NH4Cl and the cells were washed twice in fresh medium. Membrane debris was removed by filtering the cell suspensions through sterile gauze. The viability of the cells was determined by trypan blue exclusion and was always >90%. Total cell counts were performed on individual samples. For proliferation assays, spleen cells were adjusted to 2.5×106 cells/ml and aliquots of 0.1 ml were plated in triplicate in 96-well flat-bottom plates, stimulated with 1×106 washed PRBC/ml as malaria parasite antigen or medium as control and incubated for 72 h at 37° C. in a humidified CO2 incubator. During the last 16 h of culture, 1 μCi of 3H-thymidine (specific activity, 6.7 Ci/mmol) was added to each well, the cells were harvested with an automatic cell harvester, and the incorporated radioactivity was measured in a liquid scintillation counter. For determination of cytokine production, spleen cells were adjusted to 5×106 cells/ml and aliquots of 1 ml were plated in triplicate in 24-well tissue culture plates in the presence or absence of 1×106 PRBC, as described above, and incubated for 48 h at 37° C. in a humidified CO2 incubator. Supernatants were collected, centrifuged at 350×g for 5 min, and stored at 4° C. or at −20° C. until assayed for cytokine levels. Cytokine ELISAs Cytokine levels in sera and spleen cell supernatants were measured using two-site sandwich ELISAs for IFN-γ and TNF-α as previously described (34,37). For IL-4, the capturing and detecting antibodies were BVD4-1D11 mAb and biotinylated BVD6-24G2 mAb, respectively. For IL-10, JES5.2A5 mAb (American Type Culture Collection, Rockville, Md.) and biotinylated SXC-1 mAb (BD Bioscience, Mississauga, ON) were used as capturing and detecting antibodies, respectively. Standard curves for each cytokine were generated using recombinant cytokines (BD Bioscience, Mississauga, ON). Reactivity was revealed using ABTS substrate (Roche, Laval, QC) and OD values were read in a microplate reader at 405 nm with a reference wavelength of 492 nm. Malaria-Specific Antibody ELISA Serum levels of P. chabaudi AS specific antibody isotypes were determined by ELISA. P. chabaudi AS antigen was prepared as described previously (49). Immulon II plates (Dynatech, Chantilly, Va.) were coated with parasite antigen at a concentration of approximately 4-5 μg/ml in PBS based on OD at 280 nm overnight at 4° C. and subsequently blocked with 1% BSA in PBS for 1 h. Individual serum samples were serially diluted 2-fold and 50 μl of each dilution were added to the plate and incubated for 2 h at room temperature. Data shown are based on values obtained at the following dilutions: total Ig, 1:20, IgG1, 1:10, and IgG2a, 1:10. After extensive washing, horseradish peroxidase-conjugated goat anti-mouse isotype antibodies (SBA, Birmingham, Ala.) were added and incubated at room temperature for another 2 h. Reactivity was visualized using ABTS substrate and OD values were read in a microplate reader at 405 nm with a reference wavelength of 492 nm. Antibody levels in serum are expressed as relative OD. Statistical Analysis Data are presented as mean±SEM. Statistical significance of differences in means between experimental and control groups was analyzed by Student's t-test using SAS/STAT software (SAS Institute, Cary, N.C.). A p<0.05 was considered significant. EXAMPLE 2 Immunization with Malaria Antigen Plus IL-12 in Alum Induces a Th1 Immune Response. Since a strong Th1 immune response is associated with protective immunity to acute blood-stage P. chabaudi AS during a primary infection, the type of immune response induced by inclusion of IL-12 in a vaccine formulation was first evaluated. P. chabaudi AS susceptible A/J mice were immunized s.c. with a freeze-thaw preparation of blood-stage malaria antigen alone, antigen in alum, antigen plus IL-12, or antigen plus IL-12 in alum and boosted three weeks later by i.p. injection with antigen alone. Two weeks later, prior to challenge infection, immunized mice and untreated, control A/J were sacrificed and proliferation and cytokine production by spleen cells were analyzed in vitro. As shown in Table 1, immunization with either antigen in alum or the combination of antigen plus IL-12 in alum resulted in significantly increased antigen-specific proliferation compared to the response of control A/J mice (p=0.02 and p=0.037, respectively). However, the combination of antigen plus IL-12 in alum resulted in greater than a 2-fold increase in proliferation compared to antigen in alum, which represents a significant difference between the two groups. Furthermore, in comparison with spleen cells from mice immunized with antigen in alum, spleen cells from mice immunized with the combination of antigen plus IL-12 in alum produced significantly higher levels of the Th1 cytokines, IFN-γ and TNF-γ, and significantly lower levels of IL-4. Spleen cells from mice immunized with the combination of antigen plus IL-12 in alum also produced modest levels of IL-10, which were significantly higher than the response of cells from mice immunized with antigen in alum. The levels of total malaria-specific antibody and IgG1 and IgG2a in the sera of immunized A/J mice were also analyzed two weeks after boosting prior to challenge infection. Total malaria-specific antibody was significantly and similarly increased in the three groups of immunized animals compared with the levels of total specific antibody in mice immunized with antigen alone (FIG. 1A). Malaria specific IgG1 was significantly increased in the groups immunized with antigen in alum and the combination of antigen plus IL-12 in alum compared to IgG1 levels in mice immunized with antigen alone (FIG. 1B). However, the level of malaria-specific IgG1 was significantly higher in the group immunized with antigen in alum compared to those immunized with the combination of antigen plus IL-12 in alum. The levels of specific IgG2a were significantly increased compared to controls only in mice immunized with the combination of antigen plus IL-12 in alum (FIG. 1C). These findings demonstrate that immunization with the combination of malaria antigen plus IL-12 in alum induced high levels of production of the Th1 cytokine IFN-γ and parasite-specific IgG2a. In addition, mice immunized with this combination produced significantly lower levels of antigen-specific IL-4 and IgG1 compared to mice immunized with antigen in alum in the absence of IL-12. EXAMPLE 3 Immunization with Malaria Antigen Plus IL-12 in Alum Induces Protection Against Challenge Infection with Blood-stage P. chabaudi AS. To compare the efficacy of vaccination with the various combinations in conferring protective immunity, groups of A/J mice, immunized as described above, were challenged i.p. with P. chabaudi AS two weeks after boosting and the course of parasitemia and the outcome of infection were followed. Similar to control mice, mice immunized with antigen alone or antigen in alum suffered a severe course of parasitemia with high peak parasitemia levels and high mortality (FIG. 2A and 2C). Mice immunized with antigen plus IL-12 or antigen plus IL-12 in alum experienced less severe courses of infection with significantly lower peak parasitemia levels compared to control mice (p<0.001 and p<0.001, respectively; FIG. 2B). In the case of mice immunized with antigen plus IL-12 in alum, there was a delay of 1-2 days in peak parasitemia level compared to unimmunized mice. Although antigen plus IL-12 was effective in significantly reducing peak parasitemia compared to control mice, only 60% (9/15) of mice immunized with this combination survived while 100% (25/25) of mice immunized with the combination of antigen plus IL-12 in alum survived challenge infection with P. chabaudi AS. These results indicate that antigen plus IL-12 in alum was the best combination for conferring protection against blood-stage malaria in terms of reduced parasitemia and enhanced survival. EXAMPLE 4 Immunization with Malaria Antigen Plus IL-12 in Alum Induces Long-Lasting Protection An important characteristic of an effective malaria vaccine is that the elicited immunity is long-lasting. To address this issue, A/J mice were immunized with the combination of antigen plus IL-12 in alum and challenged as before, that is, 2 weeks after boosting, or 12 weeks after boosting. Similar to mice challenged 2 weeks after boosting, A/J mice challenged at 12 weeks were solidly immune (Table 2). Long-lasting protection induced in these animals by malaria antigen plus IL-12 in alum was evident by a number of parameters. Importantly, there was a significant decrease in peak parasitemia compared to unimmunized A/J mice (p<0.001). In addition, the number of days required to clear parasites from the blood of mice challenged 12 weeks after boosting was similar to mice challenged 2 weeks after boosting and there was 100% survival among all immunized mice regardless of the time of challenge infection. EXAMPLE 5 Protective Immunity Induced by Immunization with Malaria Antigen Plus IL-12 in Alum Requires CD4+ T Cells and IFN-γ. To investigate the mechanism of protective immunity induced by vaccination with the combination of antigen plus IL-12 in alum, immunized A/J mice were depleted of CD4+ T cells by treatment with GK1.5 mAb 3 days prior to and three times per week during the challenge infection with P. chabaudi AS. Parasitemia and survival were monitored for 4 weeks post challenge infection. Consistent with the results shown above, intact immunized A/J mice suffered a mild course of infection and survived challenge infection. In contrast, CD4+ T cell depleted mice experienced fulminant infections with significantly higher peak parasitemia levels than rat IgG treated mice (p=0.008) (FIG. 3A) and the animals died by day 11 post challenge. To determine the role of IFN-γ in vaccine-induced protection, GKO mice on the resistant C57BL/6 background and wildtype C57BL/6 mice (36) were immunized with antigen plus IL-12 in alum. Immunized as well as untreated, control GKO and wildtype mice were challenged with P. chabaudi AS as described above. The course of parasitemia and outcome of infection were followed for 4 weeks in control and immunized mice of both genotypes (FIG. 3B and 3C). As we have shown previously, control GKO mice developed significantly higher levels of peak parasitemia on day 7 compared to their wildtype counterparts (64.2±3.35 vs. 38.7±4.43, respectively; p<0.0001). Furthermore, immunized wildtype C57BL/6 mice had a significantly lower peak parasitemia level which occurred one day later compared to wildtype mice without immunization (p<0.0001; FIG. 3B) indicating that immunization with antigen plus IL-12 in alum induced protection in resistant C57BL/6 as well as susceptible A/J hosts. In contrast to increased protection, as defined by the level of peak parasitemia, observed in wildtype mice, there was no significant difference in peak parasitemia levels in immunized versus untreated GKO mice (55.31±1.37 vs. 64.2±3.35, respectively; p=0.05). The timing of the peak parasitemia was delayed from day 7 to day 9 in immunized compared to control GKO mice. However, 100% of GKO mice, whether immunized or not, succumbed to challenge infection by day 12 (data not shown and 40). Taken together, these results demonstrate the crucial roles of CD4+ T cells and IFN-γ in the development of protective immunity against blood-stage malaria induced by immunization with P. chabaudi AS antigen plus IL-12 co-adsorbed to alum. EXAMPLE 6 Protective Immunity Induced by Immunization with Malaria Antigen Plus IL-12 in Alum Requires B Cells. As shown above, immunization of A/J mice with malaria antigen plus IL-12 in alum induced high levels of total malaria-specific antibody, IgG2a, and IgG1, and conferred the highest level of protection against challenge infection with blood-stage P. chabaudi AS. These observations suggested to us that the B cell response is an integral component of the mechanism of protective immunity induced by immunization with the lo combination of malaria antigen and IL-12 co-adsorbed to alum. The role of B cells in protective immunity induced by vaccination with antigen plus IL-12 in alum was further investigated using B cell-deficient μ-MT mice on the resistant C57BL/10 background (36). As previously observed (41,43,44), unimmunized male (FIG. 4A) and female (FIG. 4C) B cell-deficient mice compared to intact C57BL/10 mice (FIG. 4B and 4D) experienced recurrent bouts of recrudescent parasitemia until the experiment was terminated 90 days after challenge infection. Following immunization, peak parasitemia levels in male and female intact C57BL/10 mice were significantly decreased (p<0.001 for male mice and p<0.05 for female mice). Challenge infection was cleared in both male and female immunized C57BL/10 mice although female mice experienced several recrudescent parasitemias between 5 and 10%. Despite immunization, male and female B cell-deficient mice experienced peak parasitemias which were not significantly reduced compared to unimmunized, B cell-deficient mice. Although immunized B cell-deficient mice suffered fewer and significantly lower recrudescent parasitemias compared to their unimmunized counterparts, they were unable to clear the infection completely and low levels of parasitemia (1-5%) persisted throughout the chronic stage of infection until the experiment was terminated on day 90. EXAMPLE7 CpG-ODN Can Replace IL-12 as an Adjuvant for Immunization Against Blood-Stage Malaria It is possible that other agents, such as CpG-ODN, with potent immunostimulatory properties could also be useful as an adjuvant in a vaccine against blood-stage malaria. CpG-ODN has been shown to induce production of IL-12 which, in turn, enhances IFN-γ production, antibody production by B cells, and cytotoxicity of NK cells and CD8+ T cells (4,5,7,15,23). To determine if CpG-ODN can replace IL-12 as an adjuvant in the blood-stage malaria vaccine, A/J mice were immunized with malaria antigen plus 100 μg CpG-ODN or control-ODN in alum, using the standard protocol, and challenged with P. chabaudi AS. As shown in FIG. 5, CpG-ODN was as effective as IL-12 in inducing protection against challenge infection with P. chabaudi AS. Mice immunized with malaria antigen plus CpG-ODN in alum had a course of parasitemia and 100% survival following challenge infection with P. chabaudi AS similar to mice immunized with antigen plus IL-12 in alum. There was a significant decrease in peak parasitemia level in mice immunized with antigen plus CpG-ODN in alum compared to mice immunized with antigen plus control ODN in alum (p<0.001) and mice in the former group cleared the parasite by 2 weeks post infection. The combination of antigen plus control ODN in alum was not protective and 100% of the mice in this group succumbed to challenge infection with fulminant parasitemia levels by day 10 post infection. EXAMPLE 8 Low Dose of Whole Pathogen and Heterologous Challenge Materials and Methods Mice Female C57BI/6j mice, 8-12 weeks old, were obtained from the Animal Resources Centre (Willeton, WA, Aust.). Mice were housed under specific pathogen-free conditions. All experiments were approved by the Bancroft Research Centre Ethics Committee. Parasites Recently mosquito-passaged stabilates of P. c.chabaudi AS and P. c. chabaudi CB were supplied by Richard Carter, Institute of Cell, Animal and Population Biology, University of Edinburgh, UK. Parasites were cryopreserved in glycerolyte 57 (Baxter Healthcare Corporation, Deerfield, Ill., USA). To infect mice with a specific dose of parasite, blood was collected from the tail vein of an infected animal into phosphate buffered saline, adjusted to the appropriate concentration of PRBC and injected immediately into recipient mice. Parasitaemias were monitored by Giemsa-stained thin tail blood smears and recorded as the percentage of PRBC. Anti-malarial Treatment A single tablet of the anti-malarial drug Malarone (250 mg atovaquone, 100 mg proguanil hydrochloride) (Glaxo-Wellcome Australia Ltd, Boronia, Vic, Aust.) was allowed to dissolve in 125 mL distilled water. To completely cure P.c.chabaudi AS infection in mice, 100 uL of this solution (0.2 mg atovaquone, 0.08 mg proguanil) was administered by oral gavage daily for 4 consecutive days. Collection of Primary or Recrudescent Variants of P. c.chabaudi AS Frozen PRBC, which had been passaged through mice no more than 3-4 times following mosquito passage and so consisted largely of the primary variant, were thawed and used to infect one or two passage mice. The primary variant was collected from these mice by arterial tail bleed at the time of the first parasitaemia peak (6-12 days post-infection), and stored in Glycerolyte 57 at −70° C. in 4-5 aliquots. The recrudescent variant was collected by cardiac puncture at the time of the second parasitaemia peak (28-32 days post-infection), and was stored similarly. These frozen aliquots were passaged once before experimental mice were infected. Low Dose Infection Protocol Mice were given three i.v. infections at 3-4 week intervals with 105 P. c.chabaudi AS primary variant PRBC. 48 hours after each infection mice were administered Malarone, as described above, to eliminate all live parasites and achieve a low parasite dose. Naïve control mice were injected with PBS and administered Malarone at the same time points. In separate experiments, around 40 days after the third infection mice were challenged with 106 P. c.chabaudi AS primary variant PRBC (homologous parasite) or either 106 P. c.chabaudi AS recrudescent variant PRBC or 106 P. c.chabaudi CB PRBC (heterologous parasites) and the parasitaemia monitored by blood smears every 2 days. Cell Culture Medium Cells were cultured in Minimum Essential Medium Eagle (EMEM) (Trace Scientific Ltd, Melbourne, Vic, Aust.) supplemented with 5% or 10% heat inactivated foetal calf serum (FCS) (JRH Bioscience, Lexena, Kans., USA), 50 μg/ml streptomycin (CSL Ltd., Parkville, Vic, Aust), 100 μg/ml penicillin (CSL Ltd.) and 55 μM 2-mercaptoethanol (GibcoBRL, Grand Island, N.Y., USA)—complete culture medium (CCM). Collection of PRBC and Normal Mouse RBC for Proliferation Assays Blood was collected by cardiac puncture into heparinised Vacutainers from naive mice and from infected mice with parasitaemias between 20-40%. Blood was washed twice in sterile PBS, then PRBC were resuspended at 1×108 pRBC/ml in culture medium+10% FCS. Normal mouse RBC (nmRBC) were diluted to an equivalent concentration. Cells were aliquoted and stored at −20° C. until required. Isolation of Mononuclear Cells from Spleens Spleens from low dose and control naïve mice were harvested under aseptic conditions just prior to the challenge infection and single cell suspensions were prepared. RBC were lysed using Gey's Erythrocyte Lysis Buffer [MacPherson G. G., 1998 #315] and mononuclear cells isolated by density centrifugation over NycoPrep 1.077 (Axis-Shield PoC AS, Oslo, Norway). Proliferation Assays of Splenic Mononuclear Cells Proliferation assays were performed in 96-well flat bottom tissue culture plates (Corning Incorporated, Corning, N.Y., USA). Single cell suspensions were diluted to 2×106 cells/ml in 5% FCS/CCM. Cells were stimulated in triplicate with P. c.chabaudi AS-PRBC or P. c.chabaudi CB-PRBC at final concentrations of 1×107, 5×106 or 2.5×106 PRBC/ml, nmRBC at an equivalent concentration of RBC/ml or Concanavalin A (Con A) at 10 μg/ml. Cells were incubated for 3 days, then pulsed with 0.25 μCi/well of 3H-thymidine (NEN, Boston, Mass., USA) for a further 18-24 hr. Cells were harvested onto fibreglass filter mats using a cell harvester (Harvester 96, Tomtec, Hamden, CT, USA), and radioactivity was measured in a Wallac 1205 Betaplate liquid scintillation counter. Annexin-V-fluos Staining of Splenic Mononuclear Cells MAbs were diluted at 1/50 and used at 50 ul per 5×105 cells. Incubations were performed on ice in the dark for 30 min. Spleen cells were single-stained with CD4-PE, CD8-PE or CD1 9-PE. After 2 washes in FACS Buffer (1% FCS and 0.01% w/v sodium azide in PBS), cells were stained for 15 min with the Annexin-V-Fluos Staining Kit (Roche Diagnostics) according to the manufacturer's instructions and washed once in FACS Buffer. Fluorescence was measured using a FACSCalibur (BD) and data were analysed using CellQuest software (BD). Staining of Parasite Antigens on the Surface of PRBC This procedure was based on previously described methods Gilks et al, 1990, Parasite Immunol 12 45; Staalsoe et al, 1999, Cytometry 35 329. Mice used as a source of PRBC were kept in a reverse light-cycle (2000 hrs-0800 hrs) so that late stage parasites could be collected in the morning. These mice were infected from frozen aliquots of P. c.chabaudi AS or P. c.chabaudi CB. When parasitaemia reached 10-20%, mice were sacrificed at around 1030 hrs and blood was collected by cardiac puncture into heparinised Vacutainers (Becton Dickinson). After two washes in RPMI/HEPES, cells were resuspended at 5% haematocrit in RMPI/HEPES/NaHCO3/10% FCS and cultured for 3-4 hours in 5% CO2, 5% O2 at 37° C. until late stage parasites were evident. Cells were then washed 3 times in PBS/1% FCS and resuspended at 0.2% haematocrit. 100 ul of cells were then stained using a 3-step method, sequentially incubated with a 1/10 dilution of mouse serum, goat anti-mouse IgG ( 1/50 dilution, Caltag) and FITC-conjugated swine anti-goat IgG ( 1/20 dilution, Caltag) plus ethidium bromide (20ug/ml). All incubations were for 30 mins at room temperature and cells were washed twice in PBS/1% FCS between each step. Fluorescence was measured on a FACSCalibur. Late stage parasites were gated based on higher forward scatter and side scatter properties than other RBC and 1000 events were counted per test. Data were analysed using CellQuest software. Hyperimmune Serum Mice were given 3 i.v. infections at 3-4 week intervals with 105 P. c.chabaudi AS PRBC and the infection allowed to self-cure. These mice were exposed to high doses of PRBC and had near complete protection upon rechallenge with homologous parasites. Blood containing high titres of specific antibodies was obtained from these mice by tail bleed 3 weeks after the third infection. EXAMPLE 9 A Single Low Dose Infection Primed Antigen-specific Splenic Lymphocytes without Inducing Lymphocyte Apoptosis Previous data has shown that infection with Plasmodium results in elevated levels of apoptosis in T and B lymphocytes Balde et al, 1995, Immunol Lett 46 59; Helmby et al, 2000, Infect Immun 68 1485, and that Plasmodium specific T cells are deleted following Plasmodium infection (Hirunpetcharat et al, 1998, Proc Natl Acad Sci USA 95 1715). The present investigators proposed that administration of a low dose of live parasite (infection followed by drug cure 48 hours later) would be sufficient to prime lymphocytes, but avoid the apoptotic deletion associated with an unlimited infection. To investigate this, mice were administered a single infection with 1×105 P. c.chabaudi AS PRBC. On day 2 post-infection, a sub-set of infected mice and naive controls (injected with PBS at the time of infection) were sacrificed and splenic lymphocyte subsets (CD4, CD8 and CD19) were examined for evidence of apoptosis using Annexin V. Antigen-specific proliferative responses of splenic lymphocytes were also examined. After 2 days, infected mice showed no higher levels of Annexin V staining on any of the lymphocyte subsets examined, compared with naive mice (FIG. 6). Lympho-proliferative responses to crude parasite antigen were minimal and similar in naive and infected mice. From day 2, one group of the remaining mice were drug-cured (low dose) while the infection was allowed to continue in another group (high dose). When the high dose group reached peak parasitaemia on day 8, both groups, along with a group of naive control mice, were sacrificed and Annexin V staining and antigen-specific lympho-proliferative responses were assessed. A significantly higher percentage of CD4 and CD8 positive splenic lymphocytes from mice that had a high dose were positive by Annexin V staining compared with naive mice (P<0.05). In contrast, low dose mice had no more apoptotic cells than naive controls. In lympho-proliferation assays, cells from high dose mice showed no greater response to parasite antigen than cells from naive control mice, and the response to ConA was significantly lower (P<0.05). In contrast, splenic lymphocytes from low dose mice showed significantly higher levels of proliferation in response to all doses of parasite antigen, compared with lymphocytes from naive mice (P<0.05). EXAMPLE 10 Low Dose Infection Induced Significant Protection Against a Homologous Parasite Challenge and Against Challenge with a Different Parasite Strain or Variant Once it was established that a low dose infection could prime lymphocytes without inducing apoptosis, protection induced by multiple low dose infections was examined. Mice exposed to 3 cycles of infection with P. c.chabaudi AS were significantly protected on re-challenge with homologous parasites compared with naive mice (P<0.001) (FIG. 7-A/B). Whereas naïve mice had high peak parasitaemias (mean+/−SEM: 37.7% +/−1.1) followed by multiple recrudescent peaks, low dose mice rapidly controlled the primary peak (mean+/−SEM: 1.5% +/−0.5) and rarely developed recrudescence. To examine the specificity of immunity induced by low dose infection, mice exposed to 3 low dose infections with P. c.chabaudi AS together with naïve controls were challenged with homologous parasites, or with a different parasite strain or variant. Mice given low dose infection showed significantly reduced peak parasitaemias during challenge with the heterologous strain P. c.chabaudi CB (P<0.01) compared with naïve mice (FIG. 7A). In low dose mice there was no significant difference in peak parasitaemia during homologous compared with heterologous challenge (P=0.51), suggesting immunity induced by low dose infection was predominantly targeting determinants that were commonly expressed between the two strains. Previous studies have shown that parasite variants expressed during recrudescence differ from those expressed during the primary peak {McLean, 1982 #85}. In a separate experiment, mice exposed to low dose infection with P. c.chabaudi AS primary variant parasites (collected from a donor mouse during primary peak) and naive controls, were challenged with homologous parasites or with P. c.chabaudi AS recrudescent variant is parasites (collected during recrudescence in the same donor mouse) (FIG. 7B). Mice exposed to low dose infection with P. c.chabaudi AS primary variant parasites had significantly lower peak parasitaemias during challenge with homologous parasites or with parasites differing only in expression of the variant protein, compared with naïve mice (P<0.001). EXAMPLE 11 Splenic Lymphocytes from Low Dose Mice Showed Significant Antigen-specific Proliferation in vitro Spleen cells collected prior to challenge infection from mice given 3 low dose infections with P. c.chabaudi AS proliferated strongly in response to in vitro stimulation with crude AS or CB parasite antigen (P<0.01 compared with naïve mice) (FIG. 8). This suggested that T cells specific for antigens commonly expressed on both strains were being primed. EXAMPLE 12 Low Dose Infection Induced High Levels of Parasite Specific IgG but Failed to Generate IgG to Variant Antigens on the Surface of PRBC Prechallenge sera from mice exposed to low dose infections with P. c.chabaudi AS and hyper-immune serum obtained from mice allowed to self-cure following multiple infections with P. c.chabaudi AS had equivalent high titre IgG by ELISA and immunofluorescence. In contrast, hyper-immune sera had significantly higher levels of IgG (as measured by flow cytometry) that recognised the surface of homologous P. c.chabaudi AS PRBC (P<0.01) compared to low dose sera (FIG. 9). Low dose sera bound both P. c.chabaudi AS and P. c.chabaudi CB PRBC to a similar degree with the level of binding only just over that of naïve sera. Hyper-immune sera also showed only low level binding to P. c.chabaudi CB PRBC. Although commonly expressed merozoite and intracellular antigens appear to be targets of antibody responses induced by both high dose and low dose infection only high dose infections appear to induce antibodies against antigens expressed on the surface of PRBC. This supports the data shown in humans that a natural infection induces antibodies targeting variant surface antigens and indicates that the immunity induced by a low dose infection differs from that of a high dose infection. EXAMPLE 13 Low Dose, Killed Parasite, Combined with CpG and Alum Induces Significant Protection Against Challenge and Prevents Recrudescence. In a preferred form of the invention, a pharmaceutical composition comprises a low dose of non-living (i.e. killed) antigenic component from a pathogen, such as Plasmodium spp, and an agent capable of inducing endogenous IL-12, such as a CpG nucleic acid. The pharmaceutical composition may further comprise alum. Such a preferred pharmaceutical composition may be prepared using the methods described for example in Example 1 and below. The pharmaceutical composition may be administered to a mammal, such as a human or mouse, as described herein. Preferably, the low dose of the non-living antigenic component is equivalent to about 1,000 to 3,000 live parasites per millilitre of blood in the animal, prepared as described herein. A low dose may also be selected from a value less than 1×107, 1×106, 1×105, 1×104, 1×103, 1×102 or even less than 10 equivalent whole killed Plasmodium per millilitre of blood in the animal, or per mouse as described hereinafter. Studies described in previous examples demonstrate that various combinations of low dose, live parasite combined with alum and CpG protect against parasite infection. This EXAMPLE shows for the first time that a low dose of killed parasite, combined with CpG and alum, in animals significantly protects against parasite infection, resolves parasite infection earlier, and prevents re-emergence of the disease (recrudescence). Methods Preparation of Dead Plasmodium chabaudi chabaudi AS Parasite Antigen Plasmodum Chabaudi chabaudi AS was passaged through naive C57BL/6 and A/J mice. At peak parasitemia, mice were sacrificed by CO2 inhalation and bled by cardiac puncture. Heparinised blood comprising parasites was centrifuged at 300×g for 10 mins. Supernatantwas discarded and a pellet comprising parasites was subjected to two rounds of lysis in distilled water, followed by centrifugation for 25 minutes at ×10,000 rpm at 4° C. The pellet (comprising parasite components) was resuspended in PBS (0.5 mls) and then subjected to multiple (three) cycles of freezing (−70° C.) and thawing (37° C.). Crude parasite antigen was then passaged through a 26 gauge needle, and then suspended in PBS to an equivalent of 2.5×108 pRBC/ml. Aliquots of 1 ml were stored at −70° C. for immunization studies. CpG Preparation CpG-ODN 1826 (stimulatory motif) and Control CpG-ODN 1982 (control CpG, no stimulatory sequence) was purchased from Sigma Genosys Australia and stored at 10 mg/ml in PBS. Alum Commercially prepared alum (imject™; Pierce /Endogen) was absorbed 1:1 with killed parasite or in PBS (parasite vehicle) prior to immunizing mice. Immunization Schedule Protection Study Day 0 Primary immunization of A/J mice with CpG (100 μg/mouse), alum (50 μl), combined CpG plus alum, or combined CpG alum plus killed 1×103, 1×105, or 1×107 P. c.chabaudi parasites. Day 21 Animals boosted with killed 1×103, 1×105, or 1×107 P. c.chabaudi parasites (ip) diluted in PBS or PBS alone. Day 42 Animals boosted with killed 1×103, 1×105, or 1×107 P. c.chabaudi parasites (ip) or PBS alone. Day 56 Challenge mice with 1×105 p Chabaudi (iv). Recrudescence Study Day 0 Primary immunization of C57BL/6 mice with CpG (100 μg/mouse), alum (50 μl), combined CpG plus alum, or combined CpG, alum plus killed 1×103, 1×105, or 1×107 P. c.chabaudi parasites. Day 21 Animals immunised with killed 1×103, 1×105, or 1×107 P. c.chabaudi parasites (ip) or PBS (vehicle). Day 42 Challenge mice with 1×105 p Chabaudi (iv). Parasitaemia Parasitaemia was determined from tail bleed smears every 2 days. Results and Discussion Protection Study. Peak parasitemia occurred in all control groups (Group A-C) at 10 days post infection (FIG. 10). The highest level of parasitaemia was observed in Control Group C, that had been primed with CpG plus alum (9.37±10.58). In all groups that had been immunized with killed parasite, parasitaemia was siginificantly reduced (D: 1×107, 0.03±0.03 (n=5); E: 1×105, 0.04±0.04 (n=4); F: 1×103 0.01±0.01 (n=2)). Of significance, only 2 out of 5 (40%) animals immunized with dead, low dose parasite had detectable parasitemia during the 30 day course of the experiment. That is, 60% of animals were completely protected from infection. In addition, these two animals had a delayed on set of detectable parasitemia (Day 12). These data clearly show that immunization with low dose of killed parasite, combined with CpG and alum induces significant protection against parasite challenge. Recrudescence Study Recrudescence is the process by which parasites switch their expression of different variant surface antigens in order to evade the immune response, and then re-multiply. The new parasite clone, therefore is no longer recognized by the immune system and it may have a slightly different phenotype in terms of tissue adhesion, that may result in different pathology. Eventually the host immune systems adapts and recognizes the parasite, to only have the process of recrudescence continue, resulting in sequential peaks of parasite density in the blood. Antibodies to the merozoite surface appear to constitute one important factor in controlling recrudescence, while cell mediated immunity may be another factor. Therefore, in animals and humans where it is thought that the parasite infection has been resolved, re-emergence of parasitemia occurs. This next study aimed to investigate whether low dose immunization could also prevent recrudescence as well as reduce parasitemia. In this study, peak parasitaemia was again reduced in all groups that had been immunized with killed parasite (data not shown). Animals that had been immunized with the low dose, dead parasite had completely resolved the infection by day 12, as compared to day 20 in control groups (Control CpG+alum, alum alone, CpG alone, combined CpG plus alum). Animals immunized with higher doses of parasite, also completely resolved infection before controls (1×107 at Day 14, and 1×105 at Day 16). Data in FIG. 11 show that animals immunized with low doses of parasite (1×103 and 1×105) also significantly inhibited recrudescence. These data clearly show that immunization with low doses of parasite, can protect animals against parasitaemia, resolve infection earlier, and prevent re-emergence of the disease (recrudescence). It is understood that the invention described in detail herein is susceptible to modification and variation, such that embodiments other than those described herein are contemplated which nevertheless fall within the broad scope of the invention. The disclosure of each patent and scientific document, computer program and algorithm referred to in this specification is incorporated by reference in its entirety. TABLE 1 Proliferation Cytokine Levels Antigen IFN-γ TNF-α IL-4 IL-10 Groupa (cpm ± SEM) ng/ml pg/ml pg/ml pg/ml Untreated 526 ± 71 0.39 ± 0.39 98.41 ± 10.22 254.27 ± 52.80 0.76 ± 0.01 Antigen 486 ± 44 5.13 ± 0.36 122.03 ± 17.78 178.55 ± 45.13 1.07 ± 0.11 Antigen + Alum 1162 ± 128 3.83 ± 0.86 175.03 ± 20.93 234.52 ± 20.60 1.27 ± 0.10 Antigen + IL-12 768 ± 130 11.14 ± 2.27 189.85 ± 28.58 134.19 ± 33.22 1.01 ± 0.09 Antigen + IL-12 + 2768 ± 622b 43.13 ± 5.20c 341.94 ± 44.26c 165.87 ± 42.82d 1.44 ± 0.14e Alum aGroups of A/J mice (5 per group) were immunized s.c. with malaria antigen alone, antigen in alum, antigen plus 1.0 μg IL-12, or antigen plus 1.0 μg IL-12 in alum and boosted 3 weeks later by i.p. injection with antigen. Data from one of two replicate experiments are presented. bp < 0.05 for Antigen + Alum vs Antigen + IL-12 + Alum cp < 0.0001 for Antigen + Alum vs Antigen + IL-12 + Alum dp < 0.01 for Antigen + Alum vs Antigen + IL-12 + Alum ep < 0.008 for Antigen + Alum vs Antigen + IL-12 + Alum TABLE 2 Peak Parasitemia (%) Clearance by Groupa Mean ± SEM Day Survival % Untreated (n = 10) 41.25 ± 1.29 — 0 2 weeks post boost 15.80 ± 2.29b 14 100 (n = 5) 12 weeks post boost 28.65 ± 1.29c 15 100 (n = 5) aGroups of A/J mice (n = 5) were immunized s.c. with antigen plus 1.0 μg IL-12 admixed in alum and boosted 3 weeks later by i.p. injection with antigen. For each immunization group, age-matched, untreated and immunized mice were infected i.p. with 106 PRBC at 2 or 12 weeks post boost. Since there were no significance differences in peak parasitemia or survival between the two untreated groups (n = 10), data have been pooled. bp < 0.001 compared to control cp < 0.001 compared to control REFERENCES 1. 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M. Stevenson. 2002. IL-12 is required for antibody-mediated protective immunity against blood-stage Plasmodium chabaudi AS malaria infection in mice. J. Immunol. 168:1348-1355. 40. Su, Z., and M. M. Stevenson. 2000. Central role of endogenous gamma interferon in protective immunity against blood-stage Plasmodium chabaudi AS infection. Infect. Immun. 68:4399-4406. 41. Taylor-Robinson, A. W., and R. S. Philips. 1994. B cells are required for the switch from TH1- to TH2-regulated immune response to Plasmodium chabaudi chabaudi infection. Infect. Immun. 62:2490-2498. 42. van der Heyde, H. C., B. Pepper, J. Batchelder, F. Cigel, and W. P. Weidanz. 1997. The time course of selected malarial infections in cytokine-deficient mice. Exp. Parasitol. 88:206-213. 43. von der Weid, T. and J. Langhorne. 1993. Altered response of CD4+ T cell subsets to Plasmodium chabaudi chabaudi in B cell-deficient mice. Int. Immunol. 5:1343-1348. 44. von der Weid, T. N. Honarvar, and J. Langhorne. 1996. Gene-targeted mice lacking B cells are unable to eliminate a blood stage malaria infection. J. Immunol. 156:2510-2516. 45. Weeratna, R. D., M. J. McCluskie, Y. Xu, and H. S. Davis. 2000. CpG DNA induces stronger immune responses with less toxicity than other adjuvants. Vaccine 18:1755-1762. 46. Wynn, T. A., A. W. Cheever, D. Jankovic, R. W. Poindexter, P. Caspar, F. A. Lewis, and A. Sher. 1995. An IL-12-based vaccination method for preventing fibrosis induced by schistosome infection. Nature 376:594-596. 47. Wynn, T. A., D. Jankovic, S. Hieny, A. W. Cheever, and A. Sher. 1995. IL-12 enhances vaccine-induced immunity to Schistosoma mansoni in mice and decreases T helper 2 cytokine expression, IgE production, and tissue eosinophilia. J. Immunol. 154:4701-4709. 48. Wynn, T. A., A. Reynolds, S. James, A. W. Cheever, P. Caspar, S. Hieny, D. Jankovic, M. Strand, and A. Sher. 1996. IL-12 enhances vaccine-induced immunity to schistosomes by augmenting both humoral and cell-mediated immune responses against the parasite. J. Immunol. 157:4068-4078. 49. Yap, G. S., and M. M. Stevenson. 1994. Differential requirements for an intact spleen in induction and expression of B-cell-dependent immunity to Plasmodium chabaudi AS. Infect. Immun. 62:4219-4225. 50. Hoffman S L, et al. Science. 237:639, 1987. 51. Urban B C, et al. Nature. 400:73, 1999. 52. Xu H, et al. J Exp Med. 195:881, 2002. 53. Pombo, D J, et al. The Lancet 360:610, 2002. 54. Makobongo, M O, et al. PNAS 100:2628, 2003. 55. Gilks C F, et al. Parasite Immunol. 12:45, 1990. 56. Staalsoe T, et al. Cytometry. 35:329, 1999. 57. Balde A T, et al. Immunol Lett. 46:59, 1995. 58. Helmby H, et al. Infect Immun. 68:1485, 2000. 59. Hirunpetcharat C, et al. PNAS 95:1715, 1998.

<SOH> BACKGROUND OF THE INVENTION <EOH>Diseases have plagued animals, including humans, for centuries. Modern medicine has successfully developed vaccines for some diseases, for example polio, thereby providing protection against infection by some disease causing pathogens. Such vaccines have improved human health and potentially save millions of lives annually. However, developing vaccines to protect against infection by some pathogens has proven to be challenging and remains elusive. For example, malaria vaccines against Plasmodium species and different strains thereof are yet to be successful. Early attempts to develop a malaria vaccine include irradiated sporozoites that are live, but inactived or attenuated, (i.e. are capable of infecting, but not replicating in a host), Clyde 1975, Am J Trop Med Hyg 24 397. Delivery of this type of vaccine commonly relied on the attenuated live sporozoites being inoculated through mosquito bites, see Herrington et al, 1990, Bull World Health Organ. 68 Suppl 33. This type of vaccine is difficult to implement and has not resulted in a successful malaria vaccine. Recently, a common approach in developing a vaccine is identification of a pathogen antigen, cloning of the nucleic acid encoding the antigen and protein expression of recombinant nucleic acid. This approach for developing a malaria vaccine has resulted in a number of blood-stage derived recombinant antigens for inclusion in subunit vaccines, including MSP1, MSP2, MSP3, MSP4, MSP5, AMA1, PfEMP1, RESA, RAP1, and RAP2 (Carvalhuo et al, 2002, Scand J. Immol 56 327). However, a subunit vaccine for malaria is yet to be successful. Although subunit vaccines are the most common form of a malaria vaccine currently in development, a subunit vaccine has a number of limitations, in particular in relation to developing a vaccine against a pathogen characterised by multiple strains, for example Plasmodium . An important inadequacy of subunit vaccines is their aim to mimic natural immunity, a process that in itself may be entirely inadequate. This is illustrated, for example, from a study conducted in Kenya (Hoffman et al, 1987, Science 237 639). The researchers treated adult Kenyan volunteers who had lived their entire lives in a malaria endemic area with anti-malaria drugs and then monitored each volunteer for appearance of Plasmodium parasites in their blood over the ensuing three months. By three months, 80% of the volunteers had become infected with Plasmodium parasites although antibody levels against the pathogen circumsporozoite protein were indistinguishable between individuals who developed parasitemia and those who did not. Thus, immunity to sporozoites (the form of the parasite inoculated by the mosquito) was inadequate, immunity to liver stage parasites (the next stage in the life cycle) was inadequate and immunity to blood forms (the stage of exponential growth after the liver stage) was also inadequate. Subunit vaccines that aim to mimic natural immune responses by inducing antibodies to the sporozoite coat, by inducing T cells which secrete INF-γ (gamma interferon) and which are potentially cytolytic for infected liver cells or inducing antibodies to merozoite surface proteins to block the invasion of red blood cells have not provided protection against malaria. There are three main possibilities why naturally occurring immune responses induced by subunits are not protective: (i) small molecules lack sufficient immunological determinants (or epitopes) to be widely immunogenic; (ii) many malaria proteins, and all major vaccine candidates, are polymorphic and these polymorphisms can be discriminated by antibodies or T cells raised against any one particular polymorphism; and (iii) malaria infection suppresses the induction of immunity by blocking dendritic cell maturation (Urban et al, 1999, Nature 400 73) and killing parasite-specific T cells by apoptosis (Xu et al, 2002, J Exp Med 195 881) and thus prevents the development of antibody-independent immunity as well as T cell-dependent antibody responses and subsequent memory responses. It was recently shown that it was possible to immunize humans against a single strain of Plasmodium using an ultra-low dose of live P. faiciparum infected red blood cells (Pombo et al, 2002, Lancet 360 610). In this study, naive volunteers were repeatedly infected with parasites and drug treated to stop the infection. They did not develop any symptoms of malaria during the eight days during which parasite numbers increased as determined by a very sensitive Polymerase Chain Reaction (PCR). Parasites could not be detected by microscopy. Although immunisation with ultra-low dosages of live parasite may provide some protection against subsequent infection by the same parasite, it is difficult to cultivate large numbers of live parasite for use in a vaccine. Transport of live parasites to areas requiring administration of the vaccine, maintaining the parasites viability and a requirement for blood products to propagate live parasite for the vaccine is not practical and is prohibitive for general application. Areas affected by malaria are typically remote with limited facilities. Also, inoculation with live pathogen is cumbersome and requires repeated infection/treatment cycles to prevent full infection. Rhee etal, 2002, J Exper Med 195 1565 describes vaccination of mice with heat killed Leishmania major and either IL-12 or CpG oligonucleotide (CpG-ODN). This publication relates to a specific pathogen, Leishmania major , which is the causative agent of cutaneous leishmaniasis and a vaccine for the same pathogen. There is a need for a pharmaceutical composition capable of stimulating an immune response in an animal and reducing a risk of infection or improving recovery from an infection by one or more pathogen, namely Plasmodium spp or strain.

<SOH> SUMMARY OF THE INVENTION <EOH>The inventors have developed a pharmaceutical composition that is suitable for inducing immunity against homologous and heterologous forms of a pathogen, e.g. one or more of a same or different species or strain of species. In a preferred form, the invention relates to a surprising discovery that administering an animal with a low dose of an antigenic component derived from a pathogen was capable of reducing an occurrence of pathogen infection in a same and different strain of pathogen. In particular, a preferred form of the invention relates to a composition and administration of the composition comprising a low dose of an antigenic component derived from at least one species of killed Plasmodium , which is capable of inducing an immune response for one or more strains of Plasmodium . Malaria is caused by one or more species of Plasmodium and each species of Plasmodium comprises potentially hundreds, if not thousands of identified and unidentified strains, making development of a successful pharmaceutical composition for preventing or treating malaria difficult. The present discovery provides a means for practically developing a pharmaceutical composition that when administered is preferably capable of inducing an immune response in an animal against one or more strains of Plasmodium spp. The background art does not describe this surprising discovery and a pharmaceutical composition comprising this preferred characteristic is only now possible or contemplated by the present invention. As will be described herein in more detail, the low dose of an antigenic component from a pathogen may be administered in combination with other agents, including an agent capable of increasing IL-12 in an animal, such as a CpG nucleic acid, and an adjuvant such as alum. In a first aspect, the invention provides an immunogenic agent comprising: a low dose of an antigenic component obtainable from at least one Plasmodium spp; and an agent capable of increasing an amount of IL-12 in an animal. Preferably, the antigenic component is selected from the group consisting of: live whole Plasmodium spp, inactivated whole Plasmodium spp, killed whole Plasmodium spp, an extract from Plasmodium spp, purified proteins derived from Plasmodium spp, one or more recombinantly expressed nucleic acid encoding Plasmodium spp proteins and a pool of recombinant expressed Plasmodium spp proteins. More preferably, the antigenic component comprises an extract from one or more different species of killed Plasmodium spp. Preferably, the extract comprises an equivalent of less than 10 6 whole Plasmodium spp. More preferably, the extract comprises an equivalent of less than 10 5 whole Plasmodium spp. Even more preferably, the extract comprises an equivalent of less than 10 3 whole Plasmodium spp. In one form, the extract may comprise an equivalent of less than 10 2 and even less than 10 whole Plasmodium spp. Plasmodium spp is preferably selected from the group consisting of: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, Plasmodium knowlesi, Plasmodium berghei, Plasmodium yoelii, Plasmodium chabaudi and Plasmodium vinckei. Preferably, the at least one Plasmodium spp is selected from the group consisting of: Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale. Preferably, the Plasmodium spp is Plasmodium falciparum. In one form of the first aspect, the agent capable of increasing an amount of IL-12 in the animal is capable of stimulating endogenous IL-12 expression in the animal. More preferably, the agent comprises a CpG nucleic acid. Preferably, the CpG nucleic acid comprises a nucleotide sequence selected from the group consisting of: TCGTCGTTTTGTCGTTTTGTC, (SEQ ID NO: 1) TCCATGACGTTCCTGACGTT (SEQ ID NO: 2) and TCCAGGACTTCTCTCAGGTT. (SEQ ID NO: 3) In another form of the first aspect, the agent capable of increasing an amount of IL-12 in the animal is IL-12 protein or biologically active fragment thereof. Preferably, the IL-12 protein or biologically active fragment thereof is human IL-12. In one form, the IL-12 protein or biologically active fragment thereof is recombinant the IL-12 protein or biologically active fragment thereof. In another form, the IL-12 protein or biologically active fragment thereof is isolated wild type IL-12 protein or biologically active fragment thereof. In another form of the first aspect, the agent capable of increasing an amount of IL-12 in the animal is a nucleic acid comprising a nucleotide sequence encoding IL-12 protein or biologically active fragment thereof. Preferably, the nucleic acid is operably linked to a promoter capable of expressing the nucleic acid in the animal. The immunogenic agent preferably further comprises an adjuvant. Preferably, the adjuvant is selected from the group consisting of: aluminum hydroxide (alum), IL-12, CpG-oligonucleotide (ODN), SBAS2, SBAS4, QS21 and ISCOMs In a more preferred form, the adjuvant is aluminum hydroxide. Preferably, the animal is a mammal. More preferably, the mammal is human. In a second aspect, the invention provides a pharmaceutical composition comprising the immunogenic agent of the first aspect and a pharmaceutically-acceptable carrier. Preferably, the pharmaceutical composition is an immunotherapeutic composition. More preferably, the immunotherapeutic composition is a vaccine. Preferably, the pharmaceutical composition, which when administered to the animal is capable of reducing severity of or improving recovery from infection by one or more different Plasmodium spp. Preferably, the one or more different Plasmodium spp comprises one or more respective stains thereof. Preferably, the vaccine is capable of providing protective immunity in a mammal against one or more different Plasmodium spp. Preferably, the one or more different Plasmodium spp comprises one or more respective stains thereof. In a third aspect, the invention provides a method for inducing an immune response in an animal, including the step of administering the pharmaceutical composition of the second aspect to a mammal. Preferably, the pharmaceutical composition is an immunotherapeutic composition capable of reducing severity of infection by or improving recovery from infection by Plasmodium spp in the mammal. Preferably, the immunotherapeutic composition is a vaccine capable of providing protective immunity or treating the mammal against one or more Plasmodium spp. The mammal is preferably human. In a fourth aspect, the invention relates to use of the pharmaceutical composition of the second aspect to reduce severity of infection by or improve recovery from infection by Plasmodium spp in the animal. Preferably, use of the pharmaceutical composition prevents or treats Plasmodium spp infection in the animal. Preferably, the animal is a mammal. More preferably, the mammal is human. Preferably, use of the pharmaceutical composition reduces severity of by or improves recovery from malaria. More preferably, use of the pharmaceutical composition of prevents or treats malaria. It will be appreciated that the present invention provides a pharmaceutical composition and method capable of reducing a risk of infection and/or improving recovery from an infection from a pathogen. In a preferred form of the invention, the pharmaceutical composition is an immunotherapeutic composition capable of inducing an immune response in an animal administered with the immunotherapeutic composition. In an even more preferred form, the invention is a vaccine capable of providing protection against a pathogen, in particular intracellular pathogens comprising a plurality of strains or variants characterized by heterogeneous antigens. More particularly, the present invention is preferably capable of inducing and maintaining a cellular immune response in an animal, namely a human, against one or more strains of Plasmodium spp, the causative agent of malaria. Accordingly, preferred forms of the invention relate to a pharmaceutical composition comprising an antigenic component from at least one species of Plasmodium spp capable of infecting a human, e.g. P. falciparum, P. vivax, P. malariae and P. ovale , and use of the pharmaceutical composition to prevent malaria in a human. Throughout this specification unless the context requires otherwise, the word “comprise”, and variations such as “comprises” or “comprising”, will be understood to imply the inclusion of the stated integers or group of integers or steps but not the exclusion of any other integer or group of integers.

20060901

20120626

20070517

58913.0

A61K39015

OGUNBIYI, OLUWATOSIN A

IMMUNOGENIC AGENT AND PHARMACEUTICAL COMPOSITION FOR USE AGAINST HOMOLOGOUS AND HETEROLOGOUS PATHOGENS INCLUDING PLASMODIUM SPP

SMALL

ACCEPTED

A61K

ACCEPTED

Optically active alpha-aminooxyketone derivatives and process for production thereof

The corresponding α-aminooxy ketone is manufactured with a high yield and a high enantioselectivity. A manufacturing method for an optically active α-aminooxy ketone derivative expressed by formula (1), wherein a ketone expressed by formula (2) is caused to react with a nitroso compound expressed by formula (3) in the presence of a proline derivative expressed by formula (4). In the formula, R1 and R2 respectively denote an alkyl, alkenyl or alkynyl group, and R1 and R2 may be linked to form a ring. R3 denotes an aryl, heterocyclic, alkyl, alkenyl or alkynyl group. A denotes a hydrogen atom, alkoxy group, aryloxy group, acyloxy group or silyloxy group which may have a substituent.

1. A manufacturing method for an optically active α-aminooxy ketone derivative expressed by formula (1), wherein a ketone expressed by formula (2) is caused to react with a nitroso compound expressed by formula (3) in the presence of proline or a proline derivative expressed by formula (4): wherein in formulae (1)-(4), R1 and R2 respectively denote an alkyl, alkenyl or alkynyl group which may have a substituent, and R1 and R2 may be linked to form a ring; R3 denotes an aryl, heterocyclic, alkyl, alkenyl or alkynyl group which may have a substituent; and A denotes a hydrogen atom, alkoxy group, aryloxy group, acyloxy group or silyloxy group which may have a substituent. 2. The manufacturing method of claim 1, wherein A in formula (4) is a silyloxy group which may have a substituent. 3. A manufacturing method for an optically active α-aminooxy ketone derivative expressed by formula (1′), wherein a ketone expressed by formula (2) is caused to react with a nitroso compound expressed by formula (3) in the presence of proline or a proline derivative expressed by formula (4′): wherein in formulae (1)-(4), R1 and R2 respectively denote an alkyl, alkenyl or alkynyl group which may have a substituent, and R1 and R2 may be linked to form a ring; R3 denotes an aryl, heterocyclic, alkyl, alkenyl or alkynyl group which may have a substituent; A denotes a hydrogen atom, alkoxy group, aryloxy group, acyloxy group or silyloxy group which may have a substituent. 4. The manufacturing method of claim 3, wherein A in formula (4′) is a silyloxy group which may have a substituent. 5. An optically active α-aminooxy ketone derivative or an enantiomer thereof which is expressed by formula (1a): wherein in formula (1a), —X—Y-Z- denotes one selected from the following groups:

TECHNICAL FIELD The present invention relates to an α-aminooxy ketone derivative which can be easily converted into an α-hydroxy ketone useful for medicines, agricultural chemicals, and the like, and a manufacturing method by which the α-aminooxy ketone derivative can be obtained in a high yield with a high enantioselectivity. BACKGROUND ART Conventionally, an α-hydroxy ketone has been synthesized by first converting a ketone into an enolate or an equivalent thereof once, and then causing a diastereoselective reaction or an enantioselective reaction (see non-patent literature 1). As an example of such a method, the method which converts a ketone into a lithium enolate, and causes optically active oxadilysine as an oxidizer to act thereon as an oxidizer (see patent literatures 2 to 8); the method which, as an asymmetric catalytic reaction, converts a ketone into an enol ether, and then carries out asymmetric dihydroxylation thereof (see non-patent literatures 9 to 10); and the technique which further carries out asymmetric epoxidation thereof (non-patent literatures 10 to 14), are known. As described above, with these methods, it is necessary to first convert a ketone into the corresponding enolate or an equivalent thereof, and the catalytic asymmetric oxidation reaction has presented the problem that substrates with which a high asymmetric yield can be achieved are limited. Further, there has been another problem in that the asymmetric catalytic reaction requires use of an environmentally harmful metallic salt. Recently, a method for synthesizing an α-aminooxy ketone by converting a ketone into a tin enolate, and then carrying out an asymmetric catalyzed reaction using nitrosobenzene using a catalytic amount of an optically active activating agent has been reported (non-patent literature 15). The α-aminooxy ketone can be easily converted into an α-hydroxy ketone, thus this technique provides a part of a useful α-hydroxy ketone synthesizing method. However, although this method requires a smaller amount of optically active catalyst, it has presented problems in that, for example, there is the need to first convert a ketone into a tin enolate; the tin compound has toxicity; and that the asymmetric catalyst used must be prepared from BINAP and AgOTf. Thus, no excellent method for manufacturing an optically active α-hydroxy ketone directly from a ketone by an asymmetric catalytic reaction using an easily available asymmetric source as an activating agent has been provided. In addition, no manufacturing method which proceeds with high yield and asymmetric yield, meeting the requirements for practical use, has been available. In other words, no efficient manufacturing method from a ketone to an optically active α-hydroxy ketone has been provided. Non-patent literature 1: Zhou et al. (Zhou, P.; Chen, B. C.; Davis, F. A. “Asymmetric Oxidation Reactions”, Katsuki, T., Ed.; Oxford University Press: Oxford, 2001; p 128) Non-patent literature 2: Davis et al. (Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919) Non-patent literature 3: Davis et al. (Davis, F. A.; Haque, M. S. J. Org. Chem. 1986, 51, 4083) Non-patent literature 4: Chen et al. (Chen, B. C.; Weismiller, M. C.; Davis, F. A.; Boschelli, D.; Empfield, J. R.; Smith, A. B. Tetrahedron 1991, 47, 173) Non-patent literature 5: Davis et al. (Davis, F. A.; Kumar, A. J. Org. Chem. 1992, 57, 3337) Non-patent literature 6: Davis et al. (Davis, F. A.; Weismiller, M. C.; Murphy, C. K.; Reddy, R. T.; Chen, B. C. J. Org. Chem. 1992, 57, 7274) Non-patent literature 7: Davis et al. (Davis, F. A.; Kumar, A.; Reddy, R. T.; Rajarathnam, E.; Chen, B. C.; Wade, P. A.; Shah, S. W. J. Org. Chem. 1993, 58, 7591) Non-patent literature 8: Davis et al. (Davis, F. A.; Clark, C.; Kumar, A.; Chen, B. C. J. Org. Chem. 1994, 59, 1184) Non-patent literature 9: Hashiyama et al. (Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Am. Chem. Soc. 1993, 115, 8463) Non-patent literature 10: Hashiyama et al. (Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Org. Chem. 1992, 57, 5067) Non-patent literature 11: Fukuda et al. (Fukuda, T.; Katsuki, T. Tetrahedron Lett. 1996, 37, 4389) Non-patent literature 12: Adam et al. (Adam, W.; Rainer, T. F.; Stegmann, V. R.; Saha-Moller, C. R. J. Am. Chem. Soc. 1998, 120, 708) Non-patent literature 13: Zhu et al. (Zhu, Y.; Yu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819) Non-patent literature 14: Adam et al. (Adam, W.; Fell, R. T.; Saha-Moller, C. R.; Zhao, C-G Tetrahedron: Asymmetry 1998, 9, 397) Non-patent literature 15: Momiyama et al. (Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc., 2003, 125, 6038) DISCLOSURE OF INVENTION Problems to Be Solved by the Invention Therefore, the purposes of the present invention are to provide a method for manufacturing, in a manner that is industrially advantageous, an optically active α-aminooxy ketone that is free from the above-mentioned problems and, in turn, to efficiently obtain an α-hydroxy ketone. Means to Solve the Problems In view of such circumstances, the present inventors have conducted intensive research, and have completed the present invention, finding that, by causing a ketone expressed by formula (2) to react with a nitroso compound expressed by formula (3) in the presence of proline or a specific proline derivative, an α-aminooxy ketone can be obtained in a high yield with a high enantioselectivity. That is, the present invention provides: <1> A manufacturing method for an optically active α-aminooxy ketone derivative expressed by formula (1), wherein a ketone expressed by formula (2) is caused to react with a nitroso compound expressed by formula (3) in the presence of proline or a proline derivative expressed by formula (4). In formulae (1) to (4), R1 and R2 respectively denote an alkyl, alkenyl or alkynyl group which may have a substituent, and R1 and R2 may be linked to form a ring. R3 denotes an aryl, heterocyclic, alkyl, alkenyl or alkynyl group which may have a substituent. A denotes a hydrogen atom, alkoxy group, aryloxy group, acyloxy group or silyloxy group which may have a substituent. <2> The manufacturing method of item <1>, wherein A in formula (4) is a silyloxy group which may have a substituent. <3> A manufacturing method for an optically active α-aminooxy ketone derivative expressed by formula (1′), wherein a ketone expressed by formula (2) is caused to react with a nitroso compound expressed by formula (3) in the presence of proline or a proline derivative expressed by formula (4′). In formulae (1) to (4), R1 and R2 respectively denote an alkyl, alkenyl or alkynyl group which may have a substituent, and R1 and R2 may be linked to form a ring. R3 denotes an aryl, heterocyclic, alkyl, alkenyl or alkynyl group which may have a substituent. A denotes a hydrogen atom, alkoxy group, aryloxy group, acyloxy group or silyloxy group which may have a substituent. <4> The manufacturing method of item <3>, wherein A in formula (4′) is a silyloxy group which may have a substituent. <5> An optically active α-aminooxy ketone derivative or an enantiomer thereof which is expressed by formula (1a). In formula (1a), —X—Y-Z- denotes one selected from the following groups. Effects of the Invention According to the present invention, an α-aminooxy ketone can be obtained in a high yield with a high enantioselectivity. When the catalyst is proline, the proline has the feature of being inexpensive. When the catalyst used is a proline derivative and, in particular super proline as described below, the corresponding α-aminooxy ketone can be manufactured at a stroke simply in a short period of time with a high yield and a high enantioselectivity, as compared to proline. Best Mode for Carrying Out the Invention The manufacturing method for α-aminooxy ketones of the present invention provides a manufacturing method for an α-aminooxy ketone, wherein a ketone expressed by formula (2) as given above is caused to react with a nitroso compound expressed by formula (3) in the presence of proline or a proline derivative expressed by formula (4) or (4′). First, the raw material compounds will be described. <Ketones expressed by formula (2)> In formula (2), the alkyl group denoted by R1 and R2 preferably has 1 to 20 carbons, and particularly preferably has 1 to 5 carbons or so. Specific examples of the alkyl group include a methyl group, an ethyl group, propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, a t-butyl group, a pentyl group, a hexyl group, a heptyl group, a n-octyl group, a 2-ethylhexyl group, a t-octyl group, a nonyl group, a decyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a n-hexadecyl group, a 2-hexyldecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, an icosyl group, and the like. The alkyl group may further have a substituent, and as such a substituent, the following aryl group, heterocyclic group, and the like can be mentioned. Herein, examples of the aryl group include phenyl and naphthyl groups, which may have a substituent, and the like. In addition, examples of the heterocycle in the heterocyclic group include piperidine, furan, thiophene, pyrrole, pyrazole, imidazole, triazole, oxazole, isooxazole, thiazole, isothiazole, dioxolane, pyridine, pyrimidine, pyrazine, triazine, dioxane, dithiane, morpholine, azepine, oxepine, thiepine, and the like. The aryl group and the heterocyclic group may further have a substituent, and as such a substituent, an alkyl group, an alkenyl group, a nitro group, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), and the like can be mentioned. In formula (2), the alkenyl group denoted by R1 and R2 preferably has 2 to 20 carbons, and particularly preferably has 2 to 5 carbons or so. Specific examples of the alkenyl group include a vinyl group, a propenyl group, such as an allyl group, or the like, a butylyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group, a decenyl group, an undecenyl group, a dodecenyl group, a tridecenyl group, a tetradecenyl group, a pentadecenyl group, a hexadecenyl group, a heptadecenyl group, a octadecenyl group, a nonadecenyl group, an icosenyl group, and the like. The alkenyl group may further have a substituent, and as such a substituent, the above-mentioned aryl group, heterocyclic group, and the like can be mentioned. The alkynyl group preferably has 2 to 20 carbons, and particularly preferably has 2 to 5 carbons. In the ketone expressed by formula (2), R1 and R2 may be linked to form a ring. Examples of such a ring include cyclohexane, cyclopentane, cycloheptane, cyclooctane, cyclononane, tetrahydrofuran, tetrahydropyran, piperidine, pyrrolidine, thiacyclohexane, and the like. These rings may further have a substituent, and as such a substituent, the above-mentioned alkyl group, alkenyl group, alkynyl group, aryl group, heterocyclic group, and the like can be mentioned. Specific examples of the ketone expressed by formula (2) include cyclohexanone, cyclopentanone, dimethylcyclohexanone, 1,4-cyclohexanedione, monoethyleneketal, tetrahydropyran-4-on, piperidinone, 3-pentanone, tetrahydrothiopyran-4-on, 3,3-dimethylcyclohexanone, cys-3,5-dimethylcyclohexanone, 3-methylcyclohexanone, 3-phenylcyclohexanone, 4-tert-butylcyclohexanone, 4-(tert-butyldiphenylsiloxy)cyclohexanone, cycloheptanone, 2-butanone, 1,5-dioxaspiro[5.5]undeca-9-on, 1,5-diaspiro[5.5]undeca-9-on, 4,4-dimethoxycyclohexanone, 4,4-diethoxycyclohexanone, and the like. <Nitroso Compounds Expressed by Formula (3)> In formula (3), as the aryl group denoted by R3, phenyl and naphthyl groups, which may have a substituent, and the like can be mentioned, and the aryl group is preferably a phenyl group. Examples of the heterocycle of the heterocyclic group denoted by R3 in formula (3) include piperidine, furan, thiophene, pyrrole, pyrazole, imidazole, triazole, oxazole, isooxazole, thiazole, isothiazole, dioxolane, pyridine, pyrimidine, pyrazine, triazine, dioxane, dithiane, morpholine, azepine, oxepine, thiepine, and the like. The aryl group and the heterocyclic group may further have a substituent, and as such a substituent, an alkyl group, an alkenyl group, a nitro group, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), and the like can be mentioned. In formula (3), the alkyl group denoted by R3 preferably has 1 to 20 carbons, and particularly preferably has 1 to 5 carbons or so. Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, a t-butyl group, a pentyl group, a hexyl group, a heptyl group, a n-octyl group, a 2-ethylhexyl group, a t-octyl group, a nonyl group, a decyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a n-hexadecyl group, a 2-hexyldecyl group, a heptadecyl group, a octadecyl group, a nonadecyl group, an icosyl group, and the like. The alkyl group may further have a substituent, and as such a substituent, the above-mentioned aryl group, heterocyclic group, and the like can be mentioned. In formula (3), the alkenyl group denoted by R3 preferably has 2 to 20 carbons, and particularly preferably has 2 to 5 carbons or so. Specific examples of the alkenyl group include a vinyl group, propenyl group, such as an allyl group, or the like, a butylyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octenyl group, a nonenyl group, a decenyl group, an undecenyl group, a dodecenyl group, a tridecenyl group, a tetradecenyl group, a pentadecenyl group, a hexadecenyl group, a heptadecenyl group, an octadecenyl group, a nonadecenyl group, an icosenyl group, and the like. The alkenyl group may further have a substituent, and as such a substituent, the above-mentioned aryl group, heterocyclic group, and the like can be mentioned. The alkynyl group denoted by R3 preferably has 2 to 20 carbons, and particularly preferably has 2 to 5 carbons. The nitroso compound expressed by formula (3) is preferably nitrobenzene. <Proline or Proline Derivatives Expressed by Formula (4) or (4′)> In the present invention, as the asymmetric catalyst, proline or a proline derivative expressed by formula (4) or (4′) is used. In formulae (4) and (4′), A denotes a hydrogen atom, alkoxy group, aryloxy group, acyloxy group or silyloxy group which may have a hydrogen atom. Herein, as the alkoxy group, those which have 1 to 5 carbons, for example, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, and the like can be mentioned. As the aryloxy group, a phenyloxy group, a naphthyloxy group, and the like can be mentioned. As the acyloxy group, an acetoxy group, a benzoyloxy group, and the like can be mentioned. As the substituent of the silyloxy group, an alkyl group, an aryl group, an alkenyl group, and the like can be mentioned. Those in which A is a methoxy group are described in the literature of Roda et al. (Roda, Aldo; Cerre, Carolina; Manetta, Anna C.; Cainelli, Gianfranco; Ronchi, Achille Umani; Panunzio, Mauro. Journal of Medicinal Chemistry (1996), 39 (11), 2270-6.), and those in which A is a benzoyloxy group are described in the literature of Perni et al. (Perni, Robert B.; Britt, Shawn D.; Court, John C.; Courtney, Lawrence F.; Deininger, David D.; Farmer, Luc J.; Gates, Cynthia A.; Harbeson, Scott L.; Kim, Joseph L.; Landro, James A.; Levin, Rhonda B.; Luong, Yu-Ping; O'Malley, Ethan T.; Pitlik, Janos; Rao, B. Govinda; Schairer, Wayne C.; Thomson, John A.; Tung, Roger D.; Van Drie, John H.; Wei, Yunyi. Bioorganic & Medicinal Chemistry Letters (2003), 13 (22), 4059-4063.). A is preferably a tert-butyldimethylsilyloxy group or a triisopropylsilyloxy group, and particularly preferably a tert-butyldimethylsilyloxy group (the proline which has this group may be called “super proline”) is preferable. The super proline causes the reaction to be completed in a much short period of time with the asymmetric yield being extremely high, as compared to the proline, in which A is a hydrogen atom. The super proline is public known (H. Ohtake, Y Imada, S-I. Murahashi, Bull. Chem. Soc. Jpn. 1999, 72, 2737.). <Reaction Conditions> First, by dissolving a ketone expressed by formula (2) as given above and proline or a proline derivative (4) [because, with (4′), the reaction progresses in the same way, herein (4) also means (4′)] into an organic solvent, a solution is prepared. Herein, the proline or proline derivative (4) is preferably used in an amount of 0.01 to 1 equiv., and particularly in an amount of 0.1 to 0.3 equiv, relative to a nitroso compound (3). Herein, the organic solvent to be used is preferably a polar solvent, such as DMF, DMSO, CH3NO2, NMP (N-methyl-pyrrolydinone), CH3CN, CHCl3, CH2Cl2, or the like, but it is not limited to these. The solution of the ketone and the proline or proline derivative (4) is cooled to −50 deg C. to 25 deg C., and preferably to −10 to 10 deg C., and in the subsequent reaction, it is preferable to maintain this temperature. The ketone is preferably used in an amount of 1 to 5 equiv., and particularly preferably in an amount of 2 to 3 equiv, relative to the nitroso compound. Next, the nitroso compound expressed by formula (3) is dissolved into the above-mentioned solvent, and the solution is gradually added into the solution of the ketone and the proline or proline derivative (4). The period of time for adding the nitroso compound solution into the solution of the ketone and the proline or proline derivative (4) is preferably 1 min to 24 hr, and particularly preferably 3 to 12 hr. For the above-mentioned super proline, the period of time is preferably 5 min to 5 hr. Also thereafter, the above-mentioned temperature is maintained while stirring 10 min to 1 hr, whereby an α-aminooxy ketone is obtained. In this reaction, using L-proline will provide the α-aminooxy ketone with the (R) isomer being given as the major product, while using D-proline will provide the α-aminooxy ketone with the (S) isomer as the major product. Here is an example when L-proline is used. TABLE 1 Yield, % ee, % R 1 2 1 2 t-Bu 32 32 >99 94 OSi-t-BuPh2 47 24 >99 96 Among the α-aminooxy ketones obtained by the method of the present invention, the following compounds and the enantiomers thereof are novel compounds, and these are useful as synthesized intermediate products which can be easily converted into α-hydroxy ketones useful for medicines, agricultural chemicals, and the like. EXAMPLES Hereinafter, the present invention will be described on the basis of EXAMPLES, however, the present invention is not limited to these EXAMPLES. Example 1 Table 2, No. 1 Cyclohexanone (1.2 mmol) and L-proline (0.18 mmol) are dissolved into 2.7 mL of a DMF solution, and the solution is cooled to 0 deg C. Into this solution, a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) is dropped over 5.5 hr. After completion of the dropping, the solution is stirred at the same temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 79% yield with ee of >99%. The optical purity was determined by HPLC using a chiral column. (R)-2-anilinooxy-cyclohexanone 1H NMR (CDCl3): δ 1.37-1.75 (3H, m), 1.82-1.95 (2H, m), 4.27 (2H, dd, J=11.6, 6.2 Hz), 6.82 (3H, t, J=8.1 Hz), 7.12 (2H, t, J=7.6 Hz), 7.71 (1H, s); 13C NMR (CDCl3): δ 23.6, 27.1, 32.3, 40.7, 86.1, 114.3, 114.8, 128.9, 148.0, 209.7; IR (KBr): 3041, 2942, 2865, 1716, 1600, 1494, 1132, 1099, 1072, 1027 cm−1; HRMS(FAB): Calculated value [C22H15NO2]: 205.1103, observed value: 205.1080; [α]D23 +119 (c=0.84, CHCl3). The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=34.3 min, minor enantiomer tr=28.1 min. Example 2 Table 2, No. 3 1,4-cyclohexadione monoethyleneketal (1.2 mmol) and L-proline (0.06 mmol) are dissolved into 2.7 mL of a DMF solution, and the solution is cooled to 0 deg C. Into this solution, a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) is dropped over 12 hr. After completion of the dropping, the solution is stirred at the same temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 96% yield with ee of >99%. The optical purity was determined by HPLC using a chiral column. (R)-7-anilinooxy- 1,4-dioxaspiro[4.5]decane-8-on 1H NMR (CDCl3): δ 1.88-2.04 (2H, m), 2.16 (1H, t, J=12.8 Hz), 2.36-2.46 (2H, m) 2.62 (1H, dt, J=14.0, 6.8 Hz), 4.38-4.21 (4H, m), 4.60 (1H, dd, J=12.9, 6.5 Hz), 6.87 (2H, d, J=7.7 Hz), 6.90 (1H, t, J=7.2 Hz), 7.20 (2H, t, J=7.2 Hz); 13C NMR (CDCl3): δ 34.9, 36.0, 39.7, 64.8, 64.9, 82.7, 107.6, 114.5, 122.2, 128.9, 148.0, 208.6; IR (neat): 2960, 2888, 1728, 1602, 1494, 1305, 1122, 1052 cm−1; [α]D18 +78.7 (c=1.2, CHCl3); HRMS (FAB): Calculated value [C14H17NO4]: 263.1158, observed value: 263.1172. The enantiomeric excess was determined by HPLC using a Chiralpak OD-H column (hexane:2-propanol 10:1). 0.5 mL/min; major enantiomer tr=26.5 min, minor enantiomer tr=29.1 min. Example 3 Table 2, No. 4 4,4-dimethylcyclohexanone (1.2 mmol) and L-proline (0.06 mmol) are dissolved into 2.7 mL of a DMF solution, and the solution is cooled to 0 deg C. Into this solution, a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) is dropped over 12 hr. After completion of the dropping, the solution is stirred at the same temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 87% yield with ee of >99%. The optical purity was determined by HPLC using a chiral column. (R)-2-anilinooxy-4,4-dimethylcyclohexanone 1H NMR (CDCl3): δ 0.97 (s, 3H), 1.14 (s, 3H), 1.48-1.59 (3H, m), 4.38 (1H, ddd, J=12.7, 6.4, 3.2 Hz), 2.21-2.28 (1H, m), 2.40 (1H, dt, J=14.1, 6.5 Hz), 4.38 (1H, dd, J=12.9, 6.4Hz), 6.79 (2H, d, J=7.8 Hz), 6, 81 (1H, t, J=8.1 Hz), 7.13 (2H, t, J=8.1 Hz); 13C NMR (CDCl3): δ 24.9, 31.3, 31.9, 44.4, 83.2, 114.2, 121.9, 128.8, 148.1, 210.3; IR (KBr): 3041, 2956, 2927, 1725, 1602, 1495, 1470, 1076, 740, 692 cm−1; [α]D19 +85.7 (c=0.33, CHCl3); HRMS (FAB): Calculated value [C14H19NO2]: 233.1416, observed value: 233.1423. The enantiomeric excess was determined by HPLC using a Chiralpak OD-H column (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=9.1 min, minor enantiomer tr=12.2 min. Example 4 Table 2, No. 5 Tetrahydro-4H-pyran-4-on (1.2 mmol) and L-proline (0.06 mmol) are dissolved into 2.7 mL of a DMF solution, and the solution is cooled to 0 deg C. Into this solution, a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) is dropped over 12 hr. After completion of the dropping, the solution is stirred at the same temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 55% yield with 96% ee. The optical purity was determined by HPLC using a chiral column. (R)-3-anilinooxy-tetrahydropyran-4-on 1H NMR (CDCl3): δ 2.53 (1H, dt, J=14.3, 2.9 Hz), 2.59-2.68 (1H, m), 3.60-3.72 (1H, m), 4, 09-4.17 (1H, m), 4.35-4.39 (1H, m), 4.42-4.46 (1H, m), 6.86 (2H, d, J=7.7 Hz), 6.91 (1H, t, J=7.4 Hz), 7.20 (2H, t, J=7.6 Hz), 768 (1H, s); 13C NMR (CDCl3): δ 42.3, 68.1, 70.1, 83.5, 114.8, 122.6, 128.9, 147.7, 205.1; IR (KBr): 2969, 2923, 2861, 2364, 1724, 1600, 1494, 1205, 1107, 694 cm−1; [α]D20 +47.5 (c=0.13, CHCl3); HRMS (FAB): Calculated value [C11H13NO3]: 207.0895, observed value: 207.0925. The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=18.6 min, minor enantiomer tr=23.7 min. Example 5 Table 2, No. 6 1-methyl-4-piperidinone (1.2 mmol) and L-proline (0.06 mmol) are dissolved into 2.7 mL of a nitromethane solution, and the solution is cooled to 0 deg C. Into this solution, a nitromethane solution (0.9 mL) of nitrosobenzene (0.6 mmol) is dropped over 12 hr. After completion of the dropping, the solution is stirred at the same temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 45% yield with 99% ee. The optical purity was determined by HPLC using a chiral column. (R)-3-anilinooxy-1-methylpiperidine-4-on 1H NMR (CDCl3): δ 2.36-2.41 (2H, m), 2.38 (3H, s), 2.54-2.64 (1H, m), 2.91-3.00 (1H, m), 3.31 (1H, dddd, J=6.4, 2.4, 2.4, 2.4 Hz), 4.49 (1H, dd, J=10.5, 6.4 Hz), 6.85-6.91 (3H, m), 7.17-7.21 (2H, m), 7.69 (1H, s); 13C NMR (CDCl3): δ 40.5, 45.6, 55.8, 59.4, 83.6, 115.0, 122.8, 129.3, 148.3, 207.6 IR (neat): 2948, 2852, 2798, 1727, 1600, 1494, 1143, 1060, 904, 779, 754, 694 cm−1; HRMS (FAB): Calculated value [C12H16N2O2]: 220.1211, observed value: 220.1248. The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=14.2 min, minor enantiomer tr=17.4 min. Example 6 Table 1, No. 1 4-tert-butylcyclohexanone (2.2 mmol) and L-proline (0.18 mmol) are dissolved into 8.1 mL of a DMF solution, and the solution is cooled to 0 deg C. Into this solution, a DMF solution (2.7 mL) of nitrosobenzene (1.80 mmol) is dropped over 20 hr. After completion of the dropping, the solution is stirred at the same temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the (2R,4R)-α-aminooxy ketone and the (2R,4S)-α-aminooxy ketone as a mixture. Yield is 64%; from the analysis by NMR, the respective yields of the (2R,4R)- and (2R,4S)-isomers being 32% and 32%. By taking a part, and repeating the thin-layer chromatography a few times, the (2R,4R)- and (2R,4S)-isomers were separated from each other. The optical purity was determined by HPLC using a chiral column. (2R,4R)-2-anilinooxy-4-tert-butylcyclohexanone 1H NMR (CDCl3): δ 0.83 (9H, s), 1.31 (1H, dddd, J=13.4, 4.2, 4.2, 4.2 Hz), 1.45-1.62 (2H, m), 1.93-2.02 (1H, m), 2.24 (1H, dd, J=13.7, 5.9 Hz), 2.30-2.38 (2H, m), 4.30 (1H, dd, J=12.5, 6.0 Hz), 6.78-6.85 (3H, m), 7.13 (2H, t, J=8.2 Hz), 7.76 (1H, s); 13C NMR (CDCl3): δ 27.6, 32.5, 33.6, 39.7, 45.9, 85.8, 114.5, 122.0, 128.9, 148.1, 210.2; IR (neat): 2960, 2869, 1728, 1602, 1494, 1367, 1097, 742, 692 cm−1; [α]D19 −11.8 (c=0.87, CHCl3); HRMS (FAB): Calculated value [C16H23NO2]: 261.1729, observed value: 261.1729. The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=10.2 min, minor enantiomer tr=11.0 min. (2R,4S)-2-anilinooxy-4-tert-butylcyclohexanone 1H NMR (CDCl3): δ 0.80 (9H, s), 1.40 (1H, dddd, J=13.4, 4.2, 4.2, 4.2 Hz), 1.56-1.65 (1H, m), 1.75 (1H, tt, J=12.2, 3.5 Hz), 1.93-2.01 (1H, m), 2.16-2.18 (2H, m), 2.63 (1H, dt, J=13.9, 6.0 Hz), 4.11 (1H, t, J=4.4 Hz), 6.82 (2H, d, J=8.2 Hz), 6.85 (1H, t, J=7.3 Hz), 7.06 (1H, s), 7.15-7.18 (2H, m); 13C NMR (CDCl3): δ 27.3, 32.2, 32.3, 38.0, 41.3, 84.7, 114.9, 122.6, 128.8, 147.8, 211.6; IR (neat): 2960, 2869, 1724, 1673, 1602, 1494, 1367, 1083, 748 cm−1; [α]D23 −53.0 (c=0.62, CHCl3); HRMS (FAB): Calculated value [C16H23NO2]: 261.1729, observed value: 261.1720. The enantiomeric excess was determined by HPLC using a Chiralpak OD-H column(hexane:2-propanol 100:1). 1.0 mL/min; major enantiomer tr=11.1 min, minor enantiomer tr=12.5 min. Example 7 Table 1, No. 2 4-tert-butyldiphenylsilyloxycyclohexanone (2.2 mmol) and L-proline (0.18 mmol) are dissolved into 8.1 mL of a DMF solution, and the solution is cooled to 0 deg C. Into this solution, a DMF solution (2.7 mL) of nitrosobenzene (1.80 mmol) is dropped over 20 hr. After completion of the dropping, the solution is stirred at the same temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the (2R,4R)-α-aminooxy ketone and the (2R,4S)-α-aminooxy ketone as a mixture. Yield is 71%; from the analysis by NMR, the respective yields of the (2R,4R)- and (2R,4S)-isomers being 47% and 24%. By taking a part, and repeating the thin-layer chromatography a few times, the (2R,4R)- and (2R,4S)-isomers were separated from each other. The optical purity was determined by HPLC using a chiral column. (2R,4R)-2-anilinooxy-4-(tert-butyldiphenylsiloxy)cyclohexanone 1H NMR (CDCl3): δ 0.98 (9H, s), 1.58 (1H, t, J=12.7 Hz), 1.70 (1H, J=12.9 Hz), 1.87-1.96 (1H, m), 2.22-2.32 (2H, m), 2.84 (1H, dt, Jd=6.0, Jt=13.8 Hz), 4.23 (1H, brs), 4.81 (1H, dd, J=12.6, 6.2 Hz), 6.76 (2H, d, J=8.2 Hz), 6.83 (1H, t, J=6.9 Hz), 7.13 (2H, t, J=6.9 Hz), 7.32 (6H, m), 7.57 (4H, dd, J=15.4, 7.8 Hz), 7.69 (1H, s); 13C NMR (CDCl3): δ 19.2, 27.0, 34.1, 35.7, 39.2, 67.5, 82.4, 114.5, 122.1, 127.8, 128.9, 130.0, 133.5, 135.6, 148.1, 209.9; IR (neat): 2956, 2931, 1725, 1602, 1494, 1427, 1112, 1076, 821, 701 cm−1; [α]D18 +18.2 (c=0.231, CHCl3); HRMS (FAB): Calculated value [C28H33NO3Si]: 459.2230, observed value: 459.2273. The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=6.6 min, minor enantiomer tr=7.3 min. (2R,4R)-2-anilinooxy-4-(tert-butyldiphenylsiloxy)cyclohexanone 1H NMR (CDCl3): δ 1.08 (9H, s), 1.87-1.95 (1H, m), 2.00 (1H, dt, J=12.5, 10.7 Hz), 2.04-2.18 (2H, m), 2.28-2.36 (1H, m), 2.42-2.48 (1H, m), 4.09-4.18 (2H, m), 6.81 (2H, d, J=7.9 Hz), 6.93 (1H, t, J=7.9 Hz), 7.22 (2H, t, J=7.9 Hz), 7.39-7.46 (6H, m), 7.65-7.70 (4H, m), 7.53 (1H, brs); [α]D19 +57.8 (c=1.18, CHCl3); HRMS (FAB): Calculated value [C28H33NO3Si: 459.2230, observed value: 459.2263. The enantiomeric excess was determined by HPLC using a Chiralpak OD-H column (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=10.3 min, minor enantiomer tr=11.3 min. Example 8 Table 3, Entry 1, Catalyst 10 mol %, Temperature −20 deg C. Into a CH3CN solution (3.0 mL) of proline (0.06 mmol), propanal (1.8 mmol) and nitrosobenzene (0.6 mmol) are added at −20 deg C., and the solution is stirred for 24 hr at the same temperature. i-PrOH (1.0 mL) and NaBH4 (3 mmol) are added, and the solution is stirred for 10 min; then a phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to quantitatively obtain the β-aminoalcohol with 99% ee. The optical purity was determined by HPLC using a chiral column. (R)-2-anilinooxy-propanol 1H NMR (CDCl3): δ 1.24 (3H, d, J=6.4 Hz), 2.34 (1H, brs), 3.72 (1H, dd, =12.0, 6.6 Hz), 3.80 (1H, dd, J=12.0, 2.9 Hz), 4.09-4.13 (1H, m), 6.94-6.99 (3H, m), 7.23-7.28 (2H, m); 13C NMR (CDCl3): δ 15.3, 65.9, 80.0, 114.4, 122.0, 128.9, 148.5; IR (KBr): 3270, 2929, 1600, 1492, 1062, 761, 669 cm−1; [α]D21 +1.8 (c=0.57, CHCl3), 98% ee; HRMS (FAB): Calculated value [C9H13NO2]: 167.0946, observed value: 167.0908. The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=10.3 min, minor enantiomer tr=9.3 min. Example 9 Table 3, Entry 2, Catalyst 10 mol %, Temperature −20 deg C. Into a CH3CN solution (3.0 mL) of proline (0.06 mmol), butanal (1.8 mmol) and nitrosobenzene (0.6 mmol) are added at −20 deg C., and the solution is stirred for 24 hr at the same temperature. i-PrOH (1.0 mL) and NaBH4 (3 mmol) are added, and the solution is stirred for 10 min; then a phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the β-aminoalcohol in 88% yield with 98% ee. The optical purity was determined by HPLC using a chiral column. (R)-2-anilinooxy-butanol 1H NMR (CDCl3): δ 0.98 (3H, t, J=7.5 Hz), 1.51-1.58 (1H, m), 1.65-1.70 (1H, m), 3.70-3.74 (1H, m), 3.78-3.87 (2H, m), 6.92-6.96 (3H, m), 7.23 (2H, t, J=7.6 Hz); 13C NMR (CDCl3): δ 10.1, 22.9, 64.8, 85.2, 114.8, 122, 4, 128.9, 148.4; IR (KBr): 3409, 3274, 2879, 1602, 1457, 1122, 1052, 896, 767 cm−1; [α]D16 +24.6 (c=0.74, CHCl3), 99% ee; HRMS (FAB): Calculated value [C10H15NO2]: 181.1103, observed value: 181.1128. The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=11.0 min, minor enantiomer tr=9.9 min. Example 10 Table 3, Entry 3, Catalyst 30 mol %, Temperature −20 deg C.) Into a CH3CN solution (3.0 mL) of proline (0.18 mmol), pentanal (1.8 mmol) and nitrosobenzene (0.6 mmol) are added at −20 deg C., and the solution is stirred for 24 hr at the same temperature. i-PrOH (1.0 mL) and NaBH4 (3 mmol) are added, and the solution is stirred for 10 min; then a phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the β-aminoalcohol in 81% yield with 98% ee. The optical purity was determined by HPLC using a chiral column. (R)-2-anilinooxy-pentanol 1H NMR (CDCl3): δ 0.91 (3H, m), 1.3-1.49 (3H, m), 1.58-1.67 (1H, m), 3.69 (1H, dd, J=12.0, 6.3 Hz), 3.80 (1H, dd, J=12.0, 2.6 Hz), 3.87-3.92 (1H, m), 6.90-6.96 (3H, m), 7.19-7.23 (2H, m); 13C NMR (CDCl3): δ 14.1, 18.9, 32.0, 65.0, 83.7, 114.7, 122.3, 128.9, 148.4; IR (KBr): 3400, 3282, 2958, 2933, 2873, 1602, 1494, 1465, 1124, 1027, 896, 775 cm−1; [α]D16 +24.2 (c=0.34, CHCl3), 98% ee; HRMS (FAB): Calculated value [C11H17NO2]: 195.1259, observed value: 195.1247. The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=10.3 min, minor enantiomer tr=9.3 min. Example 11 Table 3, Entry 4, Catalyst 30 mol %, Temperature 0 deg C.) Into a CH3CN solution (3.0 mL) of proline (0.18 mmol), 3-methyl-butanal (1.8 mmol) and nitrosobenzene (0.6 mmol) are added at 0 deg C., and the solution is stirred for 24 hr at the same temperature. i-PrOH (1.0 mL) and NaBH4 (3 mmol) are added, and the solution is stirred for 10 min; then a phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the β-aminoalcohol in 77% yield with 97% ee. The optical purity was determined by HPLC using a chiral column. (R)-3-methyl-2-anilinooxy-butanol 1H NMR (CDCl3): δ 0.99 (3H, d, J=6.9 Hz), 1.03 (3H, d, J=6.9 Hz), 1.99-2.04 (1H, m), 3.70-3.74 (1H, m), 3.81-3.86 (2H, m), 6.95-7.01 (3H, m), 7.23-7.28 (2H, m); 13C NMR (CDCl3): δ 19.0, 19.2, 29.2, 64.2, 89.0, 115.5, 123.0, 129.4, 148.7; IR (KBr): 3397, 3272, 2962, 2933, 2875, 1602, 1494, 1469, 1051, 1025, 898, 742, 692 cm−1; [α]D16 +35.8 (c=0.42, CHCl3), 99% ee; HRMS (FAB): Calculated value [C11H17NO2]: 195.1259, observed value: 195.1280. The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=9.4 min, minor enantiomer tr=8.4 min. Example 12 Table 3, Entry 5, Catalyst 30 mol %, Temperature 0 deg C. Into a CH3CN solution (3.0 mL) of proline (0.18 mmol), 3-phenyl-propanal (1.8 mmol) and nitrosobenzene (0.6 mmol) are added at 0 deg C., and the solution is stirred for 24 hr at the same temperature. i-PrOH (1.0 mL) and NaBH4 (3 mmol) are added, and the solution is stirred for 10 min; then a phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the β-aminoalcohol in 72% yield with 99% ee. The optical purity was determined by HPLC using a chiral column. (R)-3-phenyl-2-anilinooxy-propanol 1H NMR (CDCl3): δ 2.25 (1H, brs), 2.77 (1H, dd, J=13.7, 6.9 Hz), 2.95 (1H, dd, J=13.7, 6.9 Hz), 3.65 (1H, dd, J=11.8, 5.8 Hz), 3.77 (1H, d, J=11.8 Hz), 4.06 (1H, m), 6.76 (1H, d, J=8.0 Hz), 6.86 (1H, t, J=8.0 Hz), 6.94 (1H, brs), 7.10-7.23 (7H, m); 13C NMR (CDCl3): δ 36.5, 64.2, 85.0, 114.8, 122.5, 126.5, 128.5, 128.9, 129.4, 137.8, 148.3; IR (KBr): 3390, 3280, 1600, 1494, 1454, 1240, 1083, 1070, 1029, 898, 767, 744, 694 cm−1; [α]D16 +63.3 (c=0.71, CHCl3), 99% ee; HRMS (FAB): Calculated value [C15H17NO2]: 243.1259, observed value: 243.1228. The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=16.4 min, minor enantiomer tr=13.6 min. Example 13 Table 3, Entry 6, Catalyst 30 mol %, Temperature −20 deg C. Into a CH3CN solution (3.0 mL) of proline (0.18 mmol), phenyl acetaldehyde (1.8 mmol) and nitrosobenzene (0.6 mmol) are added at −20 deg C., and the solution is stirred for 24 hr at the same temperature. i-PrOH (1.0 mL) and NaBH4 (3 mmol) are added, and the solution is stirred for 10 min; then a phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain β-aminoalcohol in 62% yield with 99% ee. The optical purity was determined by HPLC using a chiral column. (R)-2-phenyl-2-anilinooxy-ethanol 1H NMR (CDCl3): δ 2.52 (1H, brs), 3.77 (1H, dd, J=12.2, 3.3 Hz), 3.93 (1H, dd, J=12.2, 8.1 Hz), 4.97 (1H, dd, J=8.1, 3.3 Hz), 6.92-6.95 (4H, m), 7.20-7.24 (2H, m), 7.31-7.38 (5H, m); 13C NMR (CDCl3): δ 63.3, 86.5, 115.0, 122.5, 127.1, 128.4, 128.7, 129.0, 137.8, 147.9; IR (KBr): 3272, 3031, 2921, 1600, 1494, 1454, 1309, 1072, 1027, 896, 759 cm−1; [α]D17 −126.5 (c=0.52, CHCl3), 99% ee; HRMS (FAB): Calculated value [C14H15NO2]: 229.1103, observed value: 229.1111. The enantiomeric excess was determined by HPLC using a Chiralpak OD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=10.5 min, minor enantiomer tr=11.6 min. Examples in Table 4 Example 14 Table 4, Entry 1 Into a DMF solution (2.7 mL) of 3,3-dimethylcyclohexanone (1.2 mmol) and proline (0.06 mmol), a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) is added at 0 deg C. over 38 hr, and the solution is stirred for 0.5 hr at the same temperature. A phosphate buffer solution is added to stop the reaction; organic matters are extracted three times with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 43% yield with 99% ee. Diastereomer ratio is 88:12. The optical purity was determined by HPLC using a chiral column. (R)-2-anilinooxy-5,5-dimethylcyclohexanone 1H NMR (CDCl3): δ 0.92 (3H, s), 1.06 (3H, s), 1.63-167 (1H, m), 1.63-1.96 (2H, m), 1.96 (1H, dq, J=12.7, 4.8 Hz), 2.21 (1H, dt, J=13.1, 2.5 Hz), 2.25-2.31 (2H, m), 4.33 (1H, dd, J=12.1, 7.1 Hz), 6.89-6.94 (3H, m), 7.21-7.25 (2H, m), 7.77 (1H, brs); 13C NMR (CDCl3): δ 25.4, 27.8, 31.2, 36.6, 36.8, 53.5, 85.6, 114.5, 122.1, 128.9, 148.1, 209.5; IR (KBr): 2960, 2923, 1718, 1602, 1496, 1103, 1079, 794, 757, 692 cm−1; HRMS (FAB): Calculated value [C14H19NO2]: 233.1473, observed value: 233.1395; [α]D24 +132.1 (c=0.43, CHCl3). The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=17.7 min, minor enantiomer tr=14.6 min. Example 15 Table 4, Entry 2 Into a DMF solution (2.7 mL) of cys-3,5-dimethylcyclohexanone (1.2 mmol) and proline (0.06 mmol), a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) is added at 0 deg C. over 26 hr, and the solution is stirred for 0.5 hr at the same temperature. A phosphate buffer solution is added to stop the reaction; organic matters are extracted three times with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 60% yield with 99% ee. Diastereomer ratio is 70:30. The optical purity was determined by HPLC using a chiral column. (2R,3R,5S)-2-anilinooxy-3,5-dimethylcyclohexanone 1H NMR (CDCl3): δ 1.04 (3H, d, J=6.5 Hz), 1.21 (3H, d, J=7.0 Hz), 1.53-1.59 (2H, m), 1.77-1.96 (2H, m), 2.22 (1H, dd, J=12.5, 3.9 Hz), 2.52 (1H, t, J=12.5 Hz), 3.98 (1H, d, J=1.2 Hz), 6.90-6.98 (3H, m), 7.22-7.26 (2H, m); 13C NMR (CDCl3): δ 17.6, 19.1, 22.3, 34.3, 37.6, 38.5, 45.5, 89.8, 114.9, 122.6, 128.9, 147.9, 211.4; IR (KBr): 3268, 2960, 2927, 1716, 1494, 1455, 1284, 769, 738, 692 cm−1; HRMS (FAB): Calculated value [C14H19NO2]: 233.1416, observed value: 233.1431; [α]D24 +48.1 (c=0.57, CHCl3). The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=10.7 min, minor enantiomer tr=9.8 min. The absolute configuration was determined by converting a diol obtained by causing NaBH4 to act on 13a into (1S,2R,3R,5S)-1,2-bis(p-bromobenzoyloxy)-3,5-dimethylcyclohexane, and applying the CD-chirality method thereto. (2R,3S,5R)-2-anilinooxy-3,5-dimethylcyclohexanone 1H NMR (CDCl3): δ 1.02 (3H, d, J=6.2 Hz), 1.29 (3H, d, J=6.3 Hz), 1.86-2.02 (4H, m), 2.09 (1H, t, J=13.0 Hz), 2.38-2.42 (1H, m), 4.05 (1H, d, J=11.4 Hz), 6.90-6.94 (3H, m), 7.21-7.25 (2H, m), 7.95 (1H, brs); 13C NMR (CDCl3): δ 19.5, 22.0, 33.5, 37.8, 41.8, 48.6, 91.2, 114.6, 122.0, 128.9, 148.2, 209.4; IR (KBr): 3307, 2954, 1720, 1602, 1496, 1097, 887, 761, 738, 694, 582, 501 cm−1; HRMS (FAB): Calculated value [C14H19NO2]: 233.2416, observed value: 233.1400; [α]D24 +183.6 (c=0.36, CHCl3). The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=31.1 min, minor enantiomer tr=15.3 min. The absolute configuration was determined by converting a diol obtained by causing NaBH4 to act on 13b into (1S,2R,3S,5R)-1,2-bis(p-bromobenzoyloxy)-3,5-dimethylcyclohexane, and applying the CD-chirality method thereto. Example 16 Table 4, Entry 4 Into a DMF solution (2.7 mL) of 3-phenylcyclohexanone (1.2 mmol) and proline (0.06 mmol), a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) is added at 0 deg C. over 29 hr, and the solution is stirred for 0.5 hr at the same temperature. A phosphate buffer solution is added to stop the reaction; organic matters are three times extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 72% yield with 99% ee for the major product. Diastereomer ratio is 32:32:32:4. The optical purity was determined by HPLC using a chiral column. (2R,5R)-2-anilinooxy-5-phenylcyclohexanone 1H NMR (CDCl3): δ 1.85-2.03 (2H, m), 2.14-2.18 (1H, m), 2.50-2.57 (1H, m), 2.60-2.69 (2H, m), 2.96-3.04 (1H, m), 4.52 (1H, dd, J=11.9, 6.2 Hz); 13C NMR (CDCl3): δ 31.2, 31.7, 45.3, 48.0, 85.9, 114.5, 122.2, 126.4, 127.0, 128.8, 128.9, 143.3, 148.1, 208.4; IR(KBr): 3278, 2952, 1718, 1604, 1494, 1415, 1029, 794, 748, 694 cm−1; HRMS (FAB): Calculated value [C18H19NO2]: 281.1416, observed value: 281.1396; [α]D23 +91.6 (c=0.41, CHCl3). The enantiomeric excess was determined by HPLC using a Chiralpak AD-I column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=22.4 min, minor enantiomer tr=18.4 min. Example 17 Table 5, Entry 5 Into a DMF solution (2.7 mL) of 3-(4-tert-butylphenylthio)cyclohexanone (1.2 mmol) and proline (0.06 mmol), a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) is added at 0 deg C. over 13 hr, and the solution is stirred for 0.5 hr at the same temperature. A phosphate buffer solution is added to stop the reaction; organic matters are extracted three times with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 61% yield with 99% ee for the major product. Diastereomer ratio is 46:21:33. The optical purity was determined by HPLC using a chiral column. (2R,5S)-2-anilinooxy-5-(4-tert-butylphenylthio)cyclohexanone 1H NMR (CDCl3): δ 1.28 (9H, s), 1.55-1.65 (1H, m), 1.72-1.86 (1H, m), 1.94-2.05 (1H, m), 2.18-2.37 (2H, m), 2.43-2.52 (1H, m), 3.35 (1H, dddd, J=11.5, 11.5, 4.3, 4.3 Hz), 4.26 (1H, d, J=11.2 Hz), 6.94 (1H, t, J=7.1 Hz), 7.17 (2H, d, J=7.7 Hz), 7.21-7.28 (2H, m), 7.30 (2H, d, J=8.4 Hz), 7.44 (2H, d, J=8.4 Hz); 13C NMR (CDCl3): δ 24.6, 31.2, 32.1, 34.6, 40.3, 51.0, 88.6, 114.9, 122.2, 126.1, 126.3, 128.9, 134.2, 135.1, 148.1, 151.5, 207.4; IR (KBr): 2960, 1727, 1600, 1494, 1120, 1014, 904, 829, 740, 694 cm−1; HRMS (FAB): Calculated value [C22H27NO2S]: 369.1763, observed value: 369.1769; [α]D23 +56.5 (c=0.27, CHCl3). The enantiomeric excess was determined by HPLC using a Chiralpak OD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=15.0 min, minor enantiomer tr=13.9 min. (2R,5R)-2-anilinooxy-5-(4-tert-butylphenylthio)cyclohexanone 1H NMR (CDCl3): δ 1.30 (9H, s), 1.73-1.90 (2H, m), 2.23-2.35 (1H, m), 2.35-2.50 (2H, m), 2.71-2.82 (2H, m), 3.15-3.28 (1H, m), 4.37 (1H, dd, J=11.3, 6.2 Hz), 6.85-6.96 (3H, m), 7.18-7.27 (2H, m), 7.30-7.38 (4H, m), 7.74 (1H, brs); 13C NMR (CDCl3): δ 30.1, 30.7, 31.2, 34.6, 46.3, 47.3, 85.6, 114.5, 122.3, 126.2, 128.7, 128.9, 133.8, 147.9, 151.6, 206.7; IR (KBr): 2960, 1724, 1601, 1495, 1400, 1269, 1120, 930, 829, 692 cm−1; HRMS (FAB): Calculated value [C22H27NO2S]: 369.1763, observed value: 369.1760; [α]D23 +118.1 (c=0.28, CHCl3). The enantiomeric excess was determined by HPLC using a Chiralpak OD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=22.5 min, minor enantiomer tr=19.1 min. (2S,3S)-2-anilinooxy-3-(4-tert-butylphenylthio)cyclohexanone 1H NMR (CDCl3): δ 1.25 (9H, s), 2.02-2.20 (3H, m), 2.28-2.45 (1H, m), 2.63 (2H, d, J=4.9 Hz), 3.61-3.75 (1H, m), 4.27 (1H, dd, J=4.6, 10.3 Hz), 6.80-6.97 (3H, m), 7.15-7.26 (2H, m), 7.25-7.40 (4H, m), 7.56-7.72 (1H, brs); 13C NMR (CDCl3): δ 27.8, 28.9, 31.2, 34.6, 44.9, 46.7, 85.4, 114.7, 122.3, 126.2, 128.9, 129.6, 133.3, 147.9, 151.3, 207.0; IR (KBr): 2960, 1722, 1600, 1494, 1396, 1269, 1110, 829, 757, 692 cm−1; HRMS (FAB): Calculated value [C22H27NO2S]: 369.1763, observed value: 369.1761; [α]D23 +16.5 (c=0.24, CHCl3). The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=17.1 min, minor enantiomer tr=13.8 min. Example 18 Table 5, Entry 6 Into a DMF solution (8.1 mL) of 4-tert-butylcyclohexanone (2.2 mmol) and proline (0.18 mmol), a DMF solution (2.7 mL) of nitrosobenzene (1.8 mmol) is added at 0 deg C. over 32 hr, and the solution is stirred for 0.5 hr at the same temperature. A phosphate buffer solution is added to stop the reaction; organic matters are extracted three times with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 62% yield with 99% ee for the major product. Diastereomer ratio is 50:50. The optical purity was determined by HPLC using a chiral column. (2R,4R)-2-anilinooxy-4-tert-butylcyclohexanone 1H NMR (CDCl3): δ 0.83 (9H, s), 1.31 (1H, dddd, J=13.4, 4.2, 4.2, 4.2 Hz), 1.45-1.62 (2H, m), 1.93-2.02 (1H, m), 2.24 (1H, dd, J=13.7, 5.9 Hz), 2.30-2.38 (2H, m), 4.30 (1H, dd, J=12.5, 6.0 Hz), 6.78-6.85 (3H, m), 7.13 (2H, t, J=8.2 Hz), 7.76 (1H, s); 13C NMR (CDCl3): δ 27.6, 32.5, 33.6, 39.7, 45.9, 85.8, 114.5, 122.0, 128.9, 148.1, 210.2; IR (neat): 2960, 2869, 1728, 1602, 1494, 1367, 1097, 742, 692 cm−1; [α]D20 +79.4 (c=0.33, CHCl3), >99% ee; HRMS (FAB): Calculated value [C16H23NO2]: 261.1729, observed value: 261.1729. The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=10.2 min, minor enantiomer tr=11.0 min. (2R,4S)-2-anilinooxy-4-tert-butylcyclohexanone 1H NMR (CDCl3): δ 0.80 (9H, s), 1.40 (1H, dddd, J=13.4, 4.2, 4.2, 4.2 Hz), 1.56-1.65 (1H, m), 1.75 (1H, tt, J=12.2, 3.5 Hz), 1.93-2.01 (1H, m), 2.16-2.18 (2H, m), 2.63 (1H, dt, J=13.9, 6.0 Hz), 4.11 (1H, t, J=4.4 Hz), 6.82 (2H, d, J=8.2 Hz), 6.85 (1H, t, J=7.3 Hz), 7.06 (1H, s), 7.15-7.18 (2H, m); 13C NMR (CDCl3): δ 27.3, 32.2, 32.3, 38.0, 41.3, 84.7, 114.9, 122.6, 128.8, 147.8, 211.6; IR (neat): 2960, 2869, 1724, 1673, 1602, 1494, 1367, 1083, 748 cm−1; [α]D19 −11.8 (c=0.87, CHCl3), 94% ee; HRMS (FAB): Calculated value [C16H23NO2]: 261.1729, observed value: 261.1720. The enantiomeric excess was determined by HPLC using a Chiralpak OD-H column (hexane:2-propanol 100:1). 1.0mL/min; major enantiomer tr=11.1 min, minor enantiomer tr=12.5 min. Example 19 Table 5, Entry 7 Into a DMF solution (8.1 mL) of 4-(tert-butyldiphenylsiloxy)cyclohexanone (2.2 mmol) and proline (0.18 mmol), a DMF solution (2.7 mL) of nitrosobenzene (1.8 mmol) is added at 0 deg C. over 32 hr, and the solution is stirred for 0.5 hr at the same temperature. A phosphate buffer solution is added to stop the reaction; organic matters are extracted three times with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 69% yield with 99% ee for the major product. Diastereomer ratio is 67:33. The optical purity was determined by HPLC using a chiral column. (2R,4R)-2-anilinooxy-4-(tert-butyldiphenylsiloxy)cyclohexanone 1H NMR (CDCl3): δ 0.98 (9H, s), 1.58 (1H, t, J=12.7 Hz), 1.70 (1H, J=12.9 Hz), 1.87-1.96 (1H, m), 2.22-2.32 (2H, m), 2.84 (1H, dt, Jd=6.0, Jt=13.8 Hz), 4.23 (1H, brs), 4.81 (1H, dd, J=12.6, 6.2 Hz), 6.76 (2H, d, J=8.2 Hz), 6.83 (1H, t, J=6.9 Hz), 7.13 (2H, t, J=6.9 Hz), 7.32 (6H, m), 7.57 (4H, dd, J=15.4, 7.8 Hz), 7.69 (1H, s); 13C NMR (CDCl3): δ 19.2, 27.0, 34.1, 35.7, 39.2, 67.5, 82.4, 114.5, 122.1, 127.8, 128.9, 130.0, 133.5, 135.6, 148.1, 209.9; IR (neat): 2956, 2931, 1725, 1602, 1494, 1427, 1112, 1076, 821, 701 cm−1; [α]D18 +18.2 (c=0.23, CHCl3), >99% ee; HRMS (FAB): Calculated value [C28H33NO3Si]: 459.2230, observed value: 459.2273. The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=6.6 min, minor enantiomer tr=7.3 min. (2R,4S)-2-anilinooxy-4-(tert-butyldiphenylsiloxy)cyclohexanone 1H NMR (CDCl3): δ 1.08 (9H, s), 1.87-1.95 (1H, m), 2.00 (1H, dt, J=12.5, 10.7 Hz), 2.04-2.18 (2H, m), 2.28-2.36 (1H, m), 2.42-2.48 (1H, m), 4.09-4.18 (2H, m), 6.81 (2H, d, J=7.9 Hz), 6.93 (1H, t, J=7.9 Hz), 7.22 (2H, t, J=7.9 Hz), 7.39-7.46 (6H, m), 7.65-7.70 (4H, m), 7.53 (1H, brs); [α]D19 +57.8 (c=1.18, CHCl3), 96% ee; HRMS (FAB): Calculated value [C28H33NO3Si]: 459.2230, observed value: 459.2263. The enantiomeric excess was determined by HPLC using a Chiralpak OD-H column (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=10.3 min, minor enantiomer tr=11.3 min. The results in the above EXAMPLES are given in the above Table 1 to the following Table 5. TABLE 2 Yield, ee, No. Ketone Product % % 1 79 >99a 2 77 >99 3 96 >99 4 87 >99 5 55 96 6 45 99 7 45 >99 8 41 >99 9 69 >99 acatalyst 30 mol %; for the others, catalyst 10 mol % cAmount of catalyst 10 mol % As can be seen from the above table, when cyclohexanone or dimethylcyclohexanone is used as a ketone, the corresponding α-aminooxy ketone derivative was obtained in a high yield with a high enantioselectivity. In addition, even with a ketone having the acetal site at the 4-position, the corresponding α-aminooxy ketone derivative was obtained in a high yield with a high enantioselectivity. TABLE 3 10 0 30 0 10 −20 30 −20 mol % deg C. mol % deg C. mol % deg C. mol % deg C. Entry R Yld, % ee, % Yld, % ee, % Yld, % ee, % Yld, % ee, % 1 Me 81 98 80 98 quant 98 quant 98 2 Et 64 98 64 98 88 98 87 99 3 n-Pr 55 98 71 97 53 97 81 98 4 i-Pr 72 98 77 97 77 99 77 99 5 CH2Ph 67 98 72 99 <5 70 99 6 Ph 20 44 99 <5 62 99 TABLE 4 Time, Yield, Entry Substrate hr % Product 1 38 43 2 26 60 3 24 70 4 29 72 TABLE 5 Time, Yield, Entry Substrate hr % Product 5 13 61 6 32 62 7 32 69 Experiments for Table 6 Example 20 Table 6, Entry 1 Cyclohexanone (1.2 mmol) and 4-tert-butyldimethylsiloxy-L-proline (super proline) (0.06 mmol) are dissolved into 1.0 mL of a DMF solution, and into this solution, a DMF solution (0.5 mL) of nitrosobenzene (0.6 mmol) is dropped over 15 min. After completion of the dropping, the solution is stirred at room temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 76% yield with ee of >99%. The optical purity was determined by HPLC using a chiral column. (R)-2-anilinooxy-cyclohexanone 1H NMR (CDCl3): δ 1.37-1.75 (3H, m), 1.82-1.95 (2H, m), 4.27 (2H, dd, J=11.6, 6.2 Hz), 6.82 (3H, t, J=8.1 Hz), 7.12 (2H, t, J=7.6 Hz), 7.71 (1H, s); 13C NMR (CDCl3): δ 23.6, 27.1, 32.3, 40.7, 86.1, 114.3, 114.8, 128.9, 148.0, 209.7; IR (KBr): 3041, 2942, 2865, 1716, 1600, 1494, 1132, 1099, 1072, 1027 cm−1; HRMS (FAB): Calculated value [C12H15NO2]: 205.1103, observed value: 205.1080; [α]D23 +119 (c=0.84, CHCl3). HPLC: Chiralpak AD-H column (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=34.3 min, minor enantiomer tr=28.1 min. Example 21 Table 6, Entry 2 4,4-dimethylcyclohexanone (1.2 mmol) and super proline (0.06 mmol) are dissolved into 1.0 mL of a DMF solution, and into this solution, a DMF solution (0.5 mL) of nitrosobenzene (0.6 mmol) is dropped over 2 hr. After completion of the dropping, the solution is stirred at room temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 74% yield with ee of >99%. The optical purity was determined by HPLC using a chiral column. (R)-2-anilinooxy-4,4-dimethylcyclohexanone 1H NMR (CDCl3): δ 0.97 (s, 3H), 1.14 (s, 3H), 1.48-1.59 (3H, m), 4.38 (1H, ddd, J=12.7, 6.4, 3.2 Hz), 2.21-2.28 (1H, m), 2.40 (1H, dt, J=14.1, 6.5 Hz), 4.38 (1H, dd, J=12.9, 6.4 Hz), 6.79 (2H, d, J=7.8 Hz), 6.81 (1H, t, J=8.1 Hz), 7.13 (2H, t, J=8.1 Hz); 13C NMR (CDCl3): δ 24.9, 31.3, 31.9, 44.4, 83.2, 114.2, 121.9, 128.8, 148.1, 210.3; IR (KBr): 3041, 2956, 2927, 1725, 1602, 1495, 1470, 1076, 740, 692 cm−1; [α]D19 +85.7 (c=0.33, CHCl3); HRMS (FAB): Calculated value [C14H19NO2]: 233.1416, observed value: 233.1423. HPLC: Chiralcel OD-H column (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=9.1 min, minor enantiomer tr=12.2 min. Example 22 Table 6, Entry 3 Tetrahydrothiopyran-4-on (1.2 mmol) and super proline (0.06 mmol) are dissolved into 1.0 mL of a DMF solution, and into this solution, a DMF solution (0.5 mL) of nitrosobenzene (0.6 mmol) is dropped over 2 hr. After completion of the dropping, the solution is stirred at room temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 68% yield with ee of >99%. The optical purity was determined by HPLC using a chiral column. (R)-3-anilinooxy-tetrahydrothiopyran-4 -on 1H NMR (CDCl3): δ 2.76-2.95 (4H, m), 3.04 (1H, dd, J=11.5, 13.0 Hz), 3.19 (1H, dd, J=5.4, 13.0 Hz), 4.63 (1H, dd, J=5.4, 11.5 Hz), 6.90-6.97 (3H, m), 7.22-7.26 (2H, m), 7.68 (1H, brs); 13C NMR (CDCl3): δ 30.2, 33.8, 44.9, 86.4, 114.6, 122.4, 128.9, 147.8, 206.3; IR (KBr): 3262, 2925, 1724, 1602, 1494, 1469, 1415, 1309, 1101, 1076, 993, 783, 692 cm−1; HRMS (FAB): Calculated value [C11H13NO2S]: 223.0667, observed value: 223.0667; [α]D21 +85.7 (c=0.69, CHCl3). The enantiomeric excess was determined by HPLC using a Chiralpak AS-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=19.9 min, minor enantiomer tr=22.6 min. Example 23 Table 6, Entry 4 Cycloheptanone (1.2 mmol) and super proline (0.06 mmol) are dissolved into 1.0 mL of a DMF solution, and into this solution, a DMF solution (1.0 mL) of nitrosobenzene (0.6 mmol) is dropped over 2 hr. After completion of the dropping, the solution is stirred at room temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 45% yield with ee of >99%. The optical purity was determined by HPLC using a chiral column. (R)-2-anilinooxy-cycloheptanone 1H NMR (CDCl3): δ 1.32-1.44 (1H, m), 1.59-1.78 (3H, m), 1.79-1.91 (3H, m), 2.05-2.12 (1H, m), 2.41-2.51 (1H, m), 2.52-2.61 (1H, m), 4.60 (1H, dd, J=9.4, 3.9 Hz), 6.87-6.97 (3H, m), 7.20-7.32 (2H, m), 7.53 (1H, bs); 13C NMR (CDCl3): δ 23.1, 26.5, 28.6, 30.0, 41.1, 88.2, 114.4, 122.1, 128.9, 148.0, 211.6; IR (KBr): 3021, 2979, 2402, 1752, 1603, 1520, 1472, 1215, 1026, 930 cm−1; [α]D22 +59.9 (c=0.61, CHCl3); HRMS (FAB): Calculated value [C13H17NO2]: 219.1259, observed value: 219.1235. The enantiomeric excess was determined by HPLC using a (Chiralcel) AD-H column (hexane:2-propanol 10:1). 1.0 mL/min; major enantiomer tr=20.2 min, minor enantiomer tr=16.2 min. Example 24 Table 6, Entry 5 3-pentanone (6 mmol) and super proline (0.06 mmol) are dissolved into 1.0 mL of a DMF solution, and into this solution, a DMF solution (1.0 mL) of nitrosobenzene (0.6 mmol) is dropped over 1 hr. After completion of the dropping, the solution is stirred at room temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 50% yield with ee of >99%. The optical purity was determined by HPLC using a chiral column. (R)-2-anilinooxy-3-pentanone 1H NMR (CDCl3): δ 1.09 (3H, t, J=7.3 Hz), 1.41 (3H, d, J=7.0 Hz), 2.53 (2H, q, J=7.3 Hz), 4.45 (1H, q, J=7.0 Hz), 6.89-6.99 (3H, m), 7.21-7.28 (2H, m), 7.30 (1H, bs); 13C NMR (CDCl3): δ 7.3, 15.9, 31.5, 84.1, 114.5, 122.4, 129.0, 148.0, 211.6; IR (neat): 3278, 2979, 2937, 1718, 1603, 1495, 1101, 901, 692 cm−1; [α]D23 +75.5 (c=0.29, CHCl3); HRMS (FAB): Calculated value [C11H15NO2]: 193.1103, observed value: 193.1097. The enantiomeric excess was determined by HPLC using a (Chiralcel) OD-H column (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=16.5 min, minor enantiomer tr=20.6 min. Example 25 Table 6, entry 6 Into a CH3CN solution (3.0 mL) of phenylacetoaldehyde (1.8 mmol) and nitrosobenzene (0.6 mmol), super proline (0.06 mmol) is added at 0 deg C., and the solution is stirred for 2 hr at the same temperature. i-PrOH (1.0 mL) and NaBH4 (3 mmol) are added, and stirred for 10 min; then a phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminoxy aldehyde in 50% yield with 99% ee. The method for determining the optical purity, and the physical values were the same as those in EXAMPLE 13. Example 26 Table 6, Entry 7 Into a CH3CN solution (3.0 mL) of 3-phenyl-propanal (1.8 mmol) and nitrosobenzene (0.6 mmol), super proline (0.06 mmol) is added at 0 deg C., and the solution is stirred for 2 hr at the same temperature. i-PrOH (1.0 mL) and NaBH4 (3 mmol) are added, and stirred for 10 min; then a phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminoxy aldehyde in 76% yield with 98% ee. The method for determining the optical purity, and the physical values were the same as those in EXAMPLE 12. TABLE 6 Super Proline proline Time, yld, ee, Time, yld, ee, Entry Substrate Product hr % % hr % % 1 5.5 77 >99 0.25 76 >99 2 24 84 >99 2 74 >99 3 24 69 >99 2 68 >99 4 24 <5 nd 2 45 >99 5 24 <5 nd 1 50 >99 6 24 <5 nd 2 50 99 7 24 67 98 2 76 98 Example 27 Cyclohexanone (1.2 mmol) and D-proline (0.06 mmol) are dissolved into 2.7 mL of a DMF solution, and the solution is cooled to 0 deg C. Into this solution, a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) is dropped over 5.5 hr. After completion of the dropping, the solution is stirred at the same temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 79% yield with ee of >99%. The optical purity was determined by HPLC using a chiral column. (S)-2-anilinooxy-cyclohexanone 1H NMR (CDCl3): δ 1.37-1.75 (3H, m), 1.82-1.95 (2H, m), 4.27 (2H, dd, J=11.6, 6.2 Hz), 6.82 (3H, t, J=8.1 Hz), 7.12 (2H, t, J=7.6 Hz), 7.71 (1H, s); 13C NMR (CDCl3): δ 23.6, 27.1, 32.3, 40.7, 86.1, 114.3, 114.8, 128.9, 148.0, 209.7; IR (KBr): 3041, 2942, 2865, 1716, 1600, 1494, 1132, 1099, 1072, 1027 cm−1; HRMS (FAB): Calculated value [C12H15NO2]: 205.1103, observed value: 205.1080; [α]D23 −119 (c=0.84, CHCl3). The enantiomeric excess was determined by HPLC using a Chiralpak AD-H column (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=28.1 min, minor enantiomer tr=34.3 min. Example 28 1,4-cyclohexadione monoethyleneketal (1.2 mmol) and D-proline (0.06 mmol) are dissolved into 2.7 mL of a DMF solution, and this solution is cooled to 0 deg C. Into this solution, a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) is dropped over 12 hr. After completion of the dropping, the solution is stirred at the same temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 96% yield with ee of >99%. The optical purity was determined by HPLC using a chiral column. (S)-7-anilinooxy-1,4-dioxaspiro[4.5]decane-8-on 1H NMR (CDCl3): (1.88-2.04 (2H, m), 2.16 (1H, t, J=12.8 Hz), 2.36-2.46 (2H, m), 2.62 (1H, dt, J=14.0, 6.8 Hz), 4.38-4.21 (4H, m), 4.60 (1H, dd, J=12.9, 6.5 Hz), 6.87 (2H, d, J=7.7 Hz), 6.90 (1H, t, J=7.2 Hz), 7.20 (2H, t, J=7.2 Hz); 13C NMR (CDCl3): (34.9, 36.0, 39.7, 64.8, 64.9, 82.7, 107.6, 114.5, 122.2, 128.9, 148.0, 208.6; IR (neat): 2960, 2888, 1728, 1602, 1494, 1305, 1122, 1052 cm−1; [α]D18 −78.7 (c=1.2, CHCl3); HRMS (FAB): Calculated value [C14H17NO4]: 263.1158, observed value: 263.1172. The enantiomeric excess was determined by HPLC using a Chiralcel OD-H column (hexane:2-propanol 10:1). 0.5 mL/min; major enantiomer tr=29.1 min, minor enantiomer tr=26.5 min. Example 29 4,4-dimethylcyclohexanone (1.2 mmol) and L-proline (0.06 mmol) are dissolved into 2.7 mL of a DMF solution, and this solution is cooled to 0 deg C. Into this solution, a DMF solution (0.9 mL) of nitrosobenzene (0.6 mmol) is dropped over 12 hr. After completion of the dropping, the solution is stirred at the same temperature for 30 min. A phosphate buffer solution is added to stop the reaction; organic matters are extracted with ethyl acetate; the organic phase is washed with saline, and dried with Na2SO4. After removing the Na2SO4 by filtration, the solvent is distilled away under reduced pressure. The product is purified by column chromatography to obtain the α-aminooxy ketone in 87% yield with ee of >99%. The optical purity was determined by HPLC using a chiral column. (S)-2-anilinooxy-4,4-dimethylcyclohexanone 1H NMR (CDCl3): δ 0.97 (s, 3H), 1.14 (s, 3H), 1.48-1.59 (3H, m), 4.38 (1H, ddd, J=12.7, 6.4, 3.2 Hz), 2.21-2.28 (1H, m), 2.40 (1H, dt, J=14.1, 6.5 Hz), 4.38 (1H, dd, J=12.9, 6.4 Hz), 6.79 (2H, d, J=7.8 Hz), 6.81 (1H, t, J=8.1 Hz), 7.13 (2H, t, J=8.1 Hz); 13C NMR (CDCl3): δ 24.9, 31.3, 31.9, 44.4, 83.2, 114.2, 121.9, 128.8, 148.1, 210.3; IR (KBr): 3041, 2956, 2927, 1725, 1602, 1495, 1470, 1076, 740, 692 cm−1; [α]D19 −85.7 (c=0.33, CHCl3); HRMS (FAB): Calculated value [C14H19NO2]: 233.1416, observed value: 233.1423. The enantiomeric excess was determined by HPLC using a Chiralcel OD-H column (hexane:2-propanol 40:1). 1.0 mL/min; major enantiomer tr=12.2 min, minor enantiomer tr=9.1 min. For cyclohexanone, dimethylcyclohexanone, and tetrahydro-4H-thiopyran-4-on, the product was obtained in a period of time much shorter than that when proline is used. For example, for cyclohexanone, the reaction which took 5.5 hr was completed in 15 min. In addition, cycloheptanone and diethylketone reacted slowly with proline, but by using super proline, the α-aminooxy ketones could be synthesized, although the yield was moderate. Any of the compounds obtained has an extremely high asymetric yield. Because it is already known that the compounds obtained can be induced into the α-hydroxy ketones with a divalent copper salt, (N. Momiyama, H. Yamamoto, J. Am. Chem. Soc., 2003, 125, 6038.), the present reaction can be applied to a method for synthesizing an α-hydroxy ketone having a high optical purity through the asymmetric catalytic reaction from a ketone. INDUSTRIAL APPLICABILITY According to the method of the present invention, the corresponding optically active α-aminooxy ketone can be obtained from a ketone and a nitroso compound in a high yield with a high enantioselectivity, using a catalytic amount of proline and, in turn, the α-hydroxy ketone can be effectively obtained. In other words, the method of the present invention is an advantageous method which eliminates the need for first converting a ketone into an enolate or an equivalent thereof; allows an α-aminooxy ketone derivative to be directly obtained from a ketone; allows use of proline which is low-cost and readily available as an optically active substance; and allows an α-aminooxy ketone derivative having a high yield and a high optical purity to be obtained. When the catalyst is proline, the proline has the feature of being inexpensive. In addition, when the catalyst used is a proline derivative and, in particular, the above-mentioned super proline, the corresponding α-aminooxy ketone can be manufactured simply in a short period of time with a high yield and a high enantioselectivity, as compared to proline. In addition, the α-aminooxy ketone derivatives obtained can be easily induced into α-hydroxy ketones with a divalent copper salt (Momiyama et al. (Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc., 2003, 125, 6038)), which are useful as medicines and agricultural chemicals.

<SOH> BACKGROUND ART <EOH>Conventionally, an α-hydroxy ketone has been synthesized by first converting a ketone into an enolate or an equivalent thereof once, and then causing a diastereoselective reaction or an enantioselective reaction (see non-patent literature 1). As an example of such a method, the method which converts a ketone into a lithium enolate, and causes optically active oxadilysine as an oxidizer to act thereon as an oxidizer (see patent literatures 2 to 8); the method which, as an asymmetric catalytic reaction, converts a ketone into an enol ether, and then carries out asymmetric dihydroxylation thereof (see non-patent literatures 9 to 10); and the technique which further carries out asymmetric epoxidation thereof (non-patent literatures 10 to 14), are known. As described above, with these methods, it is necessary to first convert a ketone into the corresponding enolate or an equivalent thereof, and the catalytic asymmetric oxidation reaction has presented the problem that substrates with which a high asymmetric yield can be achieved are limited. Further, there has been another problem in that the asymmetric catalytic reaction requires use of an environmentally harmful metallic salt. Recently, a method for synthesizing an α-aminooxy ketone by converting a ketone into a tin enolate, and then carrying out an asymmetric catalyzed reaction using nitrosobenzene using a catalytic amount of an optically active activating agent has been reported (non-patent literature 15). The α-aminooxy ketone can be easily converted into an α-hydroxy ketone, thus this technique provides a part of a useful α-hydroxy ketone synthesizing method. However, although this method requires a smaller amount of optically active catalyst, it has presented problems in that, for example, there is the need to first convert a ketone into a tin enolate; the tin compound has toxicity; and that the asymmetric catalyst used must be prepared from BINAP and AgOTf. Thus, no excellent method for manufacturing an optically active α-hydroxy ketone directly from a ketone by an asymmetric catalytic reaction using an easily available asymmetric source as an activating agent has been provided. In addition, no manufacturing method which proceeds with high yield and asymmetric yield, meeting the requirements for practical use, has been available. In other words, no efficient manufacturing method from a ketone to an optically active α-hydroxy ketone has been provided. Non-patent literature 1: Zhou et al. (Zhou, P.; Chen, B. C.; Davis, F. A. “Asymmetric Oxidation Reactions”, Katsuki, T., Ed.; Oxford University Press: Oxford, 2001; p 128) Non-patent literature 2: Davis et al. (Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919) Non-patent literature 3: Davis et al. (Davis, F. A.; Haque, M. S. J. Org. Chem. 1986, 51, 4083) Non-patent literature 4: Chen et al. (Chen, B. C.; Weismiller, M. C.; Davis, F. A.; Boschelli, D.; Empfield, J. R.; Smith, A. B. Tetrahedron 1991, 47, 173) Non-patent literature 5: Davis et al. (Davis, F. A.; Kumar, A. J. Org. Chem. 1992, 57, 3337) Non-patent literature 6: Davis et al. (Davis, F. A.; Weismiller, M. C.; Murphy, C. K.; Reddy, R. T.; Chen, B. C. J. Org. Chem. 1992, 57, 7274) Non-patent literature 7: Davis et al. (Davis, F. A.; Kumar, A.; Reddy, R. T.; Rajarathnam, E.; Chen, B. C.; Wade, P. A.; Shah, S. W. J. Org. Chem. 1993, 58, 7591) Non-patent literature 8: Davis et al. (Davis, F. A.; Clark, C.; Kumar, A.; Chen, B. C. J. Org. Chem. 1994, 59, 1184) Non-patent literature 9: Hashiyama et al. (Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Am. Chem. Soc. 1993, 115, 8463) Non-patent literature 10: Hashiyama et al. (Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Org. Chem. 1992, 57, 5067) Non-patent literature 11: Fukuda et al. (Fukuda, T.; Katsuki, T. Tetrahedron Lett. 1996, 37, 4389) Non-patent literature 12: Adam et al. (Adam, W.; Rainer, T. F.; Stegmann, V. R.; Saha-Moller, C. R. J. Am. Chem. Soc. 1998, 120, 708) Non-patent literature 13: Zhu et al. (Zhu, Y.; Yu, Y.; Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819) Non-patent literature 14: Adam et al. (Adam, W.; Fell, R. T.; Saha-Moller, C. R.; Zhao, C-G Tetrahedron: Asymmetry 1998, 9, 397) Non-patent literature 15: Momiyama et al. (Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc., 2003, 125, 6038)

20060224

20071009

20061228

98383.0

C07D33502

GALE, KELLETTE

OPTICALLY ACTIVE ALPHA-AMINOOXYKETONE DERIVATIVES AND PROCESS FOR PRODUCTION THEREOF

SMALL

ACCEPTED

C07D

ACCEPTED

Method for detecting neoplastic disorders in a solubilized body sample

The present invention relates to a method for the early diagnosis of neoplastic disorders such as cancers as well as their precursor stages, particularly cancers of the respiratory tract, the urinary system, the reproductive tract, cancer associated with HPV infection or cancer of the anogenital tract, from solubilized body samples. The invention is also directed to test kits usable for this purpose as well as in-vitro diagnostic devices. The development of the kits and in-vitro diagnostic devices for the above purpose is also one aspect of the present invention.

1. A method for detecting neoplastic disorders from a solubilized body sample of a human subject, the method comprises the steps of: (a) obtaining a body sample from a human subject, (b) solubilizing the body sample in a lysis medium, and (c) determining the overexpression of a marker molecule selected from the group consisting of: i) a cyclin dependent kinase inhibitor selected from the group consisting of p16INK4a, p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, and p27KIP1; and ii) the cell cycle regulatory protein p14ARF; in the solubilized body sample by comparing the level of the marker molecule within said solubilized body sample with the level of the marker molecule present in a solubilized healthy human body sample. 2. The method according to claim 1, wherein the neoplastic disorders are selected from the group consisting of i) cervical cancer or a precursor lesion thereof; ii) cancer of the respiratory tract or a precursor lesion thereof; iii) cancer of the urinary system or a precursor lesion thereof; iv) cancer associated with HPV infection or a precursor lesion thereof; v) cancer of the reproductive tract or a precursor lesion thereof; and vi) cancer of the anogenital tract or a precursor lesion thereof. 3. The method according to claim 1, wherein the body sample of a human subject is swab, lavage, smear, aspirate, biopsy, preserved cytological specimen, LBC sample, histological specimen, fixed cell preparation, fixed tissue preparation, body fluid, secretion, gastrointestinal secretion, blood, sputum, urine, stool, liquor cerebrospinalis , bile, lymph or bone marrow. 4. The method according to claim 1, wherein the body sample of a human subject is solubilized a. immediately after obtaining the sample, b. after storage and/or transport in a storage buffer, or c. after transport in a transportation buffer. 5. The method according to claim 1, wherein the levels of two or more said marker molecules are determined. 6. The method according to claim 1, wherein the detection of the marker molecules is performed using at least one probe specifically for the marker molecules. 7. The method according to claim 6, wherein the probe is detectably labeled. 8. The method according to claim 7, wherein the label is selected from the group consisting of a radioisotope, a bioluminescent compound, a chemiluminescent compound, an electroluminescent compound, a fluorescent compound, a metal chelate, an enzyme, and a biologically relevant binding structure. 9. The method according to claim 6, wherein the probe is a protein or a nucleic acid. 10. The method according to claim 9, wherein the probe is an antibody, an antibody fragment, a miniantibody, or a peptidomimetic comprising an antigen binding epitope. 11. The method according to claim 9, wherein the probe is a nucleic acid specifically hybridizing to the marker molecule. 12. The method according to claim 11, which comprises an in situ hybridization reaction and/or a nucleic acid amplification reaction. 13. The method according to claim 12, wherein the nucleic acid amplification reaction is PCR, NASBA or LCR. 14. The method according to claim 1, wherein the level of the marker molecule in the healthy human body sample is provided as a predetermined value to set up a threshold for the detection procedure. 15. The method according to claim 1, wherein the level of the marker molecule in a healthy human body sample is determined from a standardized sample solution, or from a representative number of healthy human body samples. 16. The method according to claim 1, wherein the determination of the marker molecule in a healthy human body sample is carried out: a. in the course of the detection procedure, b. in the course of calibration of the detection system, c. once for each lot of detection reagents, or d. as a standard value for the detection method. 17. An in-vitro diagnostic device comprising only probes of one specificity fixed to a solid phase, wherein the probes of the one specificity are specific for a marker molecule selected from the group consisting of i) a cyclin dependent kinase inhibitor selected from the group consisting of p16INK4a, p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, and p27KIP1; and ii) the cell cycle regulatory protein p14ARF. 18. The in-vitro diagnostic device according to claim 17, wherein the probe is an antibody, an antibody fragment, a miniantibody, or a peptidomimetic comprising an antigen binding epitope, or a nucleic acid. 19. The in-vitro diagnostic device according to claim 17 or claim 18, which is selected from the group consisting of: a. an ELISA device comprising antibodies, fragments thereof or antigen binding agents directed against a marker molecule selected from a group comprising i) a cyclin dependent kinase inhibitor selected from the group consisting of p16INK4a, p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, p27KIP1; and ii) the cell cycle regulatory protein p14ARF fixed to ELISA plates, ELISA stripes or ELISA wells; b. a lateral flow test device, comprising antibodies, fragments thereof or antigen binding agents directed against a marker molecule selected from a group comprising i) a cyclin dependent kinase inhibitor selected from the group consisting of p16INK4a, p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, p27KIP1; and ii) the cell cycle regulatory protein p14ARF fixed to test strips, colloidal gold particles or latex particles; c. a flow through assay device, comprising antibodies, fragments thereof or antigen binding agents directed against a marker molecule selected from a group comprising i) a cyclin dependent kinase inhibitor selected from the group consisting of p16INK4a, p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, p27KIP1; and ii) the cell cycle regulatory protein p14ARF fixed to a porous member, or to the surface of capillaries; d. a latex agglutination assay device, comprising antibodies, fragments thereof or antigen binding agents directed against a marker molecule selected from a group comprising i) a cyclin dependent kinase inhibitor selected from the group consisting of p16INK4a, p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, p27KIP1; and ii) the cell cycle regulatory protein p14ARF fixed to latex particles; e. an immunoassay device, comprising antibodies, fragments thereof or antigen binding agents directed against a marker molecule selected from a group comprising i) a cyclin dependent kinase inhibitor selected from the group consisting of p16INK4a, p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, p27KIP1; and ii) the cell cycle regulatory protein p14ARF fixed to beads or membranes; f. an immunoassay device, comprising antibodies, fragments thereof or antigen binding agents directed against a marker molecule selected from a group comprising i) a cyclin dependent kinase inhibitor selected from the group consisting of p16INK4a, p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, p27KIP1; and ii) the cell cycle regulatory protein p14ARF fixed to microspheres; and g. a nucleic acid detection device comprising probes specifically hybridizing to a nucleic acid gene product of a marker molecule selected from a group comprising i) a cyclin dependent kinase inhibitor selected from the group consisting of p16INK4a, p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, p27KIP1; and ii) the cell cycle regulatory protein p14ARF fixed to a solid phase. 20. An in-vitro diagnostic device comprising a probe, selected from the group consisting of an antibody, an antibody fragment, a miniantibody, or a peptidomimetic comprising an antigen binding epitope, and a nucleic acid specific for a marker molecule selected from the group consisting of i) a cyclin dependent kinase inhibitor selected from the group consisting of p16INK4a, p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, and p27KIP11; and ii) the cell cycle regulatory protein p14ARF and a lysis medium for solubilization of a body sample. 21. The in-vitro diagnostic device according to claim 20, wherein the lysis medium comprises at least one composition selected from the group consisting of chaotropic agents, anionic detergents, cationic detergents, non-ionic detergents, amphoteric detergents, and alkaline compositions. 22. The in-vitro diagnostic device according to claim 20, wherein the lysis medium comprises at least one composition selected from the group consisting of a proteinase inhibitor, a DNAse inhibitor, and an RNAse inhibitor. 23. The in-vitro diagnostic device according to claim 22, wherein the proteinase inhibitor is selected from the group consisting of inhibitors to serine proteinases, inhibitors to cysteine proteinases, inhibitors to aspartic proteinases, inhibitors to metallo proteinases, inhibitors to acidic proteinases, inhibitors to neutral proteinases, and inhibitors to alkaline proteinases. 24. The in-vitro diagnostic device according to claim 20, wherein the lysis medium comprises at least one non-ionic detergent and at least one proteinase inhibitor. 25. The in-vitro diagnostic device according to claim 24, wherein the lysis medium contains Triton X-100 and at least one inhibitor of serine proteinases. 26. The in-vitro diagnostic device according to claim 20, further comprising at least one said marker molecule for carrying out a positive control reaction, reagents and buffers commonly used for carrying out the detection reaction. 27. The in-vitro diagnostic device according to claim 26, further comprising a recombinant protein selected from the group consisting of i) a cyclin dependent kinase inhibitor protein selected from the group consisting of p16INK4a, p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, and p27KIP1; and ii) a cell cycle regulatory protein p14ARF protein, fragments thereof or peptides thereof for carrying out a positive control reaction. 28. A hybrid capture device being a research device or an in-vitro diagnostic device comprising nucleic acids complementary or reverse complementary to one or more cyclin-dependent kinase inhibitor nucleic acids, wherein the cyclin-dependent kinase inhibitor is selected from the group consisting of p16INK4a, p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, p27KIP1 and p14ARF for detection of overexpression of said one or more cyclin-dependent kinase inhibitors in a solubilized body sample. 29-41. (canceled) 42. A method for assessing diagnosis of medically relevant conditions from a solubilized LBC sample comprising a. detecting the presence or absence and/or the level of a marker molecule characteristic for a medically relevant condition on the protein, peptide, or nucleic acid level; b. comparing the presence or absence and/or the level of said marker molecule in the solubilized LBC sample to the presence or absence and/or the level of said marker molecule known to be characteristic for a healthy non-diseased body sample; and c. assessing diagnosis on the medically relevant condition based on the comparison of b. 43. The method according to claim 42, wherein the assessment of diagnosis is based on one feature selected from the following: a. the presence or absence of the marker molecule, wherein the presence or absence of the makder molecule is characteristic for a diseased sample; b. the marker molecule is overexpressed in the cells contained in the LBC sample compared to a healthy non-diseased body sample; c. expression of the marker molecule is lowered or lost in comparison to the expression present in a healthy non-diseased body sample; d. a modified form of the marker molecule is expressed in the cells present in the LBC sample compared to the marker molecule present in healthy non-diseased body samples. 44. The method according to claim 42, wherein the medically relevant condition is a disease. 45. The method according to claim 44, wherein the disease is a cell proliferative disorder, cancer or a precursor lesion. 46. The method according to claim 45, wherein the cancer is cancer of the head and the neck, cancer of the respiratory tract, cancer of the gastrointestinal tract, cancer of the skin and its appendages, cancer of the central and peripheral nervous system, cancer of the urinary system, cancer of the reproductive system, anogenital cancer, cancer of the endocrine system, cancer of the soft tissues and bone, or cancer of the lymphopoietic and hematopoietic system. 47. The method of claim 46, wherein the anogenital cancer is cervical cancer. 48. The method according to claim 42, wherein the marker molecules are selected from the group consisting of cell cycle regulatory proteins, metalloproteinases, transmembrane proteins, calcium binding proteins, growth factors, marker molecules characteristic for viral infections, cell proliferation markers, markers associated with DNA replication, tumor marker proteins, and the nucleic acids coding for the respective proteins. 49. The method of claim 48, wherein the tumor marker proteins are selected from the group consisting of cyclin-dependent kinase inhibitors, p53, pRb, p14ARF, cyclin E, cyclin A, cyclin B, MN, her2/neu, mdm-2, bcl-2, claudin 1, EGF-Receptor, MCM2, MCM3, MCM4, MCM5, MCM6, MCM7, CDC2, CDC6, CDC7 protein kinase, CDC14 protein phosphatase, Dbf4, PCNA, Ki67, KiS1, Id1, osteopontine, CD46, GRP, renal dipeptidase, and TGFβII receptor. 50. The method according to claim 49, wherein the cyclin-dependent kinase inhibitor is p16INK4a. 51. The method according to claim 49, wherein the cyclin-dependent kinase inhibitor is selected from the group consisting of p13.5, p14, p15INK4b, p18INK4c, p19INK4d, p21WAF1/CIP1, and p27KIP1. 52. The method according to claim 48, wherein the marker molecules characteristic for viral infections are viral proteins. 53. The method according to claim 52 wherein the viral protein is a HPV protein derived from a HPV gene selected from the group consisting of HPV L1, HPV L2, HPV E1, HPV E2, HPV E4, HPV E5, HPV E6 and HPV E7. 54. The method according to claim 42, wherein the detection of the marker molecules is performed using at least one probe specifically for the molecules to be detected. 55. The method according to claim 54, wherein the probe is detectably labeled. 56. The method according to claim 55, wherein the label is selected from the group consisting of a radioisotope, a bioluminescent compound, a chemiluminescent compound, an electroluminescent compound, a fluorescent compound, a metal chelate, an enzyme, or a biologically relevant binding structure. 57. The method according to claim 54, wherein the probe is an antibody, an antibody fragment, a miniantibody, a peptidomimetic comprising an antigen binding epitope, or a nucleic acid complememtary or reverse complementary to the marker molecule. 58-84. (canceled) 85. The method according to claim 42, wherein the amount of the LBC sample for application in the method is normalized with respect to information obtained from cytological specimens prepared from the LBC sample.

The present invention relates to a method for the early diagnosis of neoplastic disorders such as cancers as well as their precursor stages, particularly cancers of the respiratory tract, the urinary system, the reproductive tract, cancer associated with HPV infection or cancer of the anogenital tract, from solubilized body samples. BACKGROUND OF THE INVENTION Preventive programs have been offered for the most differing cancers since the middle of the fifties. For cervical cancer an established population wide screening program exists in various developed countries. However similar screening programs are applicable for other cancer entities and the respective precursor stages such as e.g. cancers of the urinary system, of the respiratory tract and other. In the following cervical cancer is used as an example to highlight the drawbacks of the present preventive scenario. However the facts are mutandis mutatis applicable to other preventive programs for any cancer entity. Regarding cervical intraepithelial neoplasia and cervical glandular lesions, the preventive programs are based mainly on the morphological and cytological examination of cytosmears of the cervix uteri, what is called the Pap test, which is made on the basis of gynecological routine examinations at regular intervals in women from the 20th year on. By means of the morphology of the cells, the smears are divided into various intensity degrees of dysplastic cellular changes. According to Pap I-V, these intensity degrees are referred to as normal, mild dysplasia, fairly serious dysplasia, serious dysplasia and invasive carcinoma, respectively. If the Pap test leads to a striking result, a small biopsy will be taken and subjected to a histopathologic examination, by which the kind and intensity of the dysplasia are determined and classified as cervical intraepithelial neoplasia (CIN1-3). In spite of all preventive programs, cervical cancer that lead to 400,000 new cases per year is the second most frequent neoplastic disorder in women. This is inter alia due to the fact that up to 30% of the results of individual Pap test are false-negative. In conventional screening for cervical intraepithelial neoplasia, swabs are used for detection of neoplastic lesions of the cervix uteri. In the screening procedure, different kinds of lesions have to be distinguished. Causes for lesions may for example be inflammations (due to infectious agents or physical or chemical damage) or neoplastic disorders. In morphological examinations the lesions of different characteristics are sophisticated to distinguish. Thus, for examination of cervical swabs and smears cytologists and pathologists have to be especially trained, and even experienced examiners have a high inter- and intra-observer variance in the assessment of a diagnosis based on cytological specimens. In general, the result of the examination is based upon the subjective interpretation of diagnostic criteria by the examining pathologist/cytologist. As a result, the rate of false positive and false negative results in the screening tests remains unsatisfying high. However, the reproducibility of the examination results may be enhanced by the use of supporting molecular tools. Yet the problem with the preservation and preparation of the samples may not be overcome by just additionally using molecular markers. One further complication when performing cytological or histological examinations for screening purposes and especially when applying methods for the detection of molecular markers originates from strict precautions in preserving the samples from causing artefacts or improper results. This is in part due to the instability of the cell-based morphological information and in part to the instability of the molecular markers to be detected during the tests. If the samples are not prepared, transported or stored in an appropriate manner, the cell-based information, or even the molecular information may be lost, or may be altered. So the diagnosis may be impossible, or may be prone to artefacts. For example, the interpretation of biopsies or cytological preparations is frequently made difficult or impossible by damaged (physically or bio/chemically) cells. Furthermore regarding tissue samples or biopsies, the preservation of molecular constituents of the samples, which are subject to a rapid turnover, is sophisticated due to the time passing by until penetration of the total sample by appropriate preservatives. Although the above is shown using cervical cancer as an example the overall background also applies to preventive programs of neoplastic disorders in general as the situation for other cancer entities is very much the same. Generally the morphologically supported diagnostic methods performed routinely in the art show two major disadvantages. Firstly, the methods are highly dependent on individual perception of the examiners. Secondly, the morphological information is quite sensitive to decay processes and thus to production of artefacts after preparation of the samples. Both aspects contribute to improper reproducibility of the results. Therefore, it is the object of the present invention to provide a method by which neoplastic disorders such as cancers and their precursor stages can be diagnosed early and reliably. In addition, a differentiation should be possible by this method with respect to benign inflammatory or metaplastic changes from neoplastic disorders such as dysplastic lesions and precancers. Moreover, the present invention provides methods for the detection of cancers on a biochemical basis from solubilized samples. The samples may be of any kind including cells in a cell preservation solution as is used for Liquid based cytology methods. The inventors insight that use of LBC samples as a source of sample material for the development of diagnostic test kits for the biochemical non-cell based assessment of diagnosis of medically relevant conditions is another aspect of the present invention. In the art LBC samples are used for development of cell based assay formats. Lysis of the samples in a way as disclosed herein however enables inventors to base the development of the biochemical kits on sample material which is suited to provide information on the patients disease status from other diagnostic procedures on the same sample material. A method for detection of HPV nucleic acids from LBC samples is disclosed by Digene Corp. This method uses LBC samples as basis for the analysis. Detection of the HPV nucleic acids is performed after lysis of the cells contained in the LBC samples. In this method no normalization of the amount of the LBC sample to be employed in the biochemical non-cell based detection of the HPV nudeic acid, is performed with respect to information obtained from the cytological specimen prepared out of the same LBC sample. The method disclosed by Digene is therefore restricted to mere qualitative measurements. Any biochemical non-cell based quantitative or even semiquantitatve method needs information on the composition of the samples obtainable either from biochemical markers or from the microscopic or flow cytometric analysis of the sample. In the present invention the use of LBC samples for the assessment of diagnosis or for development of kits and in-vitro diagnostic devices enables for an accurate and comparable way to provide cytological information for the biochemical non-cell based testing. The employment of biochemical normalization with respect to markers indicative for the presence or absence of cells or cell types is omissible. The advantage of using LBC samples in this respect is that the cytologically cell based information is direct related to the homogeneous LBC specimen and thus provides valuable accurate information for use in the evaluation of the biochemical non-cell based test results. A method for detection of molecular markers on the protein or nucleic acid level from solubilized specimens on the other hand is disclosed in various publications. However no link to the use of LBC samples as a source of the sample specimen in made in this respect. Generally LBC methods are applied in the art to enable for improved morphological evaluation of cytology specimens. The field of application of the LBC samples is therefore indicated only for cytology. Based on the disclosure in the prior art preparation of an LBC sample for subsequent solubilization of the sample for biochemical testing is not disclosed. Moreover the disclosure as to the advantages of LBC procedures teach away from application of LBC samples in any method that is not founded on cellular morphological evaluation of the specimens. According to the inventors findings the use of LBC samples as a source for biochemical non-cell based determination of protein levels in solubilized specimens provides the advantage that the results may be directly compared to a cytological specimen. The protein based biochemical analysis in this respect may serve as a e.g. pre-testing or to provide further information or even to confirm a cytologically equivocal result. In further embodiments the information obtained from the biochemical non-cell based testing may be for the design of the cytological procedures to be applied. The development method disclosed herein is therefore of great value for achieving effective and reliable kits and in-vitro diagnostic devices. The method for development of kits and in-vitro diagnostic devices as disclosed herein achieves comparability of the results generated by biochemical non-cell based analysis with the cytologically assessed results by means of a normalization. This normalization of the sample for application in the biochemical test format is performed with respect to information on the LBC sample obtainable from the cytological specimen prepared from the LBC sample. Such information comprises e.g. cellularity of the LBC sample, information with respect to volume of the LBC sample, information with respect to mass of the LBC sample or with respect to parameters accessible only via the generation of a thin-layer specimen out of the LBC sample. In this respect the inventors provide by the methods as claimed herein a reliable method for development of kits and in-vitro diagnostic devices on the basis of LBC samples. SUMMARY OF THE INVENTION The present invention is directed to a method for detecting neoplastic disorders from a solubilized body sample of a human subject The method comprises the steps of: (a) obtaining a body sample from a human subject, (b) solubilizing the body sample in a lysis medium, and (c) determining the overexpression of a cyclin-dependent kinase inhibitor in the solubilized body sample by comparing the level of said cyclin-dependent kinase inhibitor within said solubilized body sample with the level present in a solubilized healthy human body sample. The samples for use in the method of the present invention may be of any kind including cells in a cell preservation solution as is used for Liquid based cytology methods. The present invention is further directed to a test kit for determining the level of cyclin-dependent kinase inhibitors comprising probes specific for said cyclin-dependent kinase inhibitor and a lysis medium for solubiliation of a body sample. The test kit may be an in-vitro diagnostic device. In certain embodiments of the present invention the kit is provided as an in-vitro diagnostic device. Therefore the present invention is also directed to an in-vitro diagnostic device comprising probes directed against a cyclin-dependent kinase inhibitor fixed on solid carriers, for measuring the cyclin-dependent kinase inhibitor in a solubilized sample. The present invention is furthermore directed to a method of development of kits and in-vitro diagnostic devices for assessment of diagnosis of medically relevant conditions from solubilized body samples, wherein the development is performed using body samples provided as preserved cells in a cell-preservation medium and wherein the preserved cells are intended and prepared for use in cytological examination processes such as Liquid Based Cytology processes. The samples intended for Liquid Based Cytology processes (in the following denominated as LBC samples) are solubilized in an appropriate lysis medium and are used for development activities of kits and in-vitro diagnostic devices for detection of medically relevant conditions from solubilized body samples on the basis of biochemical non-cell-based analysis. The present invention is also directed to a method for assessment of diagnosis of medically relevant conditions by biochemical non-cell-based analysis of the presence or absence and or the level of marker molecule in solubilized body samples, wherein the body sample is an LBC sample, and wherein the detection of marker molecules is carried out by detection of the presence or absence and or the level of proteins, peptides, nucleic acids or fragments thereof in said solubilized samples. The marker molecules that may be applied for this method are disclosed above as “marker molecules characteristic for medically relevant conditions”. The method may be applied to any medically relevant condition. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the OD values returned in an ELISA test detecting the level of p16INK4a in solubilized cervical samples; for experimental details see Example 1. DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the applicant's insights that cyclin-dependent kinase inhibitor gene products are overexpressed in many neoplastic disorders such as cancers, e.g. cancers of the respiratory tract, cancers of the reproductive tract, cancers of the urinary system, HPV associated cancers or anogenital cancers, particularly cervical cancer, and precursor stages of these cancers, respectively. Examples of the cyclin-dependent kinase inhibitors are the proteins p14, p15INK4b, p16INK4a, p18INK4c, p19INK4d, p21WAF1/CIP1 and p27KIP1. The cell cycle regulatory protein p14ARF, which is by function not a cyclin-dependent kinase inhibitor, shall within the context of the present invention be included in the expression “cyclin-dependent kinase inhibitor”. The applicant has found that the intensity of cyclin-dependent kinase inhibitor overexpression as detected in cytological specimens correlates with the degree of dysplasia as detected in corresponding histological specimens. According to the invention, the applicant's insights are used for a method for the early diagnosis of neoplastic disorders such as cancers and their precursor stages, which comprises determining the overexpression of cyclin-dependent kinase inhibitors in a body sample. According to the invention, cytological and/or histological examination procedures may be supported or even substituted by the use of molecular markers. Such markers may e.g. be used in immuno-cytochemical staining reactions, or in the course of in-situ hybridization reactions. Combinations of morphological examinations and immuno-cytochemical staining reactions based on marker molecules, characteristic for neoplastic disorders such as cancers, e.g. of the cervix uteri, the bladder or the lung, may lead to enhanced results. The morphologic examination remains laborious and time consuming and thus expensive, even when supported by the molecular methods, that make the results more reliable. Additionally, the diagnosis on a morphologically cell based level is, even when supported by molecular parameters, subject to individual perception of the morphology by individual examiners. Thus the diagnosis is dependent on the person, that performs the examinations. The inventors moreover could show that in specific cases molecular markers may be used as diagnostic tools without further support by cell based morphological examinations. Methods for diagnosis of neoplastic disorders such as cancers on a molecular level only, without the support of cell based information, are restricted to cases, where markers or levels of markers are specific for the condition to be characterized. This is especially true, if the markers are non-human substances. For example detection of viral infections may be carried out in solutions of samples, because the markers characteristic for the presence of viruses in tissues do not occur in unaffected human tissues. However, the inventors found that certain human cyclin-dependent kinase inhibitors may serve as a marker for cancers in biochemical marker based detection procedures although it is a cell cycle regulatory protein being expressed at low levels in any normally proliferating human cell in certain stages of the cell cycle. Cyclin-dependent inhibitors for use in the present invention comprise the cyclin-dependent kinase inhibitors p14, p15INK4b, p16INK4a, p18INK4c, p19INK4d, p21WAF1/CIP1 and p27KIP1. Beside cyclin-dependent kinase inhibitors the cell cycle regulatory protein p14ARF encoded by an alternative reading frame of the p16INK4a gene may also be used for a method as disclosed herein. For convenience, within the context of the present invention the cell cycle regulatory protein p14ARF, which is by function not a cyclin-dependent kinase inhibitor, shall be included in the expression “cyclin-dependent kinase inhibitor”. “p16” or “cyclin-dependent kinase inhibitor p16INK4a” as used herein refers to cyclin-dependent kinase inhibitor p16INK4a (also denominated as CDKN2 or MTS1) the gene of which is located in chromosomal region 9p21. p16INK4a was first described in Serrano, M., et al., Nature, 1993 Dec. 16; 366(6456): 704-7. The terms “p16INK4a” or “cyclin-dependent kinase inhibitor p16INK4a” in all their grammatical forms as used in the context of the present invention refers to nucleic acid as well as polypeptide molecules. “p16INK4a” or “cyclin-dependent kinase inhibitor p16INK4a” thus comprises e.g. RNA (mRNA, hnRNA, etc.), DNA (cDNA, genomic DNA, etc.), proteins, polypeptides, proteoglycans, glycoproteins and the respective fragments of these molecules. The “level” of cyclin-dependent kinase inhibitors or other marker molecules as uses herein refers to a semiquantitative as well as a quantitative value regarding the amount of the marker (cyclin-dependent kinase inhibitors or other marker molecules) present in a sample. A quantitative value may e.g. be represented in terms of a concentration. A semi-quantitative value may be expressed in terms of a scale of levels e.g. undetectable levels, low levels, intermediate levels, high levels or any other suitable mode. The level of a marker such as e.g. p16INK4a may also be represented in terms of a dependent parameter such as the intensity of a signal generated in an assay format in response to the presence of e.g. a cyclin-dependent kinase inhibitor. In certain embodiments the level may also refer to a qualitative determination of the presence of a marker molecule. Due to the expression of cyclin-dependent kinase inhibitors (e.g. p16INK4a) in certain benign cell types present in body samples (e.g. cervical specimens, specimens from the oral cavity, urine, sputum etc.), the diagnosis of neoplastic disorders based on the level of cyclin-dependent kinase inhibitors without additional information on the cellular morphology seem to be difficult or impossible. It was known in the art that in up to 30% of cervical specimens, few to many metaplastic cells may be immunoreactive for cyclin-dependent kinase inhibitor p16INK4a at a moderate to high level. Moreover, endometrial cells that may under certain circumstances be present in cervical swabs may be positive for p16INK4a. In cytological or histological testing procedures, this fact does not influence the diagnosis, because the cell types may easily be distinguished from dysplastic cells with respect to their cellular morphology. Surprisingly the inventors found that by defining a threshold value of cyclin-dependent kinase inhibitors (e.g. p16INK4a), it is possible to enable the detection or diagnosis of dysplasias even without knowledge of the cellular morphology. The expression “neoplastic disorders” in all its grammatical forms as used in the context of the present invention refers to cancers of any kind and origin and precursor stages thereof, respectively. Accordingly the term “neoplastic disorder” shall comprise the subject matter identified by the terms “neoplasia”, “neoplasm”, “cancer”, “precancer” or “tumor”. Also the cytological counterpart to histological conditions identified as “dysplastic” or as “dysplasia” shall be within the scope of the term “neoplastic disorder” as used herein. Neoplastic disorders to which the methods of the present invention may be applied comprise for example, neoplastic lesions of the respiratory tract, of the urinary system, of the gastrointestinal tract of the anogenital tract, neoplastic disorders associated with HPV infection and others. They may be cancers of the respiratory tract, the urinary system, the reproductive tract or anogenital cancers, HPV associated cancers and particularly the cervical cancer. In connection with the latter, its precursor stages, e.g. cervical intraepithelial neoplasias (CINI-III), carcinomas in situ (CIS), etc., have to be mentioned particularly. The term “precursor stages” in all it's grammatical forms as used herein comprises all precursor stages and precursors of cancers or any other malignancies. With respect to cervical cancer precursor or preliminary stages as used herein may e.g. refer to stages of cervical intraepithelial neoplasias as identified by appropriate classification systems such as e.g. the CIN classification (CIN I-CIN III) the PAP classification (PAP I-PAP V) or the Bethesda Classification (NILM, LSIL, HSIL). With respect to cancers of the respiratory tract cancers may comprise any malignant condition of the respiratory tract such as, e.g., cancer of the lung, the alveoles, the bronchioles, the bronchial tree and the broncus, the nasopharyngeal space, the oral cavity, the pharynx, the nasal cavity and the paranasal sinus. Lung cancer such as small cell lung cancer, non-small cell lung cancer, squamous cell lung carcinoma, small cell lung carcinoma, adenocarcinoma of the lung, large cell lung carcinoma, adeno-squamous lung carcinoma, carcinoid tumor of the lung, broncheal gland tumor or (malignant) mesothelioma. An overview over tumors of the respiratory tract may be found in Colby TV, et al.: Tumors of the Lower RespiratoryTract, Atlas of Tumor Pathology, Third Series, Fascicle 13, AFIP: Washington 1995,” which shall be incorporated herein by reference. Tumors of the urinary system may comprise bladder cancer, cancer of the kidney, renal pelvis, cancer of the ureters and cancer of the urethra, etc. Tumors of the reproductive system may comprise cancer and precursory stages thereof of the ovary, the uterus, the testis, the prostate, the epididymis, etc. In certain embodiments of the invention neoplastic disorder shall refer generally to HPV associated neoplastic disorders. The invention in this respect is applicable to neoplastic disorders associated with HPV and especially high risk HPV types and mucosal HPV types. The high risk HPV may comprise HPV subtypes such as e.g. HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56 and 58. Markers for HPV infection may e.g. comprise HPV expression products of HPV genes L1, L2, E2, E4, E5, E6 or E7. The expression “body sample” comprises any body samples of any kind and nature. Examples of such body samples are secretions, swabs, lavages, body fluids, semen, cell- and tissue-samples, blood, smears, sputum, urine, stool, liquor cerebrospinalis , bile, gastrointestinal secretions, lymph, bone marrow, aspirates and biopsies of organs such as needle or punch biopsies and (fine)-needle aspirates. In particular, smears, swabs and biopsies are indicated when the detection of anogenital cancers, e.g. cervical cancers, is concerned. The term biopsies as used throughout this text shall comprise all kind of biopsies known to those of skill in the art. Thus biopsies as used in the context of the present invention may comprise e.g. resection samples of tumors, tissue samples prepared by endoscopic means or punch-or needle-biopsies of organs. Biopsies comprises specimens obtained by several different methods such as cold knife biopsies, LEEP (loop electrocautery excisional procedure) biopsies, etc. Body samples as used in the context of the present invention may comprise fixed or preserved cell or tissue samples. Cell or tissue samples may e.g. be preserved in a standard sample collection, storage or transportation medium, known to those of skill in the art such as e.g. commercially available preservation media (formalin solution, Cytyc “PreservCyt” or “CytoLyt”, Digene “Universal Collection Medium”, Tripath Imaging “Cytoricho”, etc.). In one embodiment of the invention the cell or tissue samples provided in standard sample collection media are liquid based cytology samples (LBC samples) which are prepared according to or analogous to the methods employed for cytological LBC methods known to those of skill in the art. Suitable cell preservation media may contain a mixture of one or more selected from a group comprising alcohols, aldehydes, ketones, acids, metal-ions or sublimates, ethers etc. for preservation of cellular components. Alcohols include methanol, ethanol, (n- or i-) propanol, (n-, i- or t-) butanol or higher branched or unbranched alcohols. Aldehydes include formaldehyde, acetaldehyde, glutaraldehyde, etc. Ketones such as Acetone may be used. Acids for use in standard sample media include organic acids (acetic acid, trichloro-acetic acid, salicylic acid, picric acid) or inorganic acids such as e.g. chromic acid. Standard sample solutions may comprise metals such as silver, copper, chromium, mercury, osmium, uranium. Solutions of salts such as uranyl-acetate, potassiumbichromate, ammonium sulfate, etc. may be components of preservative media. Cells preserved in suitable media (alcohols etc.) or fixed tissue samples may be used as raw samples in the methods according to the present invention. In one embodiment, the body sample may e.g. comprise a sputum sample, a cervical swab, an oral swab, an urethral swab or the like that has been transferred to a preservative medium containing alcohol. Furthermore, body samples that have been subjected to cell lysing conditions immediately after obtaining the samples may be used in the methods disclosed herein. Inventors have found a number of robust, fast and easy ways to preserve molecular properties of samples, in which the morphological information of samples is lost. Samples may be e.g. prepared in a reproducible and easy to store and to transport form by solubilizing the cellular components of the raw sample in a suitable lysis medium immediately after or even during obtaining the sample. Body fluids may directly be transferred from the body of an individual to a medium containing suitable detergents and preservative substances. Furthermore, tissue samples may immediately be transferred to denaturing lysis conditions (eventually supported by physical forces) and be thus preserved. Using appropriate ingredients in the lysis medium, the molecular components of the original sample may be preserved, and no degradation may occur. The degradation by enzymatic activities may for example be minimized by the use of enzyme inhibitors. Thus, a solution of test samples in said lysis medium may represent the molecular properties of a test sample at the time of solubilization. According to the present invention, the body samples may be solubilized in any suitable lysis medium. Such lysis media may far example be aqueous solutions of chaotropic agents such as e.g. urea, GuaSCN, Formamid, of detergents such as anionic detergents (e.g. SDS, N-lauryl sarcosine, sodium deoxycholate, alkyl-aryl sulphonates, long chain (fatty) alcohol sulphates, olefine sulphates and sulphonates, alpha olefine sulphates and sulphonates, sulphated monoglycerides, sulphated ethers, sulphosuccinates, alkane sulphonates, phosphate esters, alkyl isothionates, sucrose esters), cationic detergents (e.g. cetyl trimethylammonium chloride), non-ionic detergents (e.g. Tween 20, Nonidet P40, Triton X-100, NP40, Igepal CA-630, N-Octyl-Glucosid) or amphoteric detergents (e.g CHAPS, 3-Dodecyl -dimethylammonio-propane-1-sultanate, Lauryidimethylamine oxide) and/or of alkali hydroxides such as e.g. NaOH or KOH. Generally any suitable liquid may be used as a solvent in the lysis medium of the present invention. The liquid may be organic or inorganic and may be a pure liquid, a mixture of liquids or a solution of substances in the liquid and may contain additional substances to enhance the properties of the solvent. In certain embodiments, where lysis of cells may be achieved without the use of detergents, hyper- or hypotonic solutions or buffers or simply water or an organic liquid may be used as solvent. Any liquid, that is suited to solubilize the cellular components of body samples in total or in parts may be regarded as a lysis medium as used herein. Thus lysis media as used herein need not contain buffer substances or have buffer capacity. However in certain embodiments of the invention the lysis media may have buffer capacity and may contain buffer substances. In one embodiment, the lysis medium is designed, so that cells, cell debris, nucleic acids, polypeptides, lipids and other biomolecules potentially present in the raw sample are solubilized. In further embodiments of the present invention, the solvent may be designed to assure differential solubilization of specific components of the body sample, leaving other components unsolubilized. The lysis medium for solubilizing the body sample according to the present invention may furthermore comprise one or more agents that prevent the degradation of components within the raw samples. Such components may for example comprise enzyme inhibitors such as proteinase inhibitors, RNAse inhibitors, DNAse inhibitors, etc. In one embodiment of the present invention, the sample is lysed directly in the form obtained from test-individuals. Proteinase inhibitors may e.g. comprise inhibitors of serine proteinases, inhibitors of cysteine proteinases, inhibitors of aspartic proteinases, inhibitors of metally proteinases, inhibitors of acidic proteinases, inhibitors of alkaline proteinases or inhibitors of neutral proteinases. In certain embodiments of the present invention the inhibition of enzymes may be achieved by chemical means such as e.g. denaturation of the enzymes by means of salt concentration, pH, chaotropic agents or the like. In another embodiment of the present invention the body sample may be further purified before being lysed. Such purification procedures may for example comprise washing away of contaminants such as mucus or the like, separation or concentration of cellular components, preserving and transporting of the cells. In one embodiment for example the cells may be separated by means of flow cytometry or other suitable forms of cell sorting known to those of skill in the art. Thus the cellular components of the raw samples are included in a single sample solution. The preparation of a sample for use in a method as disclosed herein may also comprise several steps of further preparations of the sample, such as separation of insoluble components, isolation of polypeptides or nucleic acids, preparation of solid phase fixed peptides or nucleic acids or preparation of beads, membranes or slides to which the molecules to be determined are coupled covalently or non-covalently. The expression “determining the overexpression of cyclin-dependent kinase inhibitors proteins” comprises any methods which are suited for detecting the expression of cyclin-dependent kinase inhibitor proteins or their encoding mRNAs and an amplification of the corresponding genes, respectively. In order to determine an overexpression, the body sample to be examined may be compared with a corresponding body sample which originates from a healthy person or from a non-diseased region of the respective organ. Such a sample can be present in a standardized form. The comparison with normal healthy body samples may be achieved by different methods. In one embodiment of the present invention, the comparison may be performed directly by including a control reaction with non-diseased tissue or cell sample. This non-diseased tissue or cell samples may be provided from a healthy person or from non-diseased regions of the human subject under examination or from cell culture cells known to show the properties of non-diseased cells with respect to cyclin-dependent kinase inhibitor expression. In another embodiment, the comparison may be performed indirectly by comparing the level of cyclin-dependent kinase inhibitor within the sample under investigation to a level of said cyclin-dependent kinase inhibitor known to be present in normal healthy samples. The knowledge about the level for normal healthy issue or cell samples may be derived from a representative number of testings or from scientific publications providing information the expression level of said cyclin-dependent kinase inhibitor in normal healthy cells. Comparison may be performed by employing a value for the concentration of the cyclin-dependent kinase inhibitors protein or nucleic acids; otherwise a characteristic value depending on the protein or nucleic acid concentration such as the optical density under defined reaction conditions may be employed. Otherwise the known value may be represented by a surrogate control such as a peptide or a recombinant protein. Thus the level of p16INK4a present in normal healthy samples may be represented by a control sample of a recombinant protein or a peptide in the testing procedure. Generally, the comparison of the level present in the sample under investigation may be performed with respect to a value determined in each single testing procedure or to a predetermined value. The predetermined value may be determined for the testing procedure globally. Otherwise, the value may be valid only for a certain lot of testing reagents. For example, the reference value may be valid for a defined calibration period only and may be defined upon calibration of the testing process. For example the level of cyclin-dependent kinase inhibitor in a healthy human cervical sample can be determined from a standardized sample solution. A standardized sample solution may comprise a solution of a solubilized pool of normal cell or normal tissue samples. The sample pool may, e.g., be a pool of cytological specimens with pre-assessed normal diagnosis from a screening population, or a pool of normal cells obtained from histological specimens. Furthermore, a pool of normal cells may be obtained from tissue culture of normal cervical epithelial cells. The sample solution may, e.g., be standardized with respect to the content of cells per ml sample solution. Any other parameter for standardization may be applied. The sample solution may e.g. be provided in a standardized form to ensure stability and reproducibility of the test results. In certain embodiments such solution may be provided as a component of the kit for comparison or calibration purposes. In certain embodiments, the step of comparing the level of cyclin-dependent kinase inhibitors present in a patient sample to a level known to be present in a normal healthy body sample is embodied as employing a cut-off value or threshold value for the concentration of the respective cyclin-dependent kinase inhibitor. The cut-off in this context is a value (for example a concentration of p16INK4a protein given in e.g. mg/ml or an optical density measured under defined conditions in an ELISA test) which is suited to separate normal healthy samples from diseased samples. e.g. all samples giving values above the cut-off value are considered to be dysplastic, whereas the samples giving values below the cut-off value are considered to be healthy. In certain embodiments, the threshold or cut-off may be set in a way to separate high grade neoplastic disorders (HSIL or neoplastic disorders corresponding e.g. to invasive carcinoma, high grade dysplasia or histologically assessed CIN 3 lesions) from all less severe stages of neoplastic disorders (e.g. LSIL). In other embodiments, the cut-off may be defined to differentiate healthy samples (NILM) from neoplastic disorders including precursory stages (LSIL and HSIL). It is thus possible to tailor the testing format in order to fit different tasks such as early detection of lesions and even precursors of the lesions or detection of lesions that deserve immediate therapy. The (over) expression of cyclin-dependent kinase inhibitors can be detected on a nucleic acid level and protein level, respectively. Regarding the detection on a protein level: it is possible to use e.g. antibodies which are directed against cyclin-dependent kinase inhibitors. These antibodies can be used in the most varying methods such as Western blot, ELISA or immunoprecipitation. It may be favorable for the antibodies to be fixed on solid carriers such as ELISA plates, reaction vessels, beads, spheres, membranes, colloids such as colloidal metals (e.g. gold), porous members, surfaces of capillaries (e.g. in flow through test), test strips or latex particles. Regarding detection on the nudeic acid level methods such as nucleic acid amplification techniques or hybridization techniques may be applied. Nucleic acid amplification techniques comprise all kinds of single step or multistep reactions such as chain reactions. Chain reactions comprise but are not limited to PCR, NASBA, RT PCR, LCR etc. Hybridization reactions comprise any hybridization reactions with any kind of reporter system. Hybrid capture reactions with subsequent detection of hybrid nucleic acids by means of antibodies, directed against said hybrids. Examples for application of hybridization reactions for detection of expression on the level of RNA transcripts such as e.g. RNA in-situ hybridization reactions. In certain embodiments of the present invention, the detection of the marker molecules is performed from a solution of solubilized body samples. Therefore detection may be carried out in solution or using reagents fixed to a solid phase. A solid phase as used in the context of the present invention may comprise various embodiments of solid substances such as planar surfaces, particles including micro-, nano-particles or even smaller particles). In certain embodiments, particles may be provided as spheres, beads, colloids, or the like. The fixation of reagents to the solid phase in a test kit or an in-vitro diagnostic device may be carried out via direct fixation or via indirect fixation. Direct fixation may be carried out by covalent binding, non-covalent binding, association, or adsorption to surfaces. Indirect fixation may be carried out through binding of the antibody to agents which themselves are directly fixed to solid phases. Binding agents, for example, include avidin, streptavidin, biotin, digioxingenin, antibodies or the like. The detection of one or more molecular markers may be performed in a single reaction mixture or in two or more separate reaction mixtures. The detection reactions for several marker molecules may for example be performed simultaneously in multi-well reaction vessels. The detection reaction for marker molecules may comprise one or more further reactions with detecting agents either recognizing the initial marker molecules or preferably recognizing the prior molecules (e.g. primary antibodies) used to recognize the initial markers. The detection reaction further may comprise a reporter reaction indicating the level of the markers characteristic for cell proliferative disorders or the normalization markers. The detection reaction for detecting the level of cyclin-dependent kinase inhibitor in solubilized samples may be carried out in solution or with reagents fixed to solid phases. In certain embodiments, the detection reaction may be carried out in solution; such procedures may comprise any methods suited for the detection of molecular interactions (binding of an antibody or similar binding agent to an antigen) in solution. The methods for determination of molecular interaction (change in conductivity, mass changes, light-, UV-, IR-, magnetic spectrometric changes, plasmon resonance, etc.) are known to those of skill in the art. In certain embodiments the detection may comprise a method where a complex of detection reagent bound to antigen is adsorbed to a solid phase for detection purpose. Thus, non-covalent bonding of the analytes to solid phases in the course of the detection reaction or even before starting the detection reaction may be used in a method according to the present invention. A probe for the detection of the marker molecules may be any molecule, that specifically binds to said marker molecules. The probe may for example be an antigen binding agent such as antibodies (monoclonal or polyclonal), antibody fragments or artificial molecules comprising antigen binding epitopes, DNA or RNA binding molecules such as proteins or nucleic acids. Nucleic acids binding to other nucleic acids may for example be oligonucleotides for detection purposes or primers. In certain embodiments even larger nucleotide molecules may be applied for hybridization reactions. A molecule is said to recognize another molecule if it specifically interacts with that molecule. Specific interaction may for example be specific binding to or of the other molecule. The term “antibody” in all its grammatical forms shall in the context of the present invention refer generally to antigen binding molecules including but not limited to monoclonal and polyclonal antibodies, fragments of antibodies, antigen binding epitopes, mini-antibodies, peptidomimetics with antigen-binding properties, anticalines and diabodies. The reporter reaction may be any event producing a signal in response to the presence of the marker or to the binding of a specific probe to the marker. For example, a reaction producing a colored compound, a fluorescent compound, a light emitting compound, a radiation emitting compound, or the concentration of one or more of these compounds to a detectable concentration in a predefined area of a testing device may serve as reporter reaction. Applicable formats for the detection reaction according to the present invention may be blotting techniques, such as Western-Blot, Southern-blot, Northern-blot. The bloffing techniques are known to those of ordinary skill in the art and may be performed for example as electro-blots, semidry-blots, vacuum-blots or dot-blots. Furthermore immunological methods for detection of molecules may be applied, such as for example immunoprecipitation or immunological assays, such as EIA, ELISA, RIA, FIA (fluorescent immunoassay) lateral flow assays (using porous members or capillaries), immunochromatographic strips, flow through assays, latex agglutination assays etc. Immunoassays for use in the invention may comprise competitive as well as non-competitive immunoassays, such as sandwich assays. In nucleic acid based approaches hybridization or amplification techniques may be applied. Hybridization techniques may e.g. comprise any hybridization technique known to those of skill in the art. In certain embodiment the hybridization may be carried out as a hybrid capture assay employing antibodies directed against DNA-RNA hybrid molecules for detection. Amplification reaction may be applied as PCR, NASBA, RT-PCR, LCR or other suitable chain reactions. Otherwise even single step or sequential reactions not being chain reaction may be applied for nucleic acid amplification. In certain embodiments of the invention, immunochemical or nucleic acid based testing may be performed using a testing device for clinical laboratories. Such testing device may comprise any device suitable for immunochemical or nucleic acid based testing including any format such as point of care testing devices as well as bench top or laboratory devices. The devices may be e.g. provided as open or closed platform systems. The system may be based on any suitable methodology such as microtiter plates, multiwell plates, flow through or lateral flow systems, microchip or array based systems or bead or membrane based systems. The detection methods employed may comprise any methods known to those of skill in the art useful for immunochemical or nucleic acids based detection reactions. Such detection systems may be e.g. luminescence systems (electroluminescence, bioluminescence, photoluminescence, radioluminescence, chemiluminescence, electrochemoluminescence), fluorescence based systems, conductivity based detection systems, radiation (light, UV, X-ray, gamma etc.), plasmon resonance (e.g. Surface Plasmon Resonance SPR) or any other known method. The term porous member as used herein shall generally apply to any three dimensional arrangements of porous substances. Such porous member may e.g. comprise compounds as membranes, beads or other. By means of the present invention it is possible to diagnose cancers early, i.e. in their precursor stages. A further subject matter of the present invention relates to a kit for carrying out a method according to the invention. Such a kit comprises e.g.: (a) a reagent for detecting the expression of a cyclin-dependent kinase inhibitor, e.g. a probe directed against a cyclin-dependent kinase inhibitor protein or nucleic acid and parts thereof, respectively, (b) a lysis medium for solubilization of a body sample, (c) conventional auxiliary agents, such as buffers, carriers, markers, etc., and optionally (d) an agent for control reactions, e.g. a cyclin-dependent kinase inhibitor protein or nucleic acid and parts thereof, respectively, or a preparation of cells. Furthermore, one or several of the individual components may be present For example, the detection reagent and other reagents fixed to a solid phase may be present. In one embodiment of the present invention the kit comprises a reagent for detection of p16INK4a fixed to solid phases and no detection reagents of other specificities fixed to solid phases. In certain embodiments of the invention the kits for detection of cyclin-dependent kinase inhibitors are provided as in-vitro diagnostic devices. Generally, the lysis medium included in a kit according to the present invention may be any suitable solvent known to those of skill in the art. The lysis medium for use in the kit may, for example, be organic or aqueous solutions of chaotropic agents such as e.g. urea, GuaSCN, Formamid, of detergents such as anionic detergents (e.g. SDS, N-lauryl sarcosine, sodium deoxycholate, alkyl-aryl sulphonates, long chain (fatty) alcohol sulphates, olefine sulphates and sulphonates, alpha olefine sulphates and sulphonates, sulphated monoglycerides, sulphated ethers, sulphosuccinates, alkane sulphonates, phosphate esters, alkyl isethionates, sucrose esters), cationic detergents (e.g. cetyl trimethylammonium chloride), non-ionic detergents (e.g. Tween 20, Nonidet P40, Triton X-100, NP40, Igepal CA-630, N-Octyl-Glucosid) or amphoteric detergents (e.g CHAPS, 3-Dodecyl-dimethylammonio-propane-1-sulfonate, Lauryldimethylamine oxide) and/or of alkali hydroxides such as e.g. NaOH or KOH. In certain embodiments, where lysis of cells may be achieved without the use of detergents, hyper- or hypotonic solutions or buffers or simply water or an organic liquid may be used as solvent. Any liquid, that is suited to solubilize the cellular components of body samples in total or in parts may be regarded as a lysis medium as used herein. Thus lysis mediums as used herein need not contain buffer substances or have buffer capacity. In certain embodiments of the invention in order to obtain optimal results of the assay, the pH of a lysis medium that can be directly applied to the assay system is around neutral. In further embodiments the pH of the lysis medium is within the range of 4 to 10. In certain other embodiments, the pH is in a range from 5 to 9. In a preferred embodiment, the pH is in a range from 6 to 8. In a more preferred embodiment, the pH is in the range from 6.5 to 7.5. Examples of lysis media may for example be selected from the compositions given in Table 1. TABLE 1 solubilization of p16INK4a in compatibility Lysis medium Western blot with Elisa Detergents: 0.1-1% SDS + +/− 0.2-3% SDS + <0.5% 0.2-3% DOC ++ +/− 0.1-1% n-Octylglycoside + yes 0.1-3% Triton x-100% + yes 0.1-1% Chaps + nd Detergent-Mix: RIPA (1% NP40, 0.5% DOC, ++ yes 0.1% SDS, PBS) 40-100% SOX (0.5% DOC, 0.5% + yes n-Octylglycoside) 40-100% mtm lysis medium (3% ++ yes Tritonx-100, 0.4% SDS, PBS) Commerical lysis media: Dynal (Dynal, Oslo, ++ yes Norway) M-PER/B-PER (Pierce, ++ yes Rockford, IL) Miscellaneous: 0.5-8 M urea in PBS +++ Compatible <2 M Lämmli sample buffer +++ no 10-80% DMSO +++ no 10-80% Formamide nd no 50-70% formic acid ++ no PBS +/− yes Citrate buffer pH 6.0 +/− yes 500 mM NaCl in +/− yes Phosphate buffer nd: not determined; +/−: poor; +: good; ++: very good; +++: excellent; In certain situations, the cyclin-dependent kinase inhibitor p16INK4a can be degraded in the solubilized samples and may thus not be detected. This is particularly true, if the samples are directly transferred to a lysing medium and stored therein for a certain period of time. To prevent degradation, lysis medium may furthermore comprise one or more agents that prevent the degradation of components within the raw samples. Such components may for example comprise enzyme inhibitors such as proteinase inhibitors, RNAse inhibitors, DNAse inhibitors, etc. The inhibitors may e.g. comprise proteinase inhibitors selected from the compositions given in Table 2. TABLE 2 p16INK4a class of inhibited Solubility in stability in stabilization in mtm Inhibitor proteinase concentration water water Lysis medium Aprotinin Serine 0.6-2 μg/ml Very good good no Benzamidine Serine 0.5-4 mM good good no Bestatin Aminopeptidases 1-10 μM good good no Calpeptin Cysteine 0.3-1 μM good good no Cystatin Cysteine 1 μM good good no E-64 Cysteine 1-10 μM good good no EDTA Metallo 0.5-5 mM good good no Elastatinal Serine 0.5-2 μg/ml poor good no EST Cysteine 20-50 μg/ml bad poor no Fetal calf serum all classes 10% good good yes Leupeptin Serine/Cysteine 10-100 μM good good no a2-Macroglobulin all classes 1 μM good good no NCO-700 Cysteine 0.5-100 mM poor poor no Pefabloc = AEBSF Serine 0.2-10 μM good very poor yes Pepstatin A Aspartic 1 μM bad poor no PMSF Serine 0.2-10 μM bad very poor yes o-Phenanthroline Metallo 1-10 mM bad poor no DNase and RNase inhibitors are known to those of skill in the art and may be applied under suitable condition for use in a lysis medium according to the present invention. For stabilization purpose, the lysis medium may also comprise bulk protein (e.g. albumin such as bovine serum albumin or calf serum albumin or other bulk proteins) to compete in degradation with the sample proteins. The bulk proteins may e.g. be present in combination with proteinase inhibitors or may be added instead of proteinase inhibitors. In one embodiment, the solvent may be selected to be compatible with the assay (e.g. ELISA) performance, so that solubilized samples may directly be applied to the assay. In some embodiments of the present invention, the lysis medium may be tailored in order to enable for the setting of a specific cut-off value. In certain embodiments of the invention the kit may be provided as in-vitro diagnostic device. An in-vitro diagnostic device is a kit as defined above, that is intended for assessment of diagnosis of a medically relevant condition from human or animal body samples. In certain embodiments of the invention an in-vitro diagnostic device shall be any device that falls in the scope of the definition of in-vitro diagnostic medical device as given in the directive 98/79 EC under Article 1 (b): ‘in vitro diagnostic medical device’ means any medical device which Is a reagent product, calibrator, control material, kit, instrument, apparatus, equipment, or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information conceding a physiological or pathological slate; or concerning a congenital abnormally; or to determine the safety and compatibility with potential recipients; or to monitor therapeutic measures. In vitro diagnostic device shall also apply to U.S. Class I IVD and generally to in-vitro diagnostic devices that are provided without Claims regarding their diagnostic performance. Therefore also any kind of ASR or the like shall be understood to be an in-vitro diagnostic device as used herein. In one embodiment of the present invention the in-vitro diagnostic device is characterized by solid phase fixed detection reagents specific for a cyclin-dependent kinase inhibitor. In one embodiment, the detection reagents are specific for cyclin-dependent kinase inhibitor p16INK4a. In the art, there are some in-vitro diagnostic devices employing reagents for the detection of cyclin-dependent kinase inhibitor p16INK4a in histological or cytological specimens. These in-vitro diagnostic devices are cell-based detection devices that detect the p16INK4a antigen in cells or tissues, not in solubilized samples. Cyclin dependent kinase inhibitors such as p16INK4a being intracellular antigens, may only be accessible to detection reagents in solution after permeabilization of cells. Thus, the in-vitro diagnostic application of reagents for detection of cyclin-dependent kinase inhibitor p16INK4a known in the art excludes the fixation of the detection reagents to a solid phase. The art have not taught the design of test kits or in-vitro diagnostics containing p16INK4a-fixed solid phase detection reagents. An approach for assessing diagnosis on the basis of solubilized samples seemed not viable from the art and has not been suggested before. It is thus an aspect of the present invention to provide an in-vitro diagnostic device comprising probes directed against cyclin-dependent kinase inhibitors fixed to a solid phase allowing assessment of diagnosis of carcinomas and their precursor lesions in a solubilized sample. In certain embodiments of the present invention, the probes may e.g. comprise nucleic acids, antibodies or fragments thereof directed against p14ARF or p16INK4a protein. It is an advantage of the in-vitro diagnostic devices of the present invention to allow for easy and economic assessment of diagnosis of cancers and their precursor lesions. The test may be suited for screening purposes as well as for diagnostic purposes and may be applied in primary diagnosis as well as in monitoring of disease course. The in-vitro diagnostic devices may in certain embodiments be applicable for use in clinical laboratories, for point of care testing or even for self testing. The in-vitro diagnostic devices comprising solid phase fixed reagents for the detection of cyclin-dependent kinase inhibitors may be useful for the detection of various different cancer-entities and their respective precursor lesions. The in-vitro diagnostic devices may be applied for analysis of any kind of lysed body samples. The probes can be fixed to the solid phase via direct fixation or via indirect fixation. Direct fixation can be done by covalent or non-covalent binding or association to surfaces. Indirect fixation can be done through binding of the antibody to agents which themselves are directly fixed to solid phases. Such agents may comprise antibodies or other binding agents like avidin, streptavidin, biotin, digioxingenin or the like. The in-vitro diagnostic devices envisaged in the invention are selected from the group consisting of a. an ELISA device comprising antibodies directed against cyclin-dependent kinase inhibitor fixed to ELISA plates, ELISA stripes or ELISA wells; b. a lateral flow test device, comprising antibodies directed against cyclin-dependent kinase inhibitor fixed to test strips, colloidal gold particles or latex particles; c. a flow through assay device, comprising antibodies directed against cyclin-dependent kinase inhibitor fixed to a porous member, or to the surface of capillaries; d. a latex agglutination assay device, comprising antibodies directed against cyclin-dependent kinase inhibitor fixed to latex particles; and e. an immunoassay device, comprising antibodies directed against cyclin-dependent kinase inhibitor fixed to beads, membranes, or microspheres. The ELISA devices may be of any kind known to those of skill in the art. These devices comprise devices for sandwich ELISA formats, for competitive ELISA formats and any other ELISA formats. In one embodiment of the present invention the in-vitro diagnostic device comprises a lysis medium for solubilization of the sample. In a further embodiment of the invention the in-vitro diagnostic device comprises reagents for detection of one specific cyclin-dependent kinase inhibitor fixed to solid phases and no detection reagents of other specificities fixed to solid phases. Lateral flow assay devices for use as an in-vitro diagnostic device according to the present invention are any lateral flow assay devices employing at least one reagent binding to cyclin-dependent kinase inhibitors fixed to a solid phase. Such devices may employ various mechanisms for visualization of the test result. In certain embodiments, the tests may employ secondary detection reagents directed against cyclin-dependent kinase inhibitors or another components participating in the test coupled to detectable moieties. The detectable moieties may comprise colloidal gold, (colored) latex particles and others. Flow through assay devices for use in the present invention may comprise devices based on capillaries or on porous members (such as membranes, beads or other three dimensional arrangements of porous substances). Depending on the embodiment the size of pores or capillaries need to adjusted to ensure optimal flow conditions. A further aspect of the present invention is the use of a solid phase to which detection reagents or probes directed against cyclin dependent kinase inhibitors are fixed or adhere for the manufacture of a test kit or of an in-vitro diagnostic device or for the manufacture of a kit according to the present invention. In certain embodiments of the invention the probes are antibodies or fragments thereof. In further embodiments the probes are oligonucleotides. The solid phases that may be used for the manufacture of a test kit or of an in-vitro diagnostic device are described above and comprise any suitable solid phase. In certain embodiments the solid phases are membranes, porous member, planar surfaces, multiwell plates (with planar or non-planar surface), colloids, particles and others. All solid phases to which the probes for detection of cyclin-dependent kinase inhibitors may be fixed, may be used for the manufacture of the kits and in-vitro diagnostic devices according to the present invention. Manufacture of such kit according to the present invention may comprise any action suited to provide a finished in-vitro diagnostic device. These actions comprise all manufacturing activities but also repackaging, assembling of single components, re-labeling etc. It is one aspect of the present invention to provide a method for development of kits and in-vitro diagnostic devices for diagnosis of medically relevant conditions from solubilized body samples, wherein the development is performed using body samples provided as preserved cells in a cell-preservation medium and wherein the preserved cells are intended and prepared for use in cytological examination processes such as Liquid Based Cytology processes. The samples intended for Liquid Based Cytology processes (in the following denominated as LBC samples) are solubilized in an appropriate lysis medium and are used for development activities of kits and in-vitro diagnostic devices for detection of medically relevant conditions from solubilized body samples on the basis of biochemical non-cell-based analysis. According to the present invention the use of LBC samples for the assessment of diagnosis or for development of kits and in-vitro diagnostic devices may for example provide an accurate and comparable way to provide cytological information for the biochemical non-cell based testing. This may be achieved by employment of normalization of the sample with respect to information obtainable from a cytological specimen prepared out of the same LBC sample. Biochemical normalizaton with respect to markers indicative for the presence or absence of cells or cell types is omissible in such methods. The advantage of using LBC samples in this respect is that the cytologically cell based information is direct related to the homogeineuus LBC specimen and thus provides valuable accurate information for use in the evaluation of the biochemical non-cell based test results. In the art the filed of application of LBC samples is to enable for improved morphological evaluation of cytology specimens. The field of application of the LBC samples is therefore classically indicated only for cytology. According to the present invention the use of LBC samples as a source for biochemical non-cell based determination of protein levels in solubilized specimens provides the opportunity that the results of the biochemical non-cell based testing may be directly compared to a cytological specimen. The protein based biochemical analysis in this respect may serve as a e.g. pre-testing or to provide further information or even to confirm a cytologically equivocal result In further embodiments the information obtained from the biochemical non-cell based testing may be for the design of the cytological procedures to be applied. One advantage of such method for development of products is that the same specimen on which the diagnosis for an individual is assessed may be used for assessment of the biochemically based result. Thus comparability of the biochemical result to the diagnosis is ensured. LBC samples as used in the context of the present invention are any cell samples that are preserved in a standard sample collection, storage or transportation medium, known to those of skill in the art such as e.g. commercially available preservation media (formalin solution, Cytyc “PreservCyt” or “CytoLyt”, Digene “Universal Collection Medium”, Tripath Imaging “Cytorich”, etc.). LBC samples accordingly comprise cell samples in any suitable cell preservation medium that may contain a mixture of one or more selected from a group comprising alcohols, aldehydes, ketones, acids, metal-ions or sublimates, ethers etc. for preservation of cellular components. Alcohols include methanol, ethanol, (n- or i-) propanol, (n-, i- or t-) butanol or higher branched or unbranched alcohols. Aldehydes include formaldehyde, acetaldehyde, glutaraldehyde, etc. Ketones such as Acetone may be used. Acids for use in standard sample media include organic acids (acetic acid, trichloro-acetic acid, salicylic acid, picric acid) or inorganic acids such as e.g. chromic acid. Standard sample solutions may comprise metals such as silver, copper, chromium, mercury, osmium, uranium. Solutions of salts such as uranyl-acetate, potassiumbichromate, ammonium sulfate, etc. may be components of preservative media. LBC samples may be samples of any kind of cells taken for various diagnostic purposes. Currently LBC samples with respect to diagnostics in human healthcare are prepared from any body regions where cytological and/or microbiological testing procedures are indicated or seem to be reasonable. It is believed that for a variety of cytologic specimens LBC samples provide a way that minimizes cell loss and preserves morphologic detail. LBC samples according to the present invention therefore comprise samples obtained as Fine Needle Aspirates. Fine Needle Aspirates may comprise specimens from various sources such as e.g. from breast, thyroid (e.g. from nodules), kidneys, pancreas, prostate, lung, lymph nodes, pleura, neck masses, ovaries, synovia, tumor masses etc. LBC samples may furthermore be prepared using body fluids. Suitable body fluids comprise a large range of fluids obtainable from the human or animal body comprising but not limited to e.g. ascites, liquor cerebrospinalis, pus or effusions. Effusions wherever in the body they appear may be subjected to LBC. Some examples for effusions are pericardial, pleural, synovial and abdominal effusions. Body fluids to which LBC may be applied comprise further more e.g. the fluids present in some tumors or cysts such as e.g. breast cysts, ovary cysts or others. Samples obtainable in liquid form from the body comprise furthermore mucous specimens such as e.g. sputum. LBC is widely applied to any kind of exfoliative cytological specimen. Such exfoliative cytological specimens are obtainable by various methods such as e.g. by any by kind of swab, brushing, scrape, smear etc. Also specimens such as washes, lavages etc. from any body region shall be understood to be exfoliative cytological specimens. Washes and lavages may be obtained from a wide range of body regions including but not limited to mucosal epthelia, the skin, any inner or outer body epithelium or the like. Mucocal epithelia may be e.g. those epithelia of the gastrointestinal tract, of the urinary system, of the anogenital tract, of the respiratory tract, of the rectum, the urethra, the cervix, the vagina, the vulva the oral cavity, the endometrial cavity etc. The whole range of exfoliative cytological specimens may be subjected for LBC methods. Kits as used in the context of the present invention are compositions of components provided for performance of an analytical testing procedure. The kit may comprise all or some of the reagents and materials necessary for proper performance of the test. Furthermore the kit may in certain embodiments of the invention comprise instructions for an appropriate application of the kit components including e.g. an exemplary testing protocol, warnings and hazard information and further accessory information for the user of the kit. An in-vitro diagnostic device is a kit as defined above, that is intended for assessment of diagnosis of a medically relevant condition from human or animal body samples. In certain embodiments of the invention an in-viro diagnostic device shall be any device that falls in the scope of the definition of in-vitro diagnostic medical device as given in the directive 98/79 EC under Article 1 (b): ‘In vitro diagnostic medical device’ means any medical device which is a reagent product, calibrator, control material, kit, instrument, apparatus, equipment or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information concerning a physiological or pathological state; or concerning a congenital abnormality; or to determine the safety and compatibility with potential recipients; or to monitor therapeutic measures. In vitro diagnostic device shall also apply to U.S. Class I IVD and generally to in-vitro diagnostic devices that are provided without Claims regarding their diagnostic performance. Therefore also any kind of ASR or the like shall be understood to be an in-vitro diagnostic device as used herein. In certain embodiments of the present invention the test kits and in-vitro diagnostic devices to which the methods for development disclosed herein apply are test kits and in-vitro diagnostic devices for protein or peptide based detection of molecular markers. The testing procedures for which the kits and in-vitro diagnostic devices under development shall be applied according to the present invention include detecting the levels of marker molecules characteristic for medically relevant conditions in the test sample on the basis of biochemical non-cell-based analysis. The markers suitable for these testing procedures according to the present invention may be of various origin. The expression pattern of a marker, that is suitable for the detection of medically relevant conditions in question, may be dependent on the proliferative status of cells, on the differentiation status, on the cell type or on the organism. Examples for appropriate markers are set forth below. The term diagnosis as used with respect to the kits and in-vitro diagnostic devices under development herein generally comprises any kind of assessment of the presence of absence of a medically relevant condition. Diagnosis thus comprises processes such as screening for the predisposition for a medically relevant condition, screening for the precursor of a medically relevant condition, screening for a medically relevant condition, clinical or pathological diagnosis of a medically relevant condition, etc. Diagnosis or assessment of diagnosis as used herein may furthermore comprise assessment of prognosis or provision of information for stratification of patient therapy on the basis of the biochemical non-cell based testing. Diagnosis of medically relevant conditions as used herein may comprise examination of any condition, that is detectable on a cytological, histological, biochemical or molecular biological level, that may be useful in respect to the human health and/or body. Such examinations may comprise e.g. medically diagnostic methods and research studies in life sciences. In one embodiment of the invention, the method is used for diagnosis of medically relevant conditions such as e.g. diseases. Such diseases may for example comprise disorders characterized by non-wild type proliferation of cells or tissues. In one embodiment, the diagnosis pertains to diagnosis of neoplastic disorders and their precursor stages, to monitoring of the disease course in neoplastic disorders, to assessment of prognosis of neoplastic disorders and to detection of disseminated tumor cells e.g. in the course of minimal residual disease diagnosis. The method according to the present invention may for example be used in the course of clinical or pathological diagnosis of cancers and their precursor stages or in routine screening tests as performed for particular neoplastic disorders such as for example for examination of swabs e.g. in screening tests for cervical lesions, of bronchial lavages for lung cancer or of stool for lesions of the gastrointestinal tract, e.g. colorectal lesions. The method of development of kits and in-vitro diagnostic devices according to the present invention is applicable to kits and in-vitro diagnostic devices for the detection and diagnosis of all kinds of medically relevant conditions. Medically relevant conditions as used according to the present invention may for example be compositions of tissues, body fluids, secretions, washes or swabs. Such conditions may for example comprise the cellular composition of body fluids, such as the composition of blood, the composition of liquor cerebrospinalis or the composition of semen. In this context the compositions shall be for example the presence or absence of particular cell types (e.g. pathogens, such as, ,viruses etc., preneoplastic, neoplastic and/or dysplastic cells etc.), the presence or absence of differentiation patterns of particular cell types, the total number of a particular cell types (e.g. erythrocytes, leucocytes, sperm, etc.), the total number of all cells of any cell types or the fraction of cells of particular other characteristics present or absent in the sample. Furthermore, medically relevant conditions may also comprise disorders related to cells, or tissues. The conditions to be diagnosed may comprise parameters related to cells in cytological or histological tissue samples. The conditions may comprise a differentiation pattern of cells in a Ussue sample, such as surgical resection samples, biopsies, swabs, lavages etc. Such conditions may comprise e.g. congenital disorders, inflammatory disorders, mechanical disorders, traumatic disorders, vascular disorders, degenerative disorders, growth disorders, benign neoplasms, malignant neoplasms. Another aspect of the conditions according to the present invention may comprise conditions characterized by the presence or absence of proliferative characteristics. Conditions characterized by the presence or absence of proliferative characteristics may be for example cell proliferative disorders. Cell proliferative disorders according to the present invention comprise diseases characterized by abnormal growth properties of cells or tissues compared to the growth properties of normal control cells or tissues. The growth of the cells or tissues may be for example abnormally accelerated, decelerated or may be regulated abnormally. Abnormal regulation as used above may comprise any form of presence or absence of non wild-type responses of the cells or tissues to naturally occurring growth regulating influences. The abnormalities in growth of the cells or tissues may be for example neoplastic or hyperplastic. In one embodiment, the cell proliferative disorders are neoplastic disorders such as tumors. Tumors may comprise tumors of the head and the neck tumors of the respiratory tract, tumors of the anogenital tract, tumors of the gastrointestinal tract, tumors of the urinary system, tumors of the reproductive system, tumors of the endocrine system, tumors of the central and peripheral nervous system, tumors of the skin and its appendages, tumors of the soft tissues and bones, tumors of the lymphopoietic and hematopoietic system, etc. Tumors may comprise for example neoplasms such as benign and malignant tumors, carcinomas, sarcomas, leukemias, lymphomas or dysplasias. In a particular embodiment, the tumor is for example cancer of the head and the neck, cancer of the respiratory tract, cancer of the anogenital tract, cancer of the gastrointestinal tract, cancer of the skin and its appendages, cancer of the central and peripheral nervous system, cancer of the urinary system, cancer of the reproductive system, cancer of the endocrine system, cancer of the soft tissues and bone, cancer of the hematopoietic and lymphopoietic system. Tumors of the anogenital tract may comprise cancer of the perineal and the scrotal skin, cervical cancer, cancer of the vulva, cancer of the vagina, cancer of the penis, cancer of the anus, etc. Cervical cancer may comprise squamous lesions, glandular lesions or other epithelial tumors. Squamous lesions comprise, e.g., cervical intraepithelial neoplasias (mild, moderate and severe dysplasia), carcinoma in-situ, squamous cell carcinoma (e.g., keratinizing, nonkeratinizing, verrucous, warty, papillary, lymphoepithelioma-like). Glandular lesions may comprise atypical hyperplasias, adenocarcinoma in-situ, andenocarcinoma (such as, e.g., mucinous, endometrioid, clear cell, adenoma malignum, papillary, serous or mesonephric adenocarcinoma). Other epithelial tumors may comprise adenosquamous carcinoma, glassy cell carcinoma, adenoid cystic carcinoma, adenoid basal carcinoma, carcinoid tumor, small cell carcinoma and undifferentiated carcinoma. For more detailed information, confer “Kurman, R., Norris, H., et al., Tumors of the Cervix, Vagina, and Vulva, Atlas of Tumor Pathology, 1992, AFIP,” the contents of which shall be incorporated herein by reference. Gastrointestinal tumors may comprise colon cancer, cancer of the colon ascendens, of the colon descendens, of the colon transversum, of the sigmoidum, of the rectum, cancer of the small intestine, cancer of the jejunum, cancer of the duodenum, gastric cancer, oesophageal cancer, liver cancer, cancer of the bile, cancer of the bilary system, pancreatic cancer, etc. A comprehensive overview over gastrointestinal lesions is given in “Hamilton Sr, Aaltonen L A (Eds.): World Health Organization Classification of Tumours, Pathology and Genetics of Tumors of the Digestive System, IARC Press: Lyon 2000,” which shall be incorporated herein by reference. Tumors of the respiratory tract may comprise any malignant condition of the respiratory tract such as, e.g., cancer of the lung, the alveoles, the bronchioles, the bronchial tree and the broncus, the nasopharyngeal space, the oral cavity, the pharynx, the nasal cavity and the paranasal sinus. Lung cancer such as small cell lung cancer, non-small cell lung cancer, squamous cell lung carcinoma, small cell lung carcinoma, adenocarcinoma of the lung, large cell lung carcinoma, adeno-squamous lung carcinoma, carcinoid tumor of the lung, broncheal gland tumor or (malignant) mesothelioma. An overview over tumors of the respiratory tract may be found in Colby TV, et al.: Tumors of the Lower RespiratoryTract, Atlas of Tumor Pathology, Third Series, Fascicle 13, AFIP: Washington 1995,” which shall be incorporated herein by reference. Tumors of the urinary system may comprise bladder cancer, cancer of the kidney, renal pelvis, cancer of the ureters and cancer of the urethra, etc. Tumors of the reproductive system may comprise cancer and precursory stages thereof of the ovary, the uterus, the testis, the prostate, the epididymis, etc. In all cases, the methods for which the kits and in-vitro diagnostic devices under developed by a method according to the present invention also apply to precursor stages of the lesions, tumors or cancers. In one embodiment, the method pertains to the detection of disseminated tumor cells or metastases. In one embodiment of the invention, the cancer is e.g. cervical cancer, colon cancer, gastric cancer, breast cancer, bladder cancer, lung cancer, cancer of the oral cavity etc. Development as used in the context of the present invention shall pertain to all design and development activities performed for enabling a manufacturer for controlled production of a finished kit or in-vitro diagnostic device intended for commercial distribution or sale of said kit or in-vitro diagnostic device. Development of kits and in-vitro diagnostic devices as used in the context of the present invention accordingly shall pertain to all activities in connection with the design and development, design- and development-verification, design- and development-validation, assessment of performance data, assessment of safety and effectiveness data of kits and in-vitro diagnostic devices. In one embodiment development shall pertain to the testing of design- and development-outputs of kits and in-vitro diagnostic devices for suitability regarding the proposed intended use. Intended use in this respect shall be understood as the detection or diagnostic purposes for which the kit or in-vitro diagnostic device shall be applied. The kits and in-vitro diagnostic devices developed according to a method as disclosed herein are characterized in that the detection of the marker molecules characteristic for medically relevant conditions is performed on the basis of biochemical non-cell-based analysis. Biochemical non-cell-based analysis as used in the context of the present invention shall refer to all methods where an analyte or a marker moiecuie is detected in a solution, wherein no information on cellular morphology or on tissue architecture is used for assessment of diagnosis. (Cells and tissue remnants need not necessarily be absent from such solution). Said biochemical non-cell-based analysis is founded on information obtained from the detection of the presence or absence of one or more marker molecules in the solution under investigation or from the detection of the levels of one or more marker molecules in the solution under investigation. In certain embodiments of the present invention the kits and in-vitro diagnostic devices are designed to detect only one single marker molecule. In further embodiments of the present invention the kits and in-vitro diagnostic devices are designed to detect a set of marker molecules. Generally the method of development as disclosed herein may be applied to several types of kit and in-vitro diagnostic devices. Description of different embodiments of kits and in-vitro diagnostic devices is given above. The detection of said marker molecules in the course of a biochemical non-cell-based analysis may be carried out in solution or using reagents fixed to a solid phase. In certain embodiments of the present invention the detection of the marker molecules is performed from a solution of dissolved body samples. Therefore detection may be carried out in solution or using reagents fixed to a solid phase. A solid phase as used in the context of the present invention may comprise various embodiments of solid substances such as planar surfaces, particles (including micro-, nano-parucles or even smaller particles). In certain embodiments particles may be provided as beads, colloids or the like. The fixation of reagents to the solid phase in a test kit or an in-vitro diagnostic device may be effected via direct fixation or via indirect fixation. Direct fixation may e.g. be effected by covalent or non-covalent binding or association to surfaces. Indirect fixation may be effected through binding of the reagents (e.g. antibodies, probes etc.) to agents which themselves are directly fixed to solid phases. Such agents may comprise antibodies or other binding agents like streptavidin, biotin or the like. The detection of one or more molecular markers may be performed in a single reaction mixture or in two or more separate reaction mixtures. The detection reactions for several marker molecules may for example be performed simultaneously in mult-well reaction vessels or as the case may be on one single or two or more separate test strips. The markers characteristic for the cell proliferative disorders may be detected using reagents that specifically recognise these molecules. The detection reaction in case more than one marker are to be detected may comprise one or more further reactions with detecting agents either recognizing the initial marker molecules or preferably recognizing the prior molecules (e.g. primary antibodies) used to recognize the initial markers. The detection reaction further may comprise a reporter reaction indicating the level of the markers characteristic for cell proliferative disorders. Marker molecules as used in the context of the present invention shall all times refer to marker molecules characteristic for medically relevant conditions. The terms “marker molecule” or “marker molecule characteristic for medically relevant conditions” in all their grammatical forms as used in the context of the present invention refers to nucleic acid as well as polypeptide molecules. Such marker molecules thus comprises e.g. RNA (mRNA, hnRNA, etc.), DNA (cDNA, genomic DNA, etc.), proteins, polypeptides, proteoglycans, glycoproteins and the respective fragments of these molecules. A level of a marker molecule as used herein refers to a semiquantitative as well as a quantitative value regarding the amount of the respective marker present in a sample. A quantitative value may e.g. be represented in terms of a concentration. A semiquantitative value may be expressed in terms of a scale of levels e.g. undetectable levels, low levels, intermediate levels, high levels or any other suitable mode. The level of a marker may also be represented in terms of a dependent parameter such as the intensity of a signal generated in an assay format in response to the presence of a marker molecule. A probe for the detection of the marker molecules as used in the context of the present invention shall be any molecule, that specifically binds to said marker molecules. The probe may for example be an antigen binding agent such as antibodies (monoclonal or polyclonal), antibody fragments or artificial molecules comprising antigen binding epitopes, DNA or RNA binding molecules such as proteins or nucleic acids. Nucleic acids binding to other nucleic acids may for example be peptide nucleic acids (PNAs) or oligonucleotides (RNA, DNA, PNA, artificial nucleic acids, etc.) for detection purposes or primers. A molecule is said to recognize another molecule if it specifically interacts with that molecule. Specific interaction may for example be specific binding to or of the other molecule. The reporter reaction may be for example a reaction producing a colored compound. In one embodiment of the present invention the reporter substances correlated to the particular markers develop different colors. In another embodiment, the normalization marker specific reporter may be a molecule quenching the signal produced by the reporter molecule specific for the marker, characteristic for the medically relevant condition, in dependence on the level of the normalization marker present in the sample. In yet another embodiment the reporter reactions may produce fluorescent dyes with differing wavelength characteristics. In a further embodiment of the present invention the reporter reaction may comprise light emitting reactions with different wavelength characteristics for the reporter substances specific for either marker to be detected. In another embodiment of the present invention the reporter reaction may comprise the emission of radioactive radiation and additional methods for visualizing or quantifying the radiation. In one embodiment, the different marker molecules may be recognized by agents, that bear radio-nuclides emitting radiation with different energetic properties, so that the signals referring to marker molecules could be distinguished. Applicable formats for the detection reactions applied in the kits and in-vitro diagnostic devices according to the present invention may be blotting techniques, such as Western-Blot, Southern-blot, Northern-blot. The blotting techniques are known to those of ordinary skill in the art and may be performed for example as electro-blots, semidry-blots, vacuum-blots or dot-blots. Furthermore immunological methods for detection of molecules may be applied, such as for example immunoprecipitation or immunological assays, such as EIA, ELISA, RIA, lateral flow assays, flow through assays, immunochromatographic strips, etc. Immunoassays for use in the invention may comprise competitive as well as non-competitive immunoassays. In certain embodiments of kits and in-vitro diagnostic devices developed according to the method of the present invention immunochemical or nucleic acid based testing may be performed using a testing device for clinical laboratories. Such testing device may comprise any device suitable for immunochemical or nucleic acid based testing including any format such as e.g. Point of care testing devices as well as bench top or laboratory devices. The devices may be e.g. provided as open or closed platform systems. The system may be based on any suitable methodology such as e.g. employing microtiter plates, multiwell plates, flow through or lateral flow systems, microchip or array based systems or bead or membrane based systems. The detection methods employed may comprise any methods known to those of skill in the art useful for immunochemical or nucleic acids based detection reactions. Such detection systems may be e.g. luminescence systems (electroluminescence, bioluminescence, photoluminescence, radioluminescence, chemiluminescence, electrochemoluminescence), fluorescence based systems, conductivity based detection systems, radiation (light, UV, X-ray, gamma etc.) or any other known method. The method for detection of the level of the marker molecules, for which the kits and in-vitro diagnostic devices shall be designed and developed according to the methods disclosed herein, is in one embodiment of the present invention any method, which is suited to detect even very small amounts of specific molecules in biological samples. Furthermore any method for detection of the marker molecules irrespective of the sensitivity may be applied. The detection reaction according to the present invention may comprise for example detection reactions on the level of nucleic acids and/or detection reactions on the level of polypeptides. In one embodiment of the invention, the detection of the marker molecules may comprise the detection of particular splicing variants. In another embodiment of the present invention, the detection method may comprise the detection of modifications of marker molecules such as phosphorylation or glycosylation etc of polypeptides or the methylation of nucleic acid molecules in samples. In certain embodiments of the present invention the detection of the methylation status of nucleic acids of genes such as p16INK4a, p14ARF, TSLC1, Claudin, pRB, Her-2/Neu, p53, p21CIP1/WAF1, p27KIP1 or others may be determined. The presence or absence of hypermethylaton or detection of LOH status on the basis of methylation may be indicative of the presence of a medically relevant condition. In one embodiment of the invention, the kits and in-vitro diagnostic devices are designed in a way that detection of the level of marker molecules is carried out by detection of the level of nucleic acids coding for the marker molecules or fragments thereof present in the sample. The means for detection of nucleic acid molecules are known to those skilled in the art. The procedure for the detection of nucleic acids can for example be carried out by a binding reaction of the molecule to be detected to complementary nucleic acid probes, proteins with binding specificity for the nucleic acids or any other entities specifically recognizing and binding to said nucleic acids. This method can be performed as well in vitro as directly in-situ for example in the course of a detecting staining reaction. Another way of detecting the marker molecules in a sample on the level of nucleic acids performed in the method according to the present invention is an amplification reaction of nucleic acids, which can be carried out in a quantitative manner such as for example the polymerase chain reaction. In one embodiment of the present invention e.g. real time RT PCR may be used to quantify the level of marker RNA in samples of cell proliferative disorders. In another embodiment of the invention, the kits and in-vitro diagnostic devices are designed in a way that the detection of the level of marker molecules is carried out by determining the level of expression of a protein. The determination of the marker molecules on the protein level may for example be carried out in a reaction comprising a binding agent specific for the detection of the marker molecules. These binding agents may comprise for example antibodies and antigen-binding fragments, bifunctional hybrid antibodies, peptidomimetcs containing minimal antigen-binding epitopes etc. The binding agents may be used in many different detection techniques for example in western-blot, ELISA, RIA, EIA, flow through assay, lateral flow assay, latex-agglutination, immunochromatographic strips or immuno-precipitation. Generally binding agent based detection may be carried out as well in vitro as directly in situ for example in the course of an immunocytochemical staining reaction. Any other method suitable for determining the amount of particular polypeptides in solutions of biological samples can be used according to the present invention. Methods for the detection of the modified states of nucleic acid molecules and/or polypeptides are known to those of ordinary skill in the art. Methods for detection of methylaton of nucleic acids are known to those of skill in the art and may comprise for example methods employing chemical pre-treatment of nucleic acids with e.g. sodium bisulphite, permanganate or hydrazine, and subsequent detection of the modification by means of specific restriction endonucleases or by means of specific probes e.g. in the course of an amplification reaction. The detection of methylaton may furthermore be performed using methylation specific restriction endonucleases. Methods for the detection of methylation states in nucleic acids are e.g. disclosed in patent application EP02010272.9, U.S. Pat. No. 5,856,094, W00031294, U.S. Pat. No. 6,331,393 etc. The cited documents are incorporated herein by reference. Detection of modified states of polypeptides may for example comprise binding agents specifically recognizing modified or unmodified states of polypeptides. Attentively enzymes such as phosphatases or glycosylases may be used to remove modifications in molecules. The presence or absence of modifications can thus be detected by determination of mass or charge of the molecules by means of electrophoresis, chromatography, mass spectrometry etc. prior and subsequent to the incubation with a respective enzyme. In a further embodiment of the present invention, the kits and in-vitro diagnostic devices are designed in a way that the detection of a series of marker molecules is carried out on the level of polypeptides and simultaneously the detection of a further series of marker molecules and/or of all or some of the same marker molecules is carried out on the level of nucleic acids. Marker molecules associated with medically relevant cellular conditions may e.g. be molecules which influence and/or reflect the proliferation and/or differentiation characteristics of cells and/or tissues. Such molecules may comprise for example cell cycle regulatory proteins, proteins associated with the DNA replication, transmembrane proteins, receptor proteins, signal transducing proteins, calcium binding proteins, proteins containing DNA-binding domains, metalloproteinases, kinases, kinase inhibitors, chaperones, embryogenesis proteins, heat shock proteins or enzymes which modify other proteins posttranslationally thus regulating their activity, or nudeic acids coding for the named proteins. Also mRNA coding for the named proteins may be marker molecules useful according to the present invention. In one embodiment the marker associated with the cell proliferative disorder may be for example uniquely expressed in cells affected by the disorder, may be not expressed in said cells or may be overexpressed in said cells. The kits and in-vitro diagnostic devices developed according to a method as disclosed herein comprise one or more marker molecules (proteins as well as nucleic acids) chosen from cell cycle regulatory proteins or nucleic acids encoding the same (e.g. p53, pRb, p14ARF), cyclins (e.g. cyclin A, cyclin B, cyclin E), cyclin dependent kinase inhibitors (such as e.g. p13.5, p14, p15INK4b, p16INK4a, p18INK4c, p19INK4d, p21WAF1/CIP1, p27KIP1), tumor associated antigens (e.g. MDM-2, MCM2, MCM5, MCM6, CDC2, CDC6, Id1, osteopontine, GRP, Claudin, CD46 renal dipeptidase, her2/neu, TGFβII receptor), tumor-suppressor genes, HPV associated markers (e.g. derived from HPV genes L1, L2, E1, E2, E4, E5, E6 or E7, etc.), cell surface antigens (e.g. cytokeratins, catenins or others) or the like. In certain embodiments marker molecules detected by the kits and in-vitro diagnostic devices developed according to the method disclosed herein may comprise genes engaged in the DNA replication such as e.g. proteins or nucleic acids of the pre-initiation complex or of the replication fork. Such molecules may e.g. comprise proliferation markers (proteins as well as nucleic acids) such as e.g. helicases, (such as eucaryotic helicase or MCM proteins [MCM2, MCM3, MCM4, MCM5, MCM6, MCM7], protein TP as disclosed in WO0050451 and WO0217947 [also denominated HELAD1, Pomfil2, Uno-53], kinases or phosphatases engaged in the replication process such as e.g. CDC6, CDC7 protein kinase, Dbf4, CDC14 protein phosphatase, CDC45 and MCM10), proteins engaged in the processive replication fork (such as e.g. PCNA or DNA polymerase delta, replication protein A (RPA), replication factor C (RFC), FEN1), molecules necessary for the maintenance of cell proliferation (such as Ki67. Ki-S5 or Ki-S2), etc. Generally the method for development of kits and in-vitro diagnostic devices disclosed herein is suited for kits and in-vitro diagnostic devices based on various marker molecules characteristic for medically relevant conditions. In one embodiment the marker molecules for a medically relevant condition may be a marker for tumors (tumor markers). The marker molecules characteristic for tumors may e.g. be proteins, that are expressed in a non-wild type manner in tumors compared to normal control issue. Non-wild type expression as used herein may comprise increased or decreased levels of expression, or lack of expression, or expression of non-wild type forms of the respective molecules. Expression of non-wild type forms of a protein may comprise expression of mutated forms of proteins, arising by insertion, deletion, substitution, or frameshift mutations or any other known types of mutations in proteins or nucleic acids. In all cases of the expression of non-wild type proteins or non-wild type levels of proteins the proteins, polypeptides or fragments thereof, or nucleic acids encoding these proteins, or polypeptides or fragments of these nudeic acids may be used as molecular markers associated with tumors and may thus be understood under the term “tumor marker” as used in the context of the present invention. Proteins that show non-wild type expression in association with tumors are disclosed for example in the documents WO9904265A2, WO0149716A2, WO0055633A2 and WO0142792A2, which shall be incorporated by reference herein. In one embodiment of the invention, the marker characteristic for the medically relevant condition may be a cell cycle regulatory protein such as for example a cyclin, a cyclin-dependent kinase or a cyclin-dependent kinase inhibitor. In a further embodiment of the invention the marker characteristic for the medically relevant condition may be a marker associated with a transient or a persistent viral infection. The viral infection may comprise an infection by a human papilloma virus (HPV) such as high risk or low risk HPV. The high risk HPV may comprise HPV subtypes such as e.g. HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56 and 58. The markers for HPV infection may e.g. comprise HPV expression products of HPV genes L1, L2, E2, E4, E5, E6 or E7. In a third embodiment of the invention a marker characteristic for a viral infection may be used in combination with any other marker for a medically relevant condition such as e.g. in combination with a cell cycle regulatory protein. Combinations of marker molecules, which may be of special interest with respect to HPV association are e.g. disclosed in W00208764 which document shall be incorporated herein by reference. In one embodiment, cell cycle regulatory proteins for use in combination with HPV markers may for example be chosen from a group comprising pRb, p53, p14ARF, cyclin-dependent kinase inhibitors. In one special embodiment for example p16INK4a may be used in combination with markers for HPV infection (e.g. L1, L2, E2, E4, E5, E6 or E7). In certain embodiments of the present invention a detection of the transcript or protein level of HPV genes is performed. In this respect a normalization of the sample employed in the biochemical non-cell based testing to information from the cytological information prepared from the same LBC sample may be of certain advantage. In one embodiment of the present invention a normalization of the sample for use in the biochemical non-cell based testing with respect to the volume of the LBC sample necessary to prepare a ThinPrep™ specimen using the Cytyc™ ThinPrep™ processor is performed. This may enable to yield comparable results respective the quantity of the HPV nucleic acids compared to the cells present in the sample. If such normalization is omitted not correlation of HPV infection to cellularity may be performed. For the method of detection of medically relevant conditions as disclosed herein principally any marker molecules may be applied for several medically relevant conditions. However certain marker molecules are known to be associated with specific medically relevant conditions. Those of skill in the art know which marker molecules could reasonably be used in a method according to the present invention for the detection of a medically relevant condition in a solubilized body sample. In Table 3 below examples of medically relevant conditions and marker molecules suitable for application in a method according to the present invention are given. The information is intended to exemplify the method as disclosed herein and not to restrict the scope of the invention, which is as stated generally applicable to molecules known to those of skill in the art to be associated with specific medically relevant conditions. TABLE 3 Examples of suitable Marker Molecules for a Medically relevant method as disclosed herein condition Protein level Nucleic Acid Level Cervical Carcinoma p16INK4a, p14ARF, claudin, p19INK4d, Ki67, p16INK4a, p14ARF, claudin, p19INK4d, Ki67, Cyclin E, Cyclin D, MCM-5, MCM-2, Cyclin E, Cyclin D, MCM-5, MCM-2, HPV E7, HPV E2, HPV E4, HPV L1, HPV E7, HPV E6, HPV E2, HPV E4, CK18, CD-46, NMP-173, Brn-3, Mn-antigen; HPV L1, (any HPV nucleic acid sequence especially hrHPV), NMP-173, Brn-3, Mn-antigen, TSLC-1, PTEN, Bladder Cancer survivin, MCM-5, MCM-2, CDC-6, Her- NY-ESO1, MCM-5, MCM-2, CDC-6, p53, 2/Neu, MMP-2, Cyclin-E, KIAA1096, Her-2/Neu, MMP-2, Cyclin-E, KIAA1096, p21WAF1/CIP1, pRB, MDM2, NMP-22 p21WAF1/CIP1, pRB, MDM2, NMP-22 Colorectal Cancer Claudin, DNAseX, MCM-5, MCM-2, Claudin, DNAseX, MCM-5, MCM-2, caveolin-1. cathepsin-B, Cyclin D1, caveolin-1. cathepsin-B, Cyclin D1, Cyclin E, c-myc, TGF-beta, Her-2/Neu Cyclin E, c-myc, TGF-beta, Her-2/Neu Small Cell Lung Cancer p16INK4a, GRP, Her-2/Neu, cyclo- p16INK4a, GRP, Her-2/Neu, cyclo- oxigenase-2, NSE, CA 15-3 oxigenase-2, NSE, CA 15-3 Non Small Cell Lung Cancer NSE, GRP, Cyclin D1, Her-2/Neu, SCC, NSE, GRP, Cyclin D1, Her-2/Neu, SCC, CEA, CA 19-9 CEA, CA 19-9 Breast Cancer Cyclin D3, Her-2/Neu, e-cadherin, BRCA2, Cyclin D3, Her-2/Neu, e- survivin, cathepsin D cadherin, survivin, cathepsin D Inflammation ion various Leukocyte specific proteins; Granulocyte Leukocyte specific nucleic acids; cytological specimens specific proteins Granulocyte specific nucleic acids The marker molecules for medically relevant conditions according to the present invention may be characteristic for the presence of absence of a medically relevant condition. In one embodiment of the present invention the marker molecules may be characteristic for specific properties of medically relevant conditions. Such characteristics may comprise the progression potential, prognostic information, behavior respective certain therapeutic treatments of the medically relevant condition. The marker molecules characteristic for medically relevant conditions may therefore be marker molecules useful for the determination of prognosis of individuals affected by medically relevant conditions or for stratification of therapy of individuals affected by medically relevant conditions. This may in certain embodiments apply to the determination of presence or absence of the expression of certain marker molecules that are indicative of positive or negative prognosis in specific medically relevant conditions (e.g. expression Level of p16, Her-2/Neu, Brca-2, Claudin or others in breast cancer etc.) Examples of marker molecules that allow to assess prognosis of individuals affected with specific medically relevant conditions are known to those of skill in the art. Any such markers known from cell based cytological or histological procedures may be used in a method according to the present invention. The assessment of prognosis may e.g. be performed during or after primary diagnosis of the medically relevant condition, during or after (surgical) treatment of the medically relevant condition or at any other stage of the history of the respective medically relevant condition. In other embodiments the method according to the present invention may be used for the stratification of treatment of individuals affected with medically relevant conditions. Such stratification may e.g. comprise the selection of certain therapeutic compounds in the sense of Theragnostic procedures (as used e.g. for selection of patients for therapy with Herceptin or the like), selection of patients for chemotherapy, for radiotherapy or for any other decision on the further therapeutic treatment of individuals or generally for the decision on the medical treatment of individuals such as monitoring follow up or the like. In certain embodiments of the present invention the marker molecules characteristic for medically relevant conditions may be markers for indicative of progression of the medically relevant condition. In certain further embodiments of the present invention the marker molecules characteristic for the progression of medically relevant conditions may be used in combination with marker molecules characteristic for the mere presence of said medically relevant condition. The development according to the present invention is performed using LBC samples as raw material. In one embodiment of the present invention the kits and in-vitro diagnostic devices developed according to the method disclosed herein are intended for use with any kind of solubilized body sample. In another embodiment of the present invention the kits and in-vitro diagnostic devices developed according to the method disclosed herein are intended for use with LBC samples only. In this case the kit or in-vitro diagnostic device is developed and manufactured for analysis of solubilized LBC samples as an adjunctive or conjunctive test to the cytological analysis or as a stand alone test. The method for development of kits and in-vitro diagnostic devices according to the present invention is directed to development of kits and in-vitro diagnostic devices for biochemical testing formats. In these testing formats the presence or absence and/or the level of marker molecules in solubilized body samples is detected. Solubilization of the body samples is performed using a suitable lysis medium as detailed above. The development of a kit or in-vitro diagnostic device according to the present invention makes use of LBC samples for design, development, design and development verification, design and development validation. Furthermore a method for development of kits and in-vitro diagnostic devices on the basis of LBC samples as disclosed herein is any method that employs LBC samples for provision of technical documentation and/or of evidence for safety and effectiveness for the purpose of regulatory clearance or approval of the respective kit or in-vitro diagnostic device before the regulatory authorities and regulatory (notified) bodies if applicable. The method of development of kits and in-vitro diagnostic devices as disclosed herein may employ LBC samples in all stages of the design, development, verification, validation, provision of data for regulatory submission and clearance/approval, or may employ LBC samples only in one or some of the named steps of kit or in-vitro diagnostic device design and development. In one embodiment of the invention the method of development of the kits or in-vitro diagnostic devices according to the present invention is a method for design and development of said kits and in-vitro diagnostic devices, wherein the LBC samples are used for design and development verification and/or validation. In another embodiment of the invention the method of development of kits and in-vitro diagnostic devices is a method for provision of data for regulatory submission and clearance/approval of kits and/or in-vitro diagnostic devices before national or regional regulatory authorities and/or national or regional regulatory (notified) bodies, wherein LBC samples are used for the provision of technical data, performance data or safety and effectiveness data regarding the kit or in-vitro diagnostic device. In a further embodiment of the invention the method of development of kits and in-vitro diagnostic devices is a method where the latter methods are combined. The method for development of kits and in-vitro diagnostic devices as detailed herein makes use of LBC samples in any way that is suitable for gathering data on the performance characteristics of the kit or device under development. Generally LBC samples are used as a source of body samples to be used in the course of the kit or in-vitro diagnostic device development. In one embodiment of the present invention the LBC sample is supplied as a left over specimen, wherein a cytological specimen has been prepared from the LBC sample before, during or after use of parts of the LBC sample for the development method according to the present invention. In another embodiment the LBC sample has been obtained solely for the purpose of use in a method of development according to the present invention. In this case a second and may be third LBC sample or even sample prepared by conventional non thin-layer methods for cytological evaluation may have been obtained before or after the sampling of the respective LBC sample used in the method of development according to the present invention. Regarding the LBC samples used in the method according to the present invention information regarding the cytological procedures may be present or absent. Such information comprises e.g. the volume of an LBC sample needed for preparation of a suitable thin-layer preparation, information on the cell content of the LBC specimen, information on the adequacy of the LBC specimen or the underlying sampling procedure, information on the diagnostic information assessed on the basis of a cytological specimen, information on the patient disease and diagnosis etc. In a method according to the present invention the LBC sample obtained is used either in its entirety or only in parts. In certain embodiments of the invention the total volume of an LBC sample is used for the development purpose. In another embodiment the total number of cells contained in the sample is used for the development purpose. In yet another embodiment only a fraction of the total volume or of the total number of cells contained in the original LBC sample is used for the purpose of development. In a method according to the present invention a normalization of the LBC sample may be applied. In certain embodiments of the invention a normalization of the LBC sample may be applied to ensure the presence of a comparable amount of cells in the development processes performed using the LBC sample. This may be achieved by normalizing the volume of the LBC sample with respect to the volume of said sample necessary for preparation of an appropriate thin-layer specimen. Preparation of the thin-layer specimen may be performed by any suitable method such as e.g. employing ThinPrepxm processor or the like. In this case the volume of the fraction of the LBC sample for employment in the development process according to the present invention may be disregarded. In certain further embodiments the normalization of the LBC sample is performed with respect to the volume of the sample subjected to the testing procedure. In this case the amount of cells present in the fraction of the LBC sample for employment in the development process according to the present invention may be disregarded. Examples for performance of normalization as described herein are given in Examples 4 ff. A further aspect of the present invention is a method for assessment of diagnosis of medically relevant conditions by biochemical non-cell-based analysis of the presence or absence and or the level of marker molecule in solubilized body samples, wherein the body sample is an LBC sample. In certain embodiments of the invention the method for assessment of diagnosis comprises a normalization of the amount of sample applied for the biochemical non-cell based testing with respect to information accessible from a cytological (e.g. thin-layer) preparation generated from the LBC sample. This information may e.g. be information on the cellularity of the sample. In this respect cellularity shall be understood as the cell content per mL present in the medium. The cellularity may refer to an overall content of cells of whatsoever kind and nature. In other embodiments the term cellularity may refer to the content of specific defined call types in the LBC sample. Such cells may e.g be cells defined by means of source or location (e.g. endocervical cells, ectocervical cells, endometrial cells, cervical cells, vaginal cell) cells defined by proliferation and/or differentiation status (e.g. metaplastic cells, dysplastic cells, HPV infected cells, etc.) or any other defined type of cells. The method of detection disclosed herein in this respect pertains to detection of marker molecules sauch as nucleid acids or proteins orpepuids and the respective fragments thereof. In certain embodiments the detection of marker molecules is carried out by detection of the presence or absence and or the level of proteins, peptides or fragments thereof in said solubilized samples. The marker molecules that may be applied for this method are disclosed above as “marker molecules characteristic for medically relevant conditons”. The method may be applied to any medically relevant condition as defined above. In other embodiments of the invention nucleic acids of marker molecules characteristic for medically relevant conditions are detected. Nucleic acids as used in this respect is defined above in the description of this invention. The detection of the marker molecules in the methods as disclosed herein refers to any suitable detection methods as defined above. In certain embodiments the detection of proteins and peptides is carried out by means of immunochemical detection. By means of the present invention, it is possible to diagnose neoplastic disorders such as cancers and their precursor stages early. In particular, precursor stages of cancers can be detected early. It must also be emphasized that it is possible to make a differentiation with respect to benign inflammatory or metaplastic changes of neoplastic disorders. Another characteristic is that the results obtained by a method according to the invention do not rely on subjective evaluation, so that e.g. false-negative results and false-positive results of a Pap test or histological preparations can be reduced or avoided. In addition, the present invention distinguishes itself by rapid and simple handling, so that it can be used for extensive screening measures, particularly also in third-world countries. Thus, the present invention represents an important contribution to today's diagnostics of cancerous diseases. The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. EXAMPLES Example 1 Detection of Cervical Intraepithelial Neoplasia in an ELISA Test Format 33 cervical swabs provided in a lysis medium were subjected to ELISA based detection of overexpression of cyclin-dependent kinase inhibitor p16INK4a in solutions prepared from the cells contained in the swabs. The ELISA testing was performed as follows: (A) Cell Lysis Cervical swab brushes were given into 15 ml vessels, containing 2 ml of mtm lysis medium (2% Triton X-100, 0.4% SDS, 0.6 mM PMSF in PBS). Cervical cells present in the brush were lysed for at least 20 h. The lysates of the cervical swab samples were then transferred in 2 ml tubes and were centrifuged at 4° C. (15 min at 28.000×g (16.600 rpm Highspeed Centrifuge JEC Multi RF)); -Supernatant was transferred to a fresh tube. The Supernatant may be stored at −20° C. (B) Performing the ELISA Coating of ELISA-plates Stock-solution of p16INK4a specific antibody clone mtm E6H4 was diluted in PBS to give ready-to-use coating solution. 50 μl of the coating solution was added to each well of the ELISA plates. For coating, the plates were incubated overnight at 4° C. Coating solution was removed from the ELISA plates and the plates were rinsed using an automated ELISA washer as follows: 7×250 μl washing buffer (0.1% Tween20 (v/v) in PBS) after removing remnants of the washing buffer, 300 μl blocking buffer (2% BSA in PBS) was added to each well. Plates were incubated for 1 h on a rocking device at ambient temperature. Incubation with Samples After removing the blocking buffer, 100 μl of the lysed cell sample was added to each well. Lysates of HeLa-cells were used as positive control; For purpose of calibration of the test, different concentrations of recombinant p16INK4a protein (0 pg/ml, 50 pg/ml, 100 pg/ml, 200 pg/ml, 400 pg/ml, 800 pg/ml) were included in the test. Samples were incubated for 1 h at room temperature. Thereafter washing was performed on an automated ELISA washer as follows: 7×250 μl washing buffer. The remaining buffer was removed. Incubation with Detection Antibody Working solution of biotinylated secondary antibody clone mtm D7D7 specific for p16INK4a protein was prepared by dilution of stock solution. 100 μl of working solution was added to each well. After incubation for 1 h at RT, antibody solution was removed and ELISA plates were washed by an automated ELISA washer 7× with 250 μl washing buffer. Detection Streptavidin-HRP-polymers (1 mg/ml) were pre-diluted 1:10. (4 μl +36 μl incubation buffer); Final incubation solution was prepared by dilution 1:300 in incubation buffer (0.1% BSA in PBS) to a final concentration of 0.33 μg/ml. 100 μl of this solution were added to each well and incubated for 1 h at RT. Thereafter, the buffer was removed and the plates were washed manually with 200 μl washing buffer per well 5 times. Substrate Incubation TMB-substrate was equilibrated to 25° C. for 1 h in the dark. 100 μl of substrate solution was added to each well. The ELISA plates were incubated at 25° C. for exactly 15 min in the dark. Then the reaction was stopped by addition of 80 μl 2.5M H2SO4. Within 5 min. after stopping the reaction, OD 450 nm was determined. After evaluation of the results, each sample returned a value for the OD. Results of this experiment are given in Table 4. The ELISA results were compared to the diagnostic results of a Papanicolaou test (PAP test, cervical cytology) from the same patients. The cervical cytology were evaluated according to the Munich Classification II (1990). Pap II encompasses benign cells, cervicitis and metaplasia, Pap IV encompasses severe dysplasia and carcinoma in situ. It turned out that samples returning an OD greater than 0.9 in the ELISA correspond to samples, that are classified as dysplastic by the conventional cytological PAP test. Applying OD 0.9 as threshold for the evaluation of the samples, the ELISA results may be reported as follows: TABLE 4 Diagnosis/ELISA results ELISA positive ELISA negative Pap II 0 30 Pap IV 3 0 The ELISA test is positive in all samples (100%) from women having severe dysplasia and is negative in all 30 samples (100%) of women having no dysplasia. Using the threshold evaluated in these experiments, cytological specimens of 300 patients were tested in the presented ELISA testing format. In this experiments the specimens identified as being dysplastic by cytological examination may also be identified as dysplastic in the ELISA testing format. The results show, that the quantification of p16INK4a protein in solubilized patient samples allows to detect dysplasias from the samples. The diagnosis in the present example is based on the comparison of the level of p16INK4a determined in a specific patient sample to the level known to be present in normal non-dysplastic samples. The comparison is carried out in the testing format by applying a threshold value for the OD determined in the ELISA above which the sample is to be classified as positive. Example 2 Detection of Cervical Intraepithelial Neoplasia in an Lateral Flow Test Format Nine cervical swabs provided in PreservCyt (Cytyc Corporation, Boxborough, Mass.) solution have been subjected to conventional PAP testing and simultaneously to lateral flow based detection of overexpression of cyclin-dependent kinase inhibitor p16INK4a in solutions prepared from the cell suspensions obtained from the swabs. The lateral flow testing was performed as follows: (A) Cell Lysis 10 ml of the cell suspensions from the individual cervical swab samples provided as PreservCyt™ fixed materials were transferred to a 15 ml reaction vessel. The samples were centrifuged 15 min at ambient temperature at 1500×g (3000 rpm, Heraeus Varifuge, rotor 8074); supernatant was discarded, and remaining methanol allowed to evaporate (15 min at ambient temperature); the pellet was solubilized in 500 μl Lysisbuffer and transferred to a 1.5 ml reaction vessel. The solution was centrifuged at 4° C. (15 min at 28000×g (16600 rpm Microcentrifuge Biofuge fresco)); Supernatant was transferred to a fresh tube. Supernatant may be stored at −20° C. (B) Performing the Lateral Flow Assay Applying capture antibody to membrane Stock solution of p16INK4a specific antibody done mtm E6H4 was diluted in TBS (containing 1% bovine serum albumin) to give ready-to-use spotting solution with a final concentration of 1 mg antibody/ml. The ready-to-use solution was spotted onto nitrocellulose membrane at 30 μl/30 cm. Whatman wicks were attached to one end of the nitrocellulose and dipsticks are dried for 1 hour at 37° C. Then they were allowed to equilibrate at room temperature and cut into 4 mm width dipsticks. Preparation of Conjugate Solution Stock-solution of p16INK4a specific antibody clone mtm D7D7, conjugated to colloidal gold (40 nm particle size) was diluted in TBS (containing 1% bovine serum albumin) to give ready-to-use detection antibody solution with a final concentration of 1.0 OD at 520 nm. Incubation with Samples Then 20 μl of the lysed cell samples were added to 20 μl ready-to-use detection antibody solution in a microtiter well and mixed. Dipstick, coated with capture antibody clone E6H4 was added to the well, sample was soaked and run to completion. The signal was read while the dipstick is still wet. Results In our testing format, 2 samples (samples 1 and 2) classified as PAP IVa by PAP staining and therefore containing dysplastic cells, gave clearly visible purple bands in the area of spotted capture antibody. In contrast, no band was detected for the other 7 samples (samples 3-9), classified as PAP II-III by PAP staining and therefore not containing dysplastic cells. ELISA was performed by the same protocols given in Example 1. The results are shown in Table 5. TABLE 5 Sample Diagnosis ELISA OD 1 Pap IVa 2.209 2 PAP IVa 0.536 3 PAP III 0.067 4 PAP II 0.113 5 PAP II 0.095 6 PAP II 0.284 7 PAP II 0.192 8 PAP II 0.138 9 PAP II 0.07 The invention, and the manner and process of making and using it, are now described in such, full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the scope of the present invention as set froth in the claims. To particularly point and distinctly claim the subject matter regarded as invention, the following claims conclude this specification. Example 3 Detection of p16INK4a and p14ARF Transcripts by RT-PCR, Cervical samples from 50 individuals were used for this analysis. For each individual two samples were obtained, one in Universal Collection Medium and one in PreservCyt™ solution. Both samples were obtained during the same examination session. For each of the individuals a diagnosis based on analysis of a cervical thin layer specimen prepared out of the PreservCyt™ solution was available. 20 of the samples included in the present study were chosen to be diagnosed as NILM, 20 samples were chosen to be LSIL and 10 samples were chosen to be HSIL. From all samples the level of transcripts of p16INK4a and of p14ARF have been determined on an mRNA level by RT-PCR according to the following protocol: For performance of the analysis the cells were pelleted from the UCM and PreservCyt™ solutions by centrifugation. The pellets obtained were directly subjected to the RNA preparation procedure. The pellet was diluted and resuspended in ready to use RLT Buffer. After adding 70% Ethanol to the homogenised lysat the suspension was mixed by pipetring. Purification and isolation of RNA was performed using QIAamp Spin-columns according to the directions of the manufacturer. RNA concentration was determined photometrically at 260 nm. For reverse transcriptase reaction from 100 ng up to 500 ng RNA were used. DNA was degraded by DNase reaction as follows 17.0 μL RNA (6-30 ng/μL) 1.0 μl DNAse I Amp Grade (1 Unit/μl)(Invitrogen) 2.0 μl DNAse Reaction Buffer (10×)(Invitrogen) 20.0 μl total volume Incubation was performed for 15 Min at 25° C. and the reaction was stopped by adding 2 μl EDTA 25 mM and incubation for 10 Min at 65° C. cDNA synthesis was performed using the whole volume of the DNase digest using Omniscript reverse transcriptase in the presence of RNAsin. The reaction was performed for 2 h at 37° C. and subsequently 5 Min at 93° C. Afterwards the mixture was stored at 4° C. This renders a ready to use cDNA solution for the Taqman-PCR (corresponds to a CDNA concentration of about 7-36 ng/5 μl). For use in RT-PCR the 40 μl cDNA Reactionmixture was diluted with 30 μl RNase-free water to a volume of 70 μl. The primers used were: Primer p16INK4a, forward: 5′-CGA ATA GTT ACG GTC GGA GG-3′ Primer p16INK4a, reverse. 5′-ACC AGC GTG TCC AGG AAG-3′ Primer p14ARF, forward: 5′-CCG CCG CGA GTG AGG GTT-3′ Primer p14ARF, reverse. 5′-TGC CCA TCA TCA TGA CCT GGT CT-3′ As controls PCR reactions for mactin and GAPDH were performed using the primers: Primer (63) β-Actin, forward: 5′-CCT AAA AGC CAC CCC ACT TCT C-3′ Primer (64) β-Actin, reverse: 5′-ATG CTA TCA CCT CCC CTG TGT G-3′ Primer GAPDH, forward: 5′-ACC ACA GTC CAT GCC ATC AC-3′ Primer GAPDH, reverse: 5′-TCC ACC ACC CTG TTG CTG TA-3′ Each primer was used at a concentration of 300 nmol. The reaction mixture for RT-PCR was composed as follows: 12.5 μl SYBR-Umix 0.25 μl Primer Mix 7.25 μl Wasser för die Molekularbiologie 5.0 μl cDNA solution 25.0 μl total volume The conditions for the 2 Step Real Time PCR are: 1st Step: 50° C. 2 Min, 95° C. 10 Min 2nd Step: 95° C. 15 sec, 60° C. 1 Min 10 sec. 40 Cycles Evaluation of the RT-PCR results was performed by estimation of the degree of overexpression of the p16INK4a transcripts on the basis of the level of transcripts detected in the sample specimens compared to levels of transcripts present in normal tissue or cell specimens. Normalization with respect to the level of housekeeping genes detected in each sample was performed for the levels of p14ARF prior to analysis of overexpression. An overexpression of 0 to 24 times compared to normal tissue was regarded as not relevant. Only levels of overexpression of p16INK4a and p14ARF higher than 24 times were regarded as significantly elevated transcript levels in the samples. It must be noted, that this scheme for evaluation is only one of several equally suitable methods. Those of skill in the art know how the results of RT-PCR may be used to estimate transcript levels and to do correlations to clinical parameters of specimens. The Threshold mentioned in this example is exemplary and may vary depending on conditions. The values obtained from the UCM specimen of one sample and the corresponding PreservCyt™ specimen gave the same results. A comparison of the detected transcript level to the diagnosis of the correlated specimen from cytology showed good correlation between elevated transcript levels and presence of cervical lesions diagnosed on the basis of cytological thinlayer specimens. The correlation was as follows: TABLE 6 Level of transcripts of p16INK4a as detected in RT-PCR[expressed as times elevation compared to levels found Cytological Diagnosis in normal specimens] Gene NILM LSIL HSIL 0 to 24 times p16INK4a 19 0 — elevated p14ARF 16 3 — higher than 24 p16INK4a 1 20 10 times elevated p14ARF 4 17 10 The experiment shows that a method for detection of transcript level of p16INK4a and p14ARF in lysed cervical samples is suited for assessment of diagnosis of cervical lesions and their precursors. The tested cell preservation solutions turned out to be equally suitable for the disclosed method. The transcript levels of both tested genes may be used for adding in assessment of diagnosis of cervical intraepithelial neoplasia, wherein p16INK4a shows slightly better results than p14ARF. Example 4 Hybrid Capture Analysis of Transcript Levels of p16INK4a and p14ARF in Liquid Based Cytology Samples from Swabs from the Oral Cavity, Sputum and from Cervical Swabs Each 10 LBC samples in PreservCyt™ or CytoLyt™ solution respectively of cervical swabs from individuals with diagnosed HSIL lesion, of sputum from individuals with small cell lung cancer, and of swabs from the oral cavity from individual with cancer of the oral cavity were used for each of the marker molecules in the present example (In total 20 specimens for each cancer entity were included.). For the cervical and oral specimens a hybrid capture analysis for the presence of hrHPV types and of transcripts of p16INK4a and p14ARF was performed. Hybrid capture for hrHPV types was performed using HybridCaptrue hc2 test by Digene Corp. Hybrid capture analysis for the transcripts of the named cyclin-dependent kinase inhibitors was performed as described below. (A) Cell Lysis For the present example the amount of the LBC sample was dependent on the cell content of the LBC sample. A thin-Layer specimen of each sample was prepared using a Cytyc ThinPrep™ processor. The mass of the LKBC sample was determined before and after the preparation of the thin-layer specimen. As the ThinPrep™ processor consumes upon each processing only the amount, of sample necessary for a specific cell density on the filter the volume consumed is a measure for the relative cell concentration in the LBC sample. In the present example from each LBC two times the mass consumed for the preparation of the thin-layer specimen by the ThinPrep™ processor was applied for the hybrid capture analysis. (Samples for which the cellularity of the LBC sample was too low have been excluded.) For performance of the analysis the cells were pelleted from the CytoLyt™ and PreservCyt™ solutions by centrifugation. The pellets obtained were directly subjected to the RNA preparation procedure. The pellet was diluted and resuspended in ready to use RLT Buffer. After adding 70% Ethanol to the homogenised lysat the suspension was mixed by pipetting. Purification and isolation of RNA was performed using QIAamp Spin-columns according to the directions of the manufacturer. For detection of the p16INK4a mRNA a mixture of 40-mer DNA oligonucleotide probes specific for p16INK4a and p14ARF were used. The most suitable probes in the mixture had the following sequences: p14ARF: 5′-GCT CCG CCA CTC GGG CGC TGC CCA TCA TCA TGA CCT GGT C-3′ 5′-GCC ACT CGG GCG CTG CCC ATC ATC ATG ACC TGG TCT TCT A-3′ 5′-TCG GGC GCT GCC CAT CAT CAT GAC CTG GTC TTC TAG GAA G-3′ 5′-CGC TGC CCA TCA TCA TGA CCT GGT CTT CTA GGA AGC GGC T-3′ 5′-CCC ATC ATC ATG ACC TGG TCT TCT AGG AAG CGG CTG CTG C-3′ 5′-CAT CAT CAT GAC CTG GTC TTC TAG GAA GCG GCT GCT GCC CTA G-3′ 5′-TGC CCA TCA TCA TGA CCT GGT CTT CTA GGA AG-3′ 5′-ATC ATC ATG ACC TGG TCT TCT AGG AAG CGG CTG CTG CCC TAG-3′ It is advantageous to place the probes on the border between Exon 1β and Exon 2 of the mRNA to ensure that only p14ARF specific mRNA is recognized by the probes (the situation is similar for specific PCR conditions for p16INK4a and p14ARF respectively; primer pairs could be selected to cover the Exon boundary within the amplificat.). Any other probes specifically recognizing p14ARF mRNA may be used similarly. The probes disclosed in this example are used as an example and are not intended to restrict the scope of the invention. Probe sequence comprising the above sequences or fragments thereof may similarly be used for a method as disclosed herein. For p16INK4a promising probe sequences are the following: 5′-CTC CGC CAC TCG GGC GCT GCC CAT CAT CAT GAC CTG GAT CGG-3′ 5′-ACT CGG GCG CTG CCC ATC ATC ATG ACC TGG ATC GGC CTC-3′ 5′-CGG GCG CTG CCC ATC ATC ATG AGC TGG ATC GGC CTC CGA-3′ 5′-GCT GCC CAT CAT CAT GAC CTG GAT CGG CCT CCG AGC GTA A-3′ 5′-CAT CAT CAT GAC CTG GAT CGG CCT CCG AGC GTA ACT ATT C-3′ 5′-ATC ATC ATG AGC TGG ATC GGC CTC CGA CCG TAA CTA TTC GGT GC-3′ 5′-AGC AGC TCC GCC ACT CGG GCG CTG CCC ATC ATC ATG AGC TGG ATC-3′ 5′-ATC ATC ATG AGC TGG ATC GGC CTC CGA CCG TAA CTA TTC-3′ 5′-TCA TCA TGA CCT GGA TCG GCC TCC GAC CGT AAC TAT TCG GT-3′ Similar as to the situation with p14ARF for p16INK4a the probes preferably are places to overlap with the exon boundary of Exon 1α to Exon 2. This provision could ensure that p16INK4a is recognized and no other mRNA transcribed from the INK4 locus. Further more the comments given for the probes to p14ARF apply here mutandis mutatis. The labeled probe mixture was added to the total cellular RNA extract For hybridization the mixture was incubated at 65° C. for 30 Min. (B) Performing the ELISA For the detection of the RNA-DNA hybrids microtiter plates coated with anti-RNA/DNA-hybrid antibodies available from Digene Corp. were used. The hybridization solution was added directly to the microtiter plates and incubated for 1 h at ambient temperature. The plates are washed according to the instructions by the manufacturer. Detection was performed using the secondary anti-RNA/DNA-hybrid antibody and detection reagents provided by Digene Corp. The hybrid capture assay revealed positive results for p16INK4a for all cervical specimens. This result was in concordance with all cervical specimens being positive for hr HPV by Hybrid Capture. About half of the cancer specimens from the oral cavity was tested as p16INK4a overexpressing. All of these specimens being positive for p16INK4a have been tested for hrHPV by hc2. There was significant correlation between HPV positivity and p16INK4a overexpression in cancer of the oral cavity. For small cell lung cancer p16 could be detected as positive in 8 out of 10 of the tested cases. All results for p16INK4a obtained by the hybrid capture test could be confirmed by immuno-cytochemical analysis of the thin-layer specimens. For p14ARF the results for cervical samples were comparable to those for p16INK4a. For small cell lung cancer only two of the 10 cases under investigation showed positivity for 14AFR in hybrid capture. This result could be confirmed by immuno-cytochemistry. In the LBC samples from the oral cavity p14ARF could be detected in 7 out of 10 cases in concordance with the immuno-cytochemical findings. The results show that detection of cyclin-dependent kinase inhibitors in a habrid capture testing format from LBC samples may be used for assessment of diagnosis of several cancer entities. The results suggest that the biochemical testing could be used as an adjunct or conjunct testing to a cytological testing. Example 5 Immunochemical Analysis of Protein Levels of p16INK4a, Her-2/Neu and p14ARF in Liquid Based Cytology Samples from Urine, Sputum, BNreast Fine-needle Aspirates and from Cervical Swabs 10 cervical swabs with a cytological classification as HSIL, 10 sputum samples with cytologically diagnosed small cell lung cancer, 10 urine samples from individuals with diagnosed bladder tumors and 10 fine needle aspirates from individuals with diagnosed DCIS, all provided in PreservCyt™, medium were subjected to centrifugation of the cells and subsequent solubilization of the cells in a lysis medium. Afterwards ELISA based detection of expression level of cyclin-dependent kinase inhibitor p16INK4a, of p14ARF and of HER-2/Neu in solutions prepared from the cells contained in the swabs. The ELISA testing was performed as follows: (A) Cell Lysis Each 10 mL of the LBC samples were centrifuged to allow the cells to sediment. The cell pellet is [TIME]dissolved in 700 μl of of mtm lysis buffer lysis medium (2% Triton X-100, 0.4% SDS, 0.6 mM PMSF in PBS) by mixing and incubating for 10 Min at 80° C. The lysates of the LBC samples were then centrifuged at 4° C. (15 min at 28.000× g (16.600 rpm HighspeedCentrifuge JEC Multi RF)); -Supernatant was transferred to a fresh tube. The Supernatant may be stored at −20° C. (B) Performing the ELISA Coating of ELISA-plates For each protein separate ELISA plates were prepared as follows. Stock-solutions of the primary antibodies specific for p16INK4a, p14ARF and HER-21Neu were diluted in PBS to give ready-to-use coating solution. For p16INK4a clone mtm E6H4 was used for coating of ELISA plates. For p14ARF polyclonal antibody directed against p14ARF available from Calbiochem was used. For Her-2/Neu polyclonal antibody from DakoCytomation was used for coating. 50 μl of the coating solution was added to each well of the ELISA plates. For coating, the plates were incubated overnight at 4° C. Coating solution was removed from the ELISA plates and the plates were rinsed using an automated ELISA washer as follows: 7×250 μl washing buffer (0.1% Tween20 (v/v) in PBS) after removing remnants of the washing buffer, 300 μl blocking buffer (2% BSA in PBS) was added to each well. Plates were incubated for 1 h on a rocking device at ambient temperature. Incubation with Samples After removing the blocking buffer, 100 μl of the lysed cell sample was added to each well. For purpose of calibration of the test, different concentrations of recombinant proteins (0 pg/ml, 50 pg/ml, 100 pg/ml, 200 pg/ml, 400 pg/ml, 800 pg/ml) were included in each of the tests. Samples were incubated for 1 h at room temperature. Thereafter washing was performed on an automated ELISA washer as follows: 7×250 μl washing buffer. The remaining buffer was removed. Incubation with Detection Antibody Working solution of biotinylated secondary antibodies specific for the respective proteins were prepared by dilution of stock solution. For p16INK4a mtm clone D7D7 was applied, for p14ARF monoclonal antibody from Calbiochem was applied and for HER-2/Neu monoclonal Antibody from DakoCytomation was used. 100 μl of working solution was added to each well. After incubation for 1 h at RT, antibody solution was removed and ELISA plates were washed by an automated ELISA washer 7× with 250 μl washing buffer. Detection Streptavidin-HRP-polymers (1mg/ml) were pre-diluted 1:10. (4 μl+36 μl incubation buffer); Final incubation solution was prepared by dilution 1:300 in incubation buffer (0.1% BSA in PBS) to a final concentration of 0.33 μg/ml. 100 μl of this solution were added to each well and incubated for 1 h at RT. Thereafter, the buffer was removed and the plates were washed manually with 200 pij washing buffer per well 5 times. Substrate Incubation TMB-substrate was equilibrated to 25° C. for 1 h in the dark. 100 μl of substrate solution was added to each well. The ELISA plates were incubated at 25° C. for exactly 15 min in the dark. Then the reaction was stopped by addition of 80 μl 2,5M H2SO4. Within 5 min. after stopping the reaction, OD 450 nm was determined. After evaluation of the results, each sample returned a value for the OD. For each antibody a threshold OD was determined using the value seen for background. The ELISA results were compared to the diagnostic results of the cytological evaluation of the specimens from the same individuals. The results are as follows in Table 6: TABLE 7 Cervical Samples Cytological Diagnosis: 10 HSIL Immuno-Cytological Evaluation p16INK4a pos. 10 neg. 0 p14ARF pos. 8 neg. 2 Her-2/Neu pos. 2 neg. 8 ELISA Evaluation p16INK4a pos. 10 neg. 0 p14ARF pos. 9 neg. 1 Her-2/Neu pos. 3 neg. 7 Bladder Samples Cytological Diagnosis: 10 Carcinomas Immuno-Cytological Evaluation p16INK4a pos. 0 neg. 10 p14ARF pos. 1 neg. 9 Her-2/Neu pos. 6 neg. 4 ELISA Evaluation p16INK4a pos. 0 neg. 10 p14ARF pos. 0 neg. 10 Her-2/Neu pos. 5 neg. 5 DCIS Samples Cytological Diagnosis: 10 DCIS Immuno-Cytological Evaluation p16INK4a pos. 0 neg. 10 p14ARF pos. 0 neg. 10 Her-2/Neu pos. 6 neg. 4 ELISA Evaluation p16INK4a pos. 0 neg. 10 p14ARF pos. 1 neg. 9 Her-2/Neu pos. 7 neg. 3 It turned out that for p16INK4a in 100% of the tested cases there was good correlation between the cytologically assessed p16INK4a staining pattern and p16INK4a positivity in an ELISA testing format using solubilized preservCyt™ samples for the analysis. For p14ARF the correlation was 93%. For Her-2/Neu a correlation of more than 90% between the immuno-cytochemical detection of the overexpression and the positivity in the ELISA format could be detected. The results of the above examples show that the biochemical testing format using solubilized LBC samples may be applied on the same specimens as the immuno-cytochemical analysis. As the biochemical testing consumes only a fraction of the LBC sample i may easily applied as an adjunct to the immuno-cytochemical anlysis. There is good correlation between the immuno-cytochemical results and the ELISA results. This shows that the method according to the present invention is suited to assess diagnosis in various kinds of medically relevant conditions where liquid based cytology is currently applied either as ajunct or conjunct testing or as the case may be as a stand alone diagnostic test. Example 6 Immunochemical and RT-PCR Analysis of mRNA/protein Levels of MCM-5 and MCM-2 in Liquid Based Cytology Samples from Urine 20 LBC samples of urine cells in CytoLyt™ were used for the present example. RT-PCR was performed in the same way as given in Example 3. Protein analysis was performed in a strip test formula as given in Example 2 and in parallel in an ELISA format as given in Example 1. Experimental procedures were performed as given in these examples. It could be shown that MCM-5 may easyliy be detected in lysates from urine LBC samples. The results obtained by the biochemical non-cell based assay on the protein as well as on the nucleic acid level corresponds pretty good to the results obtained from cytology. In cytology immuno-cytological staining for MCM-5 protein was used as aid in assessment of diagnosis.

<SOH> BACKGROUND OF THE INVENTION <EOH>Preventive programs have been offered for the most differing cancers since the middle of the fifties. For cervical cancer an established population wide screening program exists in various developed countries. However similar screening programs are applicable for other cancer entities and the respective precursor stages such as e.g. cancers of the urinary system, of the respiratory tract and other. In the following cervical cancer is used as an example to highlight the drawbacks of the present preventive scenario. However the facts are mutandis mutatis applicable to other preventive programs for any cancer entity. Regarding cervical intraepithelial neoplasia and cervical glandular lesions, the preventive programs are based mainly on the morphological and cytological examination of cytosmears of the cervix uteri, what is called the Pap test, which is made on the basis of gynecological routine examinations at regular intervals in women from the 20 th year on. By means of the morphology of the cells, the smears are divided into various intensity degrees of dysplastic cellular changes. According to Pap I-V, these intensity degrees are referred to as normal, mild dysplasia, fairly serious dysplasia, serious dysplasia and invasive carcinoma, respectively. If the Pap test leads to a striking result, a small biopsy will be taken and subjected to a histopathologic examination, by which the kind and intensity of the dysplasia are determined and classified as cervical intraepithelial neoplasia (CIN1-3). In spite of all preventive programs, cervical cancer that lead to 400,000 new cases per year is the second most frequent neoplastic disorder in women. This is inter alia due to the fact that up to 30% of the results of individual Pap test are false-negative. In conventional screening for cervical intraepithelial neoplasia, swabs are used for detection of neoplastic lesions of the cervix uteri. In the screening procedure, different kinds of lesions have to be distinguished. Causes for lesions may for example be inflammations (due to infectious agents or physical or chemical damage) or neoplastic disorders. In morphological examinations the lesions of different characteristics are sophisticated to distinguish. Thus, for examination of cervical swabs and smears cytologists and pathologists have to be especially trained, and even experienced examiners have a high inter- and intra-observer variance in the assessment of a diagnosis based on cytological specimens. In general, the result of the examination is based upon the subjective interpretation of diagnostic criteria by the examining pathologist/cytologist. As a result, the rate of false positive and false negative results in the screening tests remains unsatisfying high. However, the reproducibility of the examination results may be enhanced by the use of supporting molecular tools. Yet the problem with the preservation and preparation of the samples may not be overcome by just additionally using molecular markers. One further complication when performing cytological or histological examinations for screening purposes and especially when applying methods for the detection of molecular markers originates from strict precautions in preserving the samples from causing artefacts or improper results. This is in part due to the instability of the cell-based morphological information and in part to the instability of the molecular markers to be detected during the tests. If the samples are not prepared, transported or stored in an appropriate manner, the cell-based information, or even the molecular information may be lost, or may be altered. So the diagnosis may be impossible, or may be prone to artefacts. For example, the interpretation of biopsies or cytological preparations is frequently made difficult or impossible by damaged (physically or bio/chemically) cells. Furthermore regarding tissue samples or biopsies, the preservation of molecular constituents of the samples, which are subject to a rapid turnover, is sophisticated due to the time passing by until penetration of the total sample by appropriate preservatives. Although the above is shown using cervical cancer as an example the overall background also applies to preventive programs of neoplastic disorders in general as the situation for other cancer entities is very much the same. Generally the morphologically supported diagnostic methods performed routinely in the art show two major disadvantages. Firstly, the methods are highly dependent on individual perception of the examiners. Secondly, the morphological information is quite sensitive to decay processes and thus to production of artefacts after preparation of the samples. Both aspects contribute to improper reproducibility of the results. Therefore, it is the object of the present invention to provide a method by which neoplastic disorders such as cancers and their precursor stages can be diagnosed early and reliably. In addition, a differentiation should be possible by this method with respect to benign inflammatory or metaplastic changes from neoplastic disorders such as dysplastic lesions and precancers. Moreover, the present invention provides methods for the detection of cancers on a biochemical basis from solubilized samples. The samples may be of any kind including cells in a cell preservation solution as is used for Liquid based cytology methods. The inventors insight that use of LBC samples as a source of sample material for the development of diagnostic test kits for the biochemical non-cell based assessment of diagnosis of medically relevant conditions is another aspect of the present invention. In the art LBC samples are used for development of cell based assay formats. Lysis of the samples in a way as disclosed herein however enables inventors to base the development of the biochemical kits on sample material which is suited to provide information on the patients disease status from other diagnostic procedures on the same sample material. A method for detection of HPV nucleic acids from LBC samples is disclosed by Digene Corp. This method uses LBC samples as basis for the analysis. Detection of the HPV nucleic acids is performed after lysis of the cells contained in the LBC samples. In this method no normalization of the amount of the LBC sample to be employed in the biochemical non-cell based detection of the HPV nudeic acid, is performed with respect to information obtained from the cytological specimen prepared out of the same LBC sample. The method disclosed by Digene is therefore restricted to mere qualitative measurements. Any biochemical non-cell based quantitative or even semiquantitatve method needs information on the composition of the samples obtainable either from biochemical markers or from the microscopic or flow cytometric analysis of the sample. In the present invention the use of LBC samples for the assessment of diagnosis or for development of kits and in-vitro diagnostic devices enables for an accurate and comparable way to provide cytological information for the biochemical non-cell based testing. The employment of biochemical normalization with respect to markers indicative for the presence or absence of cells or cell types is omissible. The advantage of using LBC samples in this respect is that the cytologically cell based information is direct related to the homogeneous LBC specimen and thus provides valuable accurate information for use in the evaluation of the biochemical non-cell based test results. A method for detection of molecular markers on the protein or nucleic acid level from solubilized specimens on the other hand is disclosed in various publications. However no link to the use of LBC samples as a source of the sample specimen in made in this respect. Generally LBC methods are applied in the art to enable for improved morphological evaluation of cytology specimens. The field of application of the LBC samples is therefore indicated only for cytology. Based on the disclosure in the prior art preparation of an LBC sample for subsequent solubilization of the sample for biochemical testing is not disclosed. Moreover the disclosure as to the advantages of LBC procedures teach away from application of LBC samples in any method that is not founded on cellular morphological evaluation of the specimens. According to the inventors findings the use of LBC samples as a source for biochemical non-cell based determination of protein levels in solubilized specimens provides the advantage that the results may be directly compared to a cytological specimen. The protein based biochemical analysis in this respect may serve as a e.g. pre-testing or to provide further information or even to confirm a cytologically equivocal result. In further embodiments the information obtained from the biochemical non-cell based testing may be for the design of the cytological procedures to be applied. The development method disclosed herein is therefore of great value for achieving effective and reliable kits and in-vitro diagnostic devices. The method for development of kits and in-vitro diagnostic devices as disclosed herein achieves comparability of the results generated by biochemical non-cell based analysis with the cytologically assessed results by means of a normalization. This normalization of the sample for application in the biochemical test format is performed with respect to information on the LBC sample obtainable from the cytological specimen prepared from the LBC sample. Such information comprises e.g. cellularity of the LBC sample, information with respect to volume of the LBC sample, information with respect to mass of the LBC sample or with respect to parameters accessible only via the generation of a thin-layer specimen out of the LBC sample. In this respect the inventors provide by the methods as claimed herein a reliable method for development of kits and in-vitro diagnostic devices on the basis of LBC samples.

<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is directed to a method for detecting neoplastic disorders from a solubilized body sample of a human subject The method comprises the steps of: (a) obtaining a body sample from a human subject, (b) solubilizing the body sample in a lysis medium, and (c) determining the overexpression of a cyclin-dependent kinase inhibitor in the solubilized body sample by comparing the level of said cyclin-dependent kinase inhibitor within said solubilized body sample with the level present in a solubilized healthy human body sample. The samples for use in the method of the present invention may be of any kind including cells in a cell preservation solution as is used for Liquid based cytology methods. The present invention is further directed to a test kit for determining the level of cyclin-dependent kinase inhibitors comprising probes specific for said cyclin-dependent kinase inhibitor and a lysis medium for solubiliation of a body sample. The test kit may be an in-vitro diagnostic device. In certain embodiments of the present invention the kit is provided as an in-vitro diagnostic device. Therefore the present invention is also directed to an in-vitro diagnostic device comprising probes directed against a cyclin-dependent kinase inhibitor fixed on solid carriers, for measuring the cyclin-dependent kinase inhibitor in a solubilized sample. The present invention is furthermore directed to a method of development of kits and in-vitro diagnostic devices for assessment of diagnosis of medically relevant conditions from solubilized body samples, wherein the development is performed using body samples provided as preserved cells in a cell-preservation medium and wherein the preserved cells are intended and prepared for use in cytological examination processes such as Liquid Based Cytology processes. The samples intended for Liquid Based Cytology processes (in the following denominated as LBC samples) are solubilized in an appropriate lysis medium and are used for development activities of kits and in-vitro diagnostic devices for detection of medically relevant conditions from solubilized body samples on the basis of biochemical non-cell-based analysis. The present invention is also directed to a method for assessment of diagnosis of medically relevant conditions by biochemical non-cell-based analysis of the presence or absence and or the level of marker molecule in solubilized body samples, wherein the body sample is an LBC sample, and wherein the detection of marker molecules is carried out by detection of the presence or absence and or the level of proteins, peptides, nucleic acids or fragments thereof in said solubilized samples. The marker molecules that may be applied for this method are disclosed above as “marker molecules characteristic for medically relevant conditions”. The method may be applied to any medically relevant condition.

20060801

20110426

20070816

67529.0

C12Q168

DENT, ALANA HARRIS

METHOD FOR DETECTING NEOPLASTIC DISORDERS IN A SOLUBILIZED BODY SAMPLE

UNDISCOUNTED

ACCEPTED

C12Q

ACCEPTED

Hair Drier

“IMPROVED HAIR DRIER” including a housing, inside which an electrical engine is mounted, which activates a rotor generating an axial air flow crossing the equipment and contacting the heating element represented by an electrical resistances, duly mounted in a spacing structures; the housing of the relevant hair drier further incorporates a gripping part from which the electrical cable emerges, thereby allowing to connect the equipment with the electrical network, the gripping part further incorporating keys which control independently both the activation of the electrical engine and also the activation of the electrical resistance, the relevant hair drier is characterized for incorporating an ionizing device, which essentially is a high voltage source with a limited current; the ionizing device is connected with the conventional electrical circuit of the equipment, it being activated simultaneously with the activation of the electrical engine, or further at the time of the conjoint activation of both electrical engine and electrical resistance; from the ionizing device, at least one cable emerges, which is duly insulated by a sheath, and at the end of the cable an active pole x is mounted.

1. “IMPROVED HAIR DRIER” comprising a housings, inside which an electrical engine is mounted, which activates a rotor generating an axial air flow crossing the equipment and contacting a heating element represented by an electrical resistance, duly mounted in a spacing structure; the housings of the relevant hair drier further incorporates a gripping part from which an electrical cable emerges, thereby allowing to connect the hair drier with an electrical network, said gripping part further incorporating keys which control independently both activation of the electrical engine and also activation of the electrical resistance, the hair drier further comprising an ionizing device, which is essentially a high voltage source with a limited current; the ionizing device is connected with the drier by a conventional electrical circuit, it being activated simultaneously with the activation of the electrical engine, or further at the time of the conjoint activation of both electrical engine and the electrical resistance; from the ionizing device, at least one cable emerges, which is duly insulated by a sheath, and at an end of the cable an active pole X is mounted. 2. “IMPROVED HAIR DRIER” according to claim 1, wherein the cable passes along a central region of the spacing structure where the electrical resistance is mounted. 3. “IMPROVED HAIR DRIER” according to claim 1, wherein the active pole (X) is configured by a needle-shaped element having an essentially tapered format, with a sharp-pointed end. 4. “IMPROVED HAIR DRIER” according to claim 3, wherein the needle-shaped element configuring the active pole (X) is positioned preferably near a previous end of the spacing structures, which location coincides with a point of highest air flow speed crossing the equipment. 5. “IMPROVED HAIR DRIER” according to claim 1, wherein the relevant drier may incorporate two or more active poles.

The present report describes a hand hair dryer, such as that commonly used in beauty parlors and related establishments, incorporating an improvement which is particularly associated with the incorporation, in said equipment, of a ionizing device producing negative ions. As it is known by professionals operating in electrical and/or electronic projects, a high voltage source duly installed can emit a great number of negative ions. It is further known by said professionals that a negative ion generator is essentially similar to an electrostatic generator, which is a device producing high voltage. Based on this functional principle, air-sterilizing devices were launched in the 70's, incorporating internal ionization devices, which provided ionization of the air passing inside the equipment, thereby producing ambient air sterilization effect. On the other hand, the electrostatic energy is also generated in a natural manner, for example, when hairs are brushed with combs or brushes manufactured in plastic material. Under such circumstances, friction between the hair and the comb (or brush) induces the electrical load exchange, causing the hair to be loaded with a positive polarity static electricity. When loaded with a positive load, hairs usually become ruffle or bristly, in a level proportional to the load applied to the same. To a certain extent, in some cases the static electricity ends up to damage the quality of coiffure, since hairs, when loaded, are likely not to assume the desired arrangement, such a phenomenon being more frequent in dry days, with a few air humidity. In view of such a disadvantage, the improved air drier under this invention privilege patent has been developed, which incorporates an ionizing device generating negative ions which are drawn by the air draft crossing the equipment and are directed towards user's hair, causing the same to be negatively ionized. The ionizing effect produced by the proposed hair drier allows possible positive loads present in hairs (responsible for the bristly effect) and generated, for example, by the use of combs or brushes manufactured in plastic material, to be neutralized by negative ions which are administered to the drying air flow through the ionizing device incorporated to the equipment. In view of the foregoing, one of the objectives of the present invention privilege patent is providing a hair drier incorporating in its structure, in addition to conventional components, such as electrical resistance, electrical engine, turbine or rotor driven by said electrical engine etc., an ionizing device which, as it allows neutralization of occasional positive static loads present in hairs, through generation of negative ions, it may allow to get a better quality in the execution of coiffures in general. Another objective of the present invention privilege patent is providing a hair drier with a ionizing device which, due to its technical characteristics, presents a total operating safety on the part of the user. The hair drier under the present invention patent will be described in details in drawings listed below, in which: FIG. 1 illustrates a general and schematic view of the relevant hair drier; and FIG. 2 illustrates a view showing individually the negative ion generating device and the connection thereof with the needle operating as a negative ion emitting pole; said FIG. 2 further counts on an enlarged detail showing specially the negative ion emitting pole. According to illustration of above-mentioned figures, the improved hair drier under the present invention privilege patent comprises a housing 1 inside which an electrical engine 2 is mounted, activating a rotor or turbine 3 which generates an axial air flow crossing the device and contacting the heating element represented by an electrical resistance 4, which is duly mounted in a spacing structure 5. The housing 1 of the relevant hair drier further incorporates a gripping part 6 from which the electrical cable 7 emerges, allowing to connect the device with the electrical network, said gripping part 6 further incorporating keys 8 which individually control both electrical engine 2 activation and electrical resistance 4 activation; the relevant hair drier is characterized for incorporating an ionizing device 9 which essentially is a high voltage source with a limited current. The ionizing device 9 is connected with the conventional electrical circuit of the equipment, it being activated simultaneously with activation of the electrical engine 2 or further at the conjoint activation of both electrical motor 2 and electrical resistance 4. The ionizing device 9 is illustrated in a schematic manner, as in itself it is a very known component. From the ionizing device 9, at least one cable 10 emerges, which is duly insulated by a sheath 11, said cable 10 passing along the central region of the spacing structure 5, where the electrical resistance 4 is mounted, as illustrated in FIG. 2. At the end of cable 10 a needle-shaped element 12 is connected, presenting an essentially tapered format, with a sharp-pointed end 13. Physical configuration of the needle-shaped element 12 can be best noted from the enlarged detail of FIG. 2. The needle-shaped element 12 configures an active pole X, which is positioned preferably near the previous end of the spacing structure 5, which local coincides with the point with the highest air flow speed crossing the equipment and that therefore presents a higher effectiveness and yield as to improvement of ions produced by device 9. As it happens with a conventional hair drier, air is admitted by the rear region of housing 1, it being accelerated by rotor 3 and forced to follow by duct defined along said housing 1. Further in a conventional manner, the air flow reaches the frontal region of the equipment, which presents a slight splay determining the region of a progressive pressure increase and therefore of a higher air flow speed and exactly in that region where the air flow assumes a higher speed, the active pole X is positioned, where the negative ions are generated. Air drier housing physical configuration as illustrated in FIGS. 1 and 2 should be understood as an example, since the relevant ionizing device can be easily incorporated to other hair drier models. In the present case, device 9 operates only one active pole X, and such a fact also does not impede the adoption of two or more active poles X, depending on the desired ionization level. needle-shaped element 12 can be best noted from the enlarged detail of FIG. 2. The needle-shaped element 12 configures an active pole X, which is positioned preferably near the previous end of the spacing structure 5, which local coincides with the point with the highest air flow speed crossing the equipment and that therefore presents a higher effectiveness and yield as to improvement of ions produced by device 9. As it happens with a conventional hair drier, air is admitted by the rear region of housing 1, it being accelerated by rotor 3 and forced to follow by duct defined along said housing 1. Further in a conventional manner, the air flow reaches the frontal region of the equipment, which presents a slight splay determining the region of a progressive pressure increase and therefore of a higher air flow speed and exactly in that region where the air flow assumes a higher speed, the active pole X is positioned, where the negative ions are generated. Air drier housing physical configuration as illustrated in FIGS. 1 and 2 should be understood as an example, since the relevant ionizing device can be easily incorporated to other hair drier models. In the present case, device 9 operates only one active pole X, and such a fact also does not impede the adoption of two or more active poles X, depending on the desired ionization level.

20070508

20100921

20071129

64956.0

A45D2010

ROBINSON, DANIEL LEON

HAIR DRIER

SMALL

ACCEPTED

A45D

ACCEPTED

Provision of diagnosis information

The invention relates to a method for generating a system for providing diagnosis information, and to a corresponding system. The aim of the invention is to simplify the provision of information for diagnosing technical installations or technical processes. To this end, components pertaining to an automation system and having diagnosis interfaces for providing diagnosis information for diagnosing the respective components are collected in at least one group, and the diagnosis information of the respective group is provided by combining the diagnosis information of the components collected in the respective group.

1.-22. (canceled) 23. A method of providing diagnosis information for an automation system, comprising: providing a plurality of components of an automation system, at least a part of the components each comprising a diagnosis interface for transmitting diagnosis information related to the respective component; forming at least one component group including the part of the components; interrelating the diagnosis information of the part of the components to form a group diagnosis information; and providing the group diagnosis information. 24. The method in accordance with claim 23, further comprising: forming a higher-ranking group by assigning at least one of the component groups and/or individual components to the higher-ranking group; and interrelating the group diagnosis information of the assigned component groups and/or the diagnosis information of the assigned individual components to form a higher-ranking group diagnosis information. 25. The method in accordance with claim 23, wherein the components are part of an installation layout, and the group diagnosis information is formed based on the installation layout. 26. The method in accordance with claim 25, wherein the installation layout includes tasks and a networking plan of the components. 27. The method in accordance with claim 25, wherein the installation layout includes a definition of which component groups and/or which individual components are part of a higher-ranking group. 28. The method in accordance with claim 23, wherein the diagnosis information of each component included in the part of the components has the same semantic structure. 29. The method in accordance with claim 23, wherein the diagnosis information includes rules for logically combining input variables and for providing at least one output variable based on the combined input variables. 30. The method in accordance with claim 23, wherein the components and the component groups are assigned to classes, each class defining functions and attributes of the assigned components respectively groups. 31. A system for providing diagnosis information of an automation system, wherein the automation system has a plurality components, at least a part of the components each comprise a diagnosis interface for transmitting diagnosis information related to the respective component, and at least one component group including the part of the components is formed, the system comprising a computing unit configured to interrelate the diagnosis information of the part of the components to form a group diagnosis information. 32. The system in accordance with claim 31, wherein a higher-ranking group is formed by assigning at least one of the component groups and/or individual components to the higher-ranking group, and the computing unit is further configured to interrelate the group diagnosis information of the assigned component groups and/or the diagnosis information of the assigned individual components to form a higher-ranking group diagnosis information. 33. The system in accordance with claim 31, wherein the components are part of an installation layout, and the group diagnosis information is formed based on the installation layout. 34. The system in accordance with claim 33, wherein the installation layout includes tasks and a networking plan of the components. 35. The system in accordance with claim 33, wherein the installation layout includes a definition of which component groups and/or which individual components are part of a higher-ranking group. 36. The system in accordance with claim 31, wherein the diagnosis information of each component included in the part of the components has the same semantic structure. 37. The system in accordance with claim 31, wherein the diagnosis information includes rules for logically combining input variables and for providing at least one output variable based on the combined input variables. 38. The system in accordance with claim 31, wherein the components and the component groups are assigned to classes, each class defining functions and attributes of the assigned components respectively groups. 39. The system in accordance with claim 33, further comprising a display device for visualizing the diagnosis information based on the installation layout.

CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to the German application No. 10343963.3, filed Sep. 19, 2003 and to the International Application No. PCT/EP2004/009445, filed Aug. 24, 2004 which are incorporated by reference herein in their entirety. FIELD OF INVENTION The invention relates to a method for generation of a system for provision of diagnosis information and to a corresponding system. BACKGROUND OF INVENTION DE 100 08 020 A1 describes a diagnosis device in a process control system which uses multi-variable control techniques, with a diagnosis tool automatically recording and storing data which specifies a control parameter, a mode parameter, a status parameter and a limit value parameter which belong to each of the different devices, groups or functional blocks within a process control system in order to determine which devices, groups or functional blocks have problems which lead to a reduced performance of the process control system, displaying a list of the recorded problems to an operator and subsequently suggesting the use of further more specific diagnosis tools to further pinpoint the problems or to correct them. SUMMARY OF INVENTION An object of the invention is to simplify the provision of information for diagnosis of technical installations or technical processes. This object is achieved by a method for generation of a systems for provision of diagnosis information, said method collecting into at least one group components of an automation system which feature diagnosis interfaces for provision of diagnosis information for diagnosis of the relevant components and the provision of diagnosis information of the relevant group is undertaken by logical combination of the diagnosis information of the components collected in the relevant group. This object is achieved by a system for provision of diagnosis information, with components of an automation system, which feature diagnosis interfaces for provision of diagnosis information for diagnosis of the relevant component collected into at least one group, with means being provided for the provision of diagnosis information of the relevant group by logical combination of the diagnosis information of the components collected in the respective group. The invention is based on the knowledge that the proportion of distributed, component-based automation systems is increasing and that thus there is a need to be able to diagnose these systems when faults occur. The diagnosis should not be limited just to single automation components in such cases but must make it possible to enable the entire automation system or its subsystems to be investigated and where possible to do this with a uniform, end-to-end operating paradigm. The engineering outlay involved in creating a system-wide diagnosis for a distributed automation system is usually very high, also conditional on the fact that the diagnostic system has previously had to be created specifically for a specific installation. The diagnosis of distributed automation solutions has up to now been aimed as a rule at the diagnosis of individual components (e.g. the diagnosis software is supplied together with the relevant hardware component) or can only be established through expensive project planning for the relevant installation. This project planning is usually created manually by automation specialists with reference to the installation layout (paper printout) and the functional description of the installation. Thus the diagnosis of a component (diagnosis tool is supplied by the component manufacturer) has differed from the diagnosis of the installation (is supplied by the installation manufacturer). The invention makes possible both a component-based diagnosis and also simultaneously a diagnosis of groups comprising components. A group will also be referred to below as a subsystem or diagnosis subsystem. The diagnosis information of the groups can be supplied in such cases by logical linkage of the diagnosis information of the components collected in the respective group. This especially provides the opportunity to generate the system for provision of diagnosis information or to provide the diagnosis information automatically. The engineering outlay for creating a diagnosis system is significantly reduced in this way. As described, the invention provides an access path to component diagnosis. On the other hand the invention also offers the option of installation diagnosis, with on the one hand the [;ant diagnosis starting at a higher level of abstract ion than the component diagnosis, but on the other hand building on component diagnosis. In accordance with an advantageous embodiment of the invention, subordinate groups or subordinate groups and components are collected into at least one higher-ranking group, with the generation of diagnosis information of the relevant higher-ranking group being provided by logically combining the diagnosis information of the groups or components collected in the respective higher-ranking group. At the highest level of the diagnosis hierarchy thus produced stands the diagnosis system of the installation or of the process, which is thus made up of groups or diagnosis subsystems, with these diagnosis subsystems able to contain further diagnosis subsystems. A self-similar, a fractal system is produced. The fractality in particular includes the fact that the installation description, like the component description, is based on the same interfaces and can thereby be processed directly by existing diagnosis tools developed for component diagnosis or by further developments of such tools. This enables a uniform, end-to-end operation, a reduction of the costs for installation diagnosis tool development and further development. It is advantageous if the interfaces of the automation components are described in a standardized manner, by a specification of PROFInet Webintegration for example. The standardized interfaces of the components, which also include diagnosis functionality, enable a control system to create a complete diagnosis system for one group of components in each case through logical combination with the layout information. In this case the diagnosis function of a subsystem is based on the standardized diagnosis functions of the automation components that it contains. In accordance with a further advantageous embodiment of the invention the components are elements of an installation layout and the diagnosis information is logically combined as a function of information contained in the installation layout. One object of the system diagnose is the detection of errors which arise from the interaction of the components of the installation. The installation manufacturer defines the interaction of the components through the layout planning of the installation. The proposed embodiment of the invention makes it possible to derive an installation diagnosis from the digital installation layout created during the installation planning phase by generating it automatically. In addition to shortening the engineering times, this also leads to a reduction in the probability of errors during creation of the diagnosis system. A novel method is thus proposed which makes it possible to automatically derive from layout information a diagnosis system, especially for a distributed automation system including its components, with this system having the attribute of fractality as regards its diagnosis functions. The installation components are collected in the installation layout into logically associated groups, known as diagnosis subsystems This process can for example correspond to the determination of the technological hierarchy often to be defined in the planning phase. In this case a specific definition of a hierarchy of diagnosis subsystems based on the layout is omitted. Ex ante however the diagnosis subsystems do not have to cover the same areas as the elements of the technological hierarchy required for operational control (subsystems, units, . . . ), in particular entirely different aspects, e.g. locality, can determine the structuring of the diagnosis hierarchy. These diagnosis subsystems encapsulate the automation components contained within them and thus reduce the complexity of the diagnosis of the overall system. In accordance with a further advantageous embodiment of the invention, tasks and networking of the components are also specified by the installation layout. Advantageously the membership of the groups in higher-ranking groups, i.e. of diagnosis subsystems in the next higher hierarchy level, can also be defined in the installation layout. This corresponds to the collection of the associated diagnosis subsystems into an encapsulating diagnosis subsystem at a higher level. In accordance with a further advantageous embodiment of the invention the diagnosis information is structured in a semantically similar manner. On the basis of the diagnosis hierarchy defined in the installation layout a semantically similar diagnosis function can be generated automatically for all elements of the hierarchy. This is based on the following principle: The generated diagnosis function of a component checks its own status when called. Depending on the result, the diagnosis function reports an error including description. At the level of the next-highest level the generated diagnosis function of a subsystem for example checks its own status and calls the diagnosis function of the associated component. Depending on the values obtained, the diagnosis function reports an error with description if necessary. This means that the purely logical diagnosis subsystems also possess a diagnosis function. This principle is applied recursively up to the highest level, i.e. the diagnosis function of the diagnosis subsystem is characterized so that it calls the diagnosis functions of the directly subordinate subsystems in each case. In addition to this propagation of diagnosis function calls from a higher level down to the respective subordinate level of the diagnosis hierarchy, higher-value diagnosis functionality can be generated automatically in the sense of induction by including the installation logic. Advantageously the diagnosis information includes functions which combine input variables—especially logically combining them—and provide at least one output variable as a result of the logical combination of the input variables. The applicable installation or system logic can be subdivided in this case into two categories. “Single Level Logic” maps the logic of an element of the diagnosis hierarchy. In this case internal information of the element concerned is logically combined. “Multi Level Logic” maps the logic of a subsystem, building on the subordinate elements “contained with in it”. For recursive generation of the diagnosis functions (these are for example characterized as a script) the rules are then incorporated into the characterization of the diagnosis functions. In the case of single level logic the defined roles are accepted directly into the diagnosis function. In the case of multi-level logic, the rule to be used in the given case is determined on the basis of the installation layout, since multi-level logic arises from the interaction between different components. Diagnosis information is thus generated by recursive application of a system of rules which logically combines standardized diagnosis interfaces with layout information. Consistency rules (“constraints”) can be defined for both categories or can already be present as type attribute of the components or also the subsystem classes used. These rules are generally already present when the invention is used as part of a component (e.g. as what is referred to as a facet) or diagnosis subsystems (e.g. for re-use of the planning information of parts of older installations). In accordance with a further advantageous embodiment of the invention classes are assigned to the components and the groups which define functions and properties of the relevant component or group. The definition of device classes (relative to components and subsystems) with defined functions and properties can be the basis for the creation of single-level and multi-level logic. By using the inherent rules or rules building on them and by including the installation layout, diagnosis functionality can be derived and generated automatically, as outlined above. The rules can be applied recursively because of the fractality and thus, starting from smaller component groups, a diagnosis system can be built up for the entire installation. The invention can advantageously be used to supply diagnosis information in a distributed, component-based automation system. Thus a method is proposed in particular for the automatic generation of a function-fractal installation diagnosis system for a distributed, component-based automation system from layout information. If, in accordance with a further advantageous embodiment of the invention, the components are PROFInet components, the automation functionality is produced by what are known as RT-Autos, so that diagnosis subsystems at the lowest level encapsulate the associated RT-Autos. Advantageously means are provided for the visualization of the diagnosis information on the basis of the installation layout. It is proposed that the inventive system be used for the diagnosis of a technical installation or a technical process. BRIEF DESCRIPTION OF THE DRAWINGS The invention is described and explained in more detail below on the basis of the exemplary embodiments shown in the figures. The figures show: FIG. 1 a system for provision of diagnosis information, FIG. 2 a logical diagnosis hierarchy derived from the installation layout, FIG. 3 the execution sequence for generating diagnosis information, FIG. 4 a diagnosis script function, FIG. 5 information contained in the installation layout, FIG. 6 the fractality of the diagnosis functionality, FIG. 7 the planning of an installation layout with a CAD system, FIG. 8 a diagnosis network from the installation layout, FIG. 9 the engineering workflow and FIG. 10 the visualization of diagnosis information. DETAILED DESCRIPTION OF INVENTION FIG. 1 shows a system for provision of diagnosis information. An automation system 5 features components 4 which feature diagnosis interfaces for providing diagnosis information for diagnosis of the relevant component 4. The components 4 are divided into two groups 6 in the example shown. The system features means for provision of diagnosis information 2 of the relevant group 6 by logically combining the diagnosis information 1 of the components 4 collected into the relevant group 6. The two groups 6 and a further component 4 are collected into a higher-ranking group 7. Diagnosis information 3 of the higher-ranking group 7 is generated by logically combining the diagnosis information 1, 2 of the groups 6 or components 4 collected in the higher ranking group 7. The system is used in the example shown for diagnosis of a technical process 8. The automation system 5 is used for automation of the technical process 8. FIG. 2 shows a logical diagnosis hierarchy derived from the installation layout using PROFInet as an example (see below for a more detailed explanation of the PROFInet technology). An installation 10 is divided up into what are known as physical device objects P (also called PDev). PROFInet defines a runtime object model which each PROFInet device must implement. In this case each of the objects of the object module is usually realized by a COM object. In detail the objects are as follows: The Physical Device object P, which represents the device as a whole. It serves as an entry point for other devices, i.e. the first contact with a PROFInet device is made via this object. The Physical Device object P represents the physical properties of the component concerned. Precisely one instance of the physical device object P exists on each hardware component (e.g. PLC, drive, PC). The Logical Device object L (also known as LDev) represents the runtime environment in which the user program will be processed. The distinction between physical and logical device object P or L is generally unnecessary for embedded devices, but for runtime systems this distinction is however important since two soft PLCs can execute on one PC. The PC is in this case the physical device, the soft PLC is a logical device in each case. The logical device object L possesses interfaces for requesting the operating state, the time of day, collective and detailed diagnosis. What are known as runtime automation objects (also called RT-auto) represent the actual technological functionality of the device. The interfaces of the objects are thus dependent on the task which the object fulfills. An interface can contain both data (read and write) and also methods and events. The concrete properties of a PROFInet device are described by an XML file. This device description contains for the different objects of a PROFInet device its interfaces, the methods and data contained within them. Thus in particular the technical functionality of a device represented by the runtime automation object A can be described in the simplest manner. On the bas is of the diagnosis hierarchy defined in the installation layout, a semantically similar diagnosis function is automatically generated for all elements of the hierarchy. The principle is illustrated below using PROFInet as an example. A generated diagnosis function of a Logical Device object L checks its own status when called. Depending on the result, the diagnosis function reports an error inclusive of description. At the level of the runtime automation object A the generated diagnosis function checks the status of the relevant object and calls the diagnosis function of the associated logical device object L. Depending on the values received, the diagnosis function where necessary forms an error message with description. At the lowest level of the diagnosis subsystem S, the generated diagnosis function of a subsystem S calls the diagnosis functions of the subordinate runtime automation object A. Thus purely logical subsystems S also possess a diagnosis function. This system is applied recursively up to the highest level 11, i.e. the diagnosis function of the diagnosis subsystem S is characterized so that it calls the diagnosis functions of the directly subordinate subsystems S in each case. As well as this propagation of diagnosis function calls from a higher level to the subordinate level of the diagnosis hierarchy in each case higher-value diagnosis functionality can be generated automatically in the sense of the induction by including the installation logic. The layout of the installation, i.e. the topological arrangement of the components of the distributed automation system, is usually created in the planning phase of an installation. In this case a technology-driven hierarchical division of the overall installation into sub-installations, machines etc is undertaken (also known as sub-division into “subsystems”). It is assumed below that these technologically-based subsystems cover the same areas as the diagnosis subsystems. FIG. 2 illustrates the division of the overall installation into subsystems on the basis of the installation layout. FIG. 3 shows the execution sequence of the generation of diagnosis information 17, 26. The applicable installation or system logic can be subdivided into two categories. Single-level logic maps the logic of precisely one element 12 of the diagnosis hierarchy. In this case internal information 14 of the element 12 is logically combined. Thus for example the logic of a subsystem of class 13 “gate” indicates that a system error is present if the gate (because of a defective sensor for example) reports “OPEN=1” and “CLOSED=1”. This logical rule 15 will be converted in an automatic generation step 16 into an item of diagnosis Information 17, e.g. a diagnosis script. So called Multi-level logic maps the logic of a subsystem building on the underlying elements 18 or 21 which it contains. If for example a subsystem contains an element 21 of the class 22 “flow meter” and a second element 18 of the class 19 “valve”, there is a system error if the element 21 reports a “flow”>0″ while the second element 18 reports the position “closed”. The characteristics of the elements 18, 21 are identified by the reference symbols 20 or 23. As in the examples, consistency rules (constraints) can be defined for both categories or can already be present as type attributes of the components or also of the subclasses used. These rules are generally already present as part of a component (e.g. as a facet) or diagnosis subsystem when the invention is applied (e.g. for re-use of the planning information of parts of older installations). For recursive generation of the diagnostic functions (those characterized as a script for example) the rules are then incorporated into the characterization of the diagnosis functions. In the case of single-level logic the defined roles are accepted directly into the diagnosis function, in FIG. 3 the diagnosis function 17. In the case of multi-level logic the rule to be used in the given case is determined on the basis of the installation layout, since multi-level logic arises from the interaction between different components. FIG. 4 shows an example of diagnosis information which is executed as a diagnosis script function. FIG. 5 shows the information included in the installation layout. In the exemplary embodiment in accordance with FIG. 5 information is included in the installation layout about PROFInet components 30, about the hierarchical structure 31 from the diagnosis viewpoint and about generic diagnosis functions 32. The basis for the creation of single-level and multi-level logic is the definition of device classes (components and subsystems) with defined functions and properties. By using the inherent rules or rules building on them and by including the installation layout, diagnosis functionality can be derived and generated automatically as outlined above. FIG. 6 shows the fractality of the diagnosis functionality. The diagnosis hierarchy finally produced thus exhibits from the point of view of the installation the attribute of self-similarity (fractality). This means that all elements of the hierarchy have semantically the same self-similar diagnosis functionality 38, 40. This also includes subsystems 35, although these purely logical elements are not represented by any real automation component 36. In this case all the information needed for the automatic generation can be derived from the installation layout 37, 42. Individually these are the components used (e.g. PROFInet) 36, the collection of these components 36 into subsystems 35, and the further diagnosis hierarchy up to installation level. Information contained in the installation layout 37, 42 is used in such cases for generation of rules 39 or 41 for diagnosis of components 36 or subsystems 35, with the aid of diagnosis functions 38 or 40. FIG. 7 shows the planning of the installation layout with a CAD system. Here a subsystem is defined either through the definition of the tree-type installation structure (node is a subsystem, leaves are system components or again subsystem nodes) or through aggregation. With a CAD system usually used for planning of an installation layout subsystems can be defined for diagnosis by marking the components belonging to a subsystem. In FIG. 6 the components belonging to a subsystem are defined for example by drawing a polygon (lasso) which encloses the components. In this case a polygon can entirely enclose further polygons. These embedded polygons then correspond to the visual definition of subordinate diagnosis subsystems. FIG. 8 shows a diagnosis network created from the installation layout The installation layout already includes all the information needed for the further steps of the generation of a system for provision of diagnosis information, such as the assignment of runtime automation objects 47 to components 45 and thereby to subsystems 48. The components handled in the planning phase possess a diagnosis view as well as a topological view (position in the installation, dimensions, form, etc.). The connection of the diagnosis view of the components with the hierarchy enables the diagnosis functionality to be generated automatically as described above. Building on the diagnosis view of the components, diagnosis functions for the enclosing subsystems included can be generated in a first step. From this in the second step diagnosis functions for further subsystems right up to installation level are generated recursively. In the generated diagnosis functions the constraints already present for the relevant hierarchy levels (e.g. as a class attribute of a component) or those specified explicitly are included for the single-level or multi-level logic FIG. 9 shows the engineering workflow for generating a system for the supply of diagnosis information. Staring from an installation layout 50, an XML configuration file 52 is created automatically in a step identified by reference symbol 51. This XML document contains the information contained in the installation layout 50 about the PROF Inet components used, the hierarchical structure (subsystems) as well as the automatically generated diagnosis functions in the form of script functions. The XML Config File 52 is for example loaded and processed by an installation diagnosis server 53. The installation diagnosis server 53 is then in a position to execute all diagnosis script functions and thereby to diagnose the installation, subsystems and components. FIG. 10 shows a prototypical visualization which builds on an installation diagnosis server. The visualization shown is based on a concept which combines graphics components with the diagnosis subsystems and thereby makes it possible to show faults of a subsystem in the installation graphics. The implementation consists of the installation diagnosis server and a client application for visualization purposes. The communication between client and server is undertaken by means of Web services and is based on the HTTP protocol. Both server and client can be used in a plurality of different installations without modifications being required since the server is initialized by means of the XML document containing the necessary information. The approach described here it not only provides the opportunity of automatic generation of the diagnosis functionality and thus of a significant reduction in the engineering effort required, but also the advantage of an end-to-end diagnosis concept. The end-to-end diagnosis concept is not restricted in this case to component diagnoses but, by forming subsystems with diagnoses functionality, reduces the complexity of the installation as a whole, especially for the installation operators. The combination of the installation topology with the rule-based diagnosis hierarchy of the subsystems derived from it can also been used to derive a diagnosis interface in accordance with FIG. 10 directly. The faulty components and the subsystems enclosing them in the layout can for example be highlighted by marking them in color. This can also be done accordingly in the tree presentation, for example recursively, beginning with the faulty components and moving upwards to the installation node. By directly selecting the component marked as faulty in the layout by clicking on it with the mouse, comprehensive component-related diagnosis information can be called up. One possible option for executing the automatically generated diagnosis functions is the generation of script functions. These script functions can for example be executed in a so-called installation diagnosis server and process the diagnosis functions. In principal this concept can also be realized decentrally, for example in a subsystem diagnosis server which resides in a PDev. This concept additionally guarantees that the approach of automatic generation of an installation diagnosis system can also be integrated without any adverse effects in existing installations. In summary the invention thus relates to a method for generating a system for provision diagnosis information 1, 2, 3 as well as to a corresponding system. To simplify the supply of information for diagnosis of technical installations or technical processes it is proposed that the components 4 of an automation system 5 which have diagnosis interfaces for supply of diagnosis information 1 for diagnosis of the relevant component 4 are collected into at least one group 6 and that the supply of diagnosis information 2 of the relevant group 6 is provided by combining the diagnosis information 1 of the components 4 collected in the relevant group 6. Information about the technical background of the invention is given below. This is based on the technical articles published on the Internet (http://www.elektroniknet.DE/topics/automatisieren/fachthemen/artikel/2001/01018.htm or . . . /01027.htm) by Georg H. Biehler, Wolfram Gierling, “Das Engineering-Modell” (the engineering model) and Joachim Feld, Ronald Lange, Norbert Bechstein, “Das Laufzeit-Modell” (the runtime model). The Profibus user organization presented the communication, automation and engineering model PROFInet in August 2000. The coalescence of industrial automation and the IT of the higher corporate levels and the global networking of corporations at all levels of the Internet is the decisive factor in the known Profibus technology having been expanded vertically. An end-to-end concept for the vertical data integration was created under the term PROFInet. In this case, for reasons of consistency with higher levels of an automation system, the communication means Ethernet is employed. with full compatibility to conventional Profibus technology being retained. The PROFInet concept comprises three aspects: For the project planning of PROFInet systems a non-proprietary engineering concept was defined. It is based on an engineering object model with which not only project planning tools can be developed which can use the components of different manufacturers but with which proprietary or user-specific functional expansions can be defined by means of so-called facets. Thus, by the clear separation between the proprietary programming of the individual devices and the installation-wide connection to a higher-ranking engineering tool, known as the connection editor, products from different manufacturers can be integrated into an installation. Furthermore PROFInet specifies an open object-oriented runtime concept. The runtime concept defines the widely used mechanisms from the Ethernet sector such as TCP(UDP)/IP as a basis for communication. DCOM mechanisms are accommodated above the basic mechanisms. Alternatively for application areas with strict real time, a communication mechanism optimized for this purpose is available. The PROFInet components are mapped in the form of objects for which the communication is guaranteed by the mechanisms of the object protocol. The projected connections are ensured by the creation of the communication relationships and the exchange of data between PROFInet subscribers. In the term PROFInet covers a uniform object-based architecture concept for distributed automation systems from the I/O level to the control level, which integrates systems which follow the conventional Profibus technology seamlessly into the overall system. The Profibus system and other field bus systems are integrated into a PROFInet-system by means of proxies. A proxy is a software module that implements by proxy the functionality of automation objects both for the subscribers on the Profibus and also in relation to the other PROFInet subscribers on the Ethernet. Through the specification of the three aspects named above allows PROFInet to cover all lifecycle phases of a distributed automation system. The topic of engineering is that aspect of PROFInet which has the greatest points of contact to the users of the technology. This applies equally to the system designers and also the installation operators. It is also that aspect of PROFInet which involves the greatest cost transparency potential for the setting-up and the operation of installations, since the costs at product level have been on a downward trend for many years now and the potential may well be largely exhausted. The simplification of the handling with the system played a significant role in the specification of PROFInet. In this connection the engineering tools have an important part to play. Only with their help can the costs for the installation builders and operators be significantly reduced. And in actual fact the engineering of an automation solution with PROFInet is a simple matter from the user's standpoint. However the more user friendly a system is for the users, the more complex it is under the surface. The engineering tool can be expanded dynamically so that components from any manufacturers can interoperate smoothly in an engineering tool. The widest variety of engineering aspects such as connection, parameterization, test, commissioning and diagnosis are to be made available. Existing (proprietary) programming and engineering tools must be able to continue to be used. Existing concepts such as OLE for Process Control (OPC) and Fieldbus Device Tool (FDT) are to be integrated. PROFInet should be able to interact with other DP methods in the company as a whole. These include for example Management Information (MIS) systems and Enterprise Resource Planning (ERP) systems. It must also be possible without special tools to copy data into the PROFInet engineering model or to transfer it from the system into other applications such as to Excel for example. Existing field buses, especially Profibus-DP must be able to be linked in. Before the characteristics of the engineering concept are mentioned it is important to present the underlying models. The openness of the system required in many aspects requires an end-to-end concept which takes account of these requirements. Thus PROFInet is based on an object-oriented approach—the Component Object Model (COM) of Microsoft. In this case self-contained modules are created of which the external functionality can be reached via unique interfaces, the interfaces of the object. An interface is the collection of a specific set of functions by which the service which is to be performed by a server for a client is defined. In this case one speaks of a component implementing the interface. The type of implementation itself is not however prescribed for the creator of the component Script languages such as Visual Basic for Applications (VBA) can access PROFInet objects via the OLE automation interfaces also standardized by COM. This means that the user has an especially simple option for adapting the functional scope of the PROFInet engineering tool through their own expansions to suit their requirements. A PROFInet automation solution consists at run time of automation objects communicating with each other, the runtime automation objects, abbreviated to RT-Autos. These are software components which run on the physical PROFlnet devices. The interaction of the RT-Autos must be specified with the aid of the project planning tool. For this purpose the RT-Autos have counterparts in the project planning tool which contain all necessary information for complete project planning: The engineering system automation objects (ES-Autos). On compilation and loading of application a corresponding RT-Auto is generated from each ES-Auto. So that the project planning tool knows on which device an automation object lies it has a counterpart of the object in the shape of what is known as an Engineering System Device (ES-Device). To put it precisely the ES-Device corresponds to a “logical device”. In addition there is an assignment between “logical” and “physical” devices. Mostly there is a “1:1” assignment here, which means: There is precisely one firmware for one hardware (physical device). It is however also possible for a number of independent software packages to run on an item of hardware. Examples of this are especially devices with free computing power: A PC with Slot-PLC or a Windows-CE device with user interface and PLC-Component. The term Engineering System Object (ES object) is used as a generic term for all objects in the context of the project planning tool. It includes everything that the user takes into account during project planning and everything with which he is involved. It is also the “basic class” for the engineering objects. Through the instantiation, connection and parameterization of the ES objects the model of the automation solution of a concrete installation is produced. Initiated by a download, the runtime software is created by evaluating the engineering model. The PROFInet specification describes an object model which defines the technical framework conditions for use of ES objects. PROFInet-conformant engineering systems can then be realized on this basis. On the other hand not every manufacturer of PROFInet devices is forced to develop their own project planning tool and thereby to keep reinventing the wheel. An important concept for expanding the PROFInet object model is represented by the facets. A facet implements a quite specific (part) functional scope of the ES and presents itself to the user as a special view of the object. Thus the connection facet merely considers the communication relationships of the object to other objects. For the parameterization of the object the user switches to the parameterization facet. The assignment of an automation object to a physical device is realized with the aid of the device assignment facet. Finally the connection information is downloaded onto a devices using the download facet. A number of facets are defined by the PROFInet standard. Other facets are application-specific. Each component manufacturer who implements automation objects can de fine their own types of facets. The PROFInet standard ensures these are able to be inserted into the ES object. Diagnosis facets which present the specific diagnosis information of the device in the optimum way might be mentioned as an example of these types of facets. The method which determines compatible devices for a specific automation object is implemented in the device assignment facet. This has the advantage of only allowing the project planning tool to display those devices on which the selected automation object can also be run. For devices with fixed functionality on the other hand the user can first select the device, after which the project planning tool merely displays those RT-Autos which are available on this device. The PROFInet specification discloses the interface descriptions of a project planning tool, with each manufacturer being able to create their own PROFInet-conformant project planning tool. Since this tool does not however contain any proprietary implementations it is possible at any time to use the tool of another manufacturer. Proprietary parts link the engineering tool in via defined interfaces. In accordance with the basic idea of COM programming, no implementations are prescribed but only unique interfaces defined. The PROFInet strategy then ensures that the communication functions smoothly over the bus, but on the other hand gives the manufacturers every freedom to differentiate themselves from the competition by their own implementations. The advantages of PROFInet can be seen especially in engineering. The fact that communication no longer has to be programmed but can be planned into the project simplifies the creation of an automation solution significantly. The re-use of tested solutions shortens development and commissioning times and can thereby contribute to a significant cost reduction. PROFInet is an end-to-end concept for vertical data integration, with Profibus-specific communication mechanisms deliberately being dispensed with and instead open standards having been adopted to enable Fieldbus-independent communication. The PROFInet concept defines an object model for the engineering system which is implemented with the COM component technology from Microsoft. The actual relationship of different components is described by XML (extensible Markup Language). The seven layers of the ISO/OSI reference model must be defined for the runtime system. For peer-to-peer communication between autonomous functional units Ethernet with the TCP/IP protocol suite up to layer 4 is the obvious choice. This can be understood as protocols such as TCP, UDP or ICMP which represent undisputed de-facto standards in the IT landscape. But how is Layer 7 created? In the PROFInet concept components (“objects”) are formed which are only accessible from outside via their interfaces. An interface is the collection of a specific set of functions, and thereby a type of contract. It defines which service is to be provided by a server for a client. In this case one speaks of a component implementing the interface. The type of implementation itself is however not prescribed for the creator of an object. It is thus obvious to also use an object protocol for communication between the objects at run time. PROFInet uses Microsoft DCOM (Distributed COM) in these points. DCOM is the extension of the COM technology for distributed applications. It is based on the DCE RPC (Distributed Computing Environment Remote Procedure Call) standard. One of the most important advantages of DCOM lies in the fact that the same component technology can be used for engineering and for runtime. DCOM has previously primarily been implemented on PC architectures. In the embedded area it is not necessary to implement the entire DCOM such as within Microsoft Windows. It is sufficient to implement those parts which will be visible in the network via the so-called DCOM Wire Protocol and were published as an Internet Draft. Within embedded devices the programming can remain unchanged. In particular a strict COM architecture does not have to be implemented. All implementation parts of the automation objects as COM objects with the corresponding interfaces are allowed, provided the PROFInet object impression remains preserved to the outside world. For example for a controller the objects are created in the language necessary for this controller and are run as modules. As in engineering however in runtime mode as well the syntax is defined by the (D)COM technology, but the specific expansions for the automation technology do not however have to be defined (semantics). To this end the interfaces of the automation objects can be divided up into four categories in PROFInet depending on the functionality which they cover: Mandatory interfaces: These interfaces define a standard which all resources (devices) of a PROFInet-based automation solution must implement. As well as the interfaces defined by COM—such as those of identification—the support of data and event connection is part of mandatory functionality. Optional interfaces: These are options which not every device must provide If this function is to be provided however the interface implementation is mandatory by default. Device-specific interfaces: These of the interfaces which make access to device-specific services possible. These interfaces cannot be standardized and as a rule are implemented in the firmware. The objects which implement the device-specific interfaces form the device object model. Application-specific interfaces: Here the application-specific automation objects needed are developed with programming tools which under some circumstances are target system-specific. PROFInet defines a runtime object model which each PROFInet device which is operated on the Ethernet must implement. Each of the available objects is realized by a DCOM object. Individually these are as follows: The Physical Device object (PDev): It represents the device as a whole. It serves as the entry point for other devices, meaning the first contact with a PROFInet device is made via this object. The PDev expresses the physical attributes of the component. Exactly one instance of the PDev exists on each hardware component (PLC, drive, PC). The Logical Device Object (LDev): It represents the actual program medium, meaning the parts of the device which represent the actual PROFInet nodes. Although the distinction between physical and logical device is in general unnecessary with embedded devices, this distinction is important however for runtime systems on a PC since two soft-PLCs can executed on a PC. The PC is in this case the physical device, the soft-PLC a logical device in each case. The logical device possesses interfaces for requesting the operating state, the time of day, collective and detailed diagnosis. Runtime automation objects (RT-Auto): They represent the actual technological functionality of the device. The interfaces of the objects are thus dependent on the task which the object fulfills. So for example a lifting platform has an interface to move the platform. An interface can in this case contain both data (read, write) and also methods and events. The proxies of LDev or RT-Auto respectively in the engineering are the ES-Device and the ES-Auto respectively described above. The most important object for the interaction with other PROFInet devices is the ACCO (Active Control Connection Object). This object is used for the planned establishment of communication relationships between objects. The ACCO implements a consumer-provider model. The elements of the interface of the RT-Autos are made available to other devices via the ACCO (provider). The ACCO however also registers with ACCOs of other devices and supplies the RT-Autos of its device with data or events (consumer). Communication relationships are always established from the communications side. A data or event connection between two objects (such as for example two consecutive conveyor elements) can be simply specified by project planning of the connection on the consumer side. The ACCO then automatically takes care of establishing the communication relationship and the exchange of the data. An important aspect of the ACCO is error handling. This comprises the transmission of quality code and time stamp with the values as well as the automatic provision of a planned replacement value in the event of an error. Also the monitoring of the communication partner, the reconnect after loss of a connection as well as the diagnosis and test options for connect ions. The transmission with DCOM is event-controlled, which means that the provider monitors its data for change. The subordinate layers look after securing the connection.

<SOH> BACKGROUND OF INVENTION <EOH>DE 100 08 020 A1 describes a diagnosis device in a process control system which uses multi-variable control techniques, with a diagnosis tool automatically recording and storing data which specifies a control parameter, a mode parameter, a status parameter and a limit value parameter which belong to each of the different devices, groups or functional blocks within a process control system in order to determine which devices, groups or functional blocks have problems which lead to a reduced performance of the process control system, displaying a list of the recorded problems to an operator and subsequently suggesting the use of further more specific diagnosis tools to further pinpoint the problems or to correct them.

<SOH> SUMMARY OF INVENTION <EOH>An object of the invention is to simplify the provision of information for diagnosis of technical installations or technical processes. This object is achieved by a method for generation of a systems for provision of diagnosis information, said method collecting into at least one group components of an automation system which feature diagnosis interfaces for provision of diagnosis information for diagnosis of the relevant components and the provision of diagnosis information of the relevant group is undertaken by logical combination of the diagnosis information of the components collected in the relevant group. This object is achieved by a system for provision of diagnosis information, with components of an automation system, which feature diagnosis interfaces for provision of diagnosis information for diagnosis of the relevant component collected into at least one group, with means being provided for the provision of diagnosis information of the relevant group by logical combination of the diagnosis information of the components collected in the respective group. The invention is based on the knowledge that the proportion of distributed, component-based automation systems is increasing and that thus there is a need to be able to diagnose these systems when faults occur. The diagnosis should not be limited just to single automation components in such cases but must make it possible to enable the entire automation system or its subsystems to be investigated and where possible to do this with a uniform, end-to-end operating paradigm. The engineering outlay involved in creating a system-wide diagnosis for a distributed automation system is usually very high, also conditional on the fact that the diagnostic system has previously had to be created specifically for a specific installation. The diagnosis of distributed automation solutions has up to now been aimed as a rule at the diagnosis of individual components (e.g. the diagnosis software is supplied together with the relevant hardware component) or can only be established through expensive project planning for the relevant installation. This project planning is usually created manually by automation specialists with reference to the installation layout (paper printout) and the functional description of the installation. Thus the diagnosis of a component (diagnosis tool is supplied by the component manufacturer) has differed from the diagnosis of the installation (is supplied by the installation manufacturer). The invention makes possible both a component-based diagnosis and also simultaneously a diagnosis of groups comprising components. A group will also be referred to below as a subsystem or diagnosis subsystem. The diagnosis information of the groups can be supplied in such cases by logical linkage of the diagnosis information of the components collected in the respective group. This especially provides the opportunity to generate the system for provision of diagnosis information or to provide the diagnosis information automatically. The engineering outlay for creating a diagnosis system is significantly reduced in this way. As described, the invention provides an access path to component diagnosis. On the other hand the invention also offers the option of installation diagnosis, with on the one hand the [;ant diagnosis starting at a higher level of abstract ion than the component diagnosis, but on the other hand building on component diagnosis. In accordance with an advantageous embodiment of the invention, subordinate groups or subordinate groups and components are collected into at least one higher-ranking group, with the generation of diagnosis information of the relevant higher-ranking group being provided by logically combining the diagnosis information of the groups or components collected in the respective higher-ranking group. At the highest level of the diagnosis hierarchy thus produced stands the diagnosis system of the installation or of the process, which is thus made up of groups or diagnosis subsystems, with these diagnosis subsystems able to contain further diagnosis subsystems. A self-similar, a fractal system is produced. The fractality in particular includes the fact that the installation description, like the component description, is based on the same interfaces and can thereby be processed directly by existing diagnosis tools developed for component diagnosis or by further developments of such tools. This enables a uniform, end-to-end operation, a reduction of the costs for installation diagnosis tool development and further development. It is advantageous if the interfaces of the automation components are described in a standardized manner, by a specification of PROFInet Webintegration for example. The standardized interfaces of the components, which also include diagnosis functionality, enable a control system to create a complete diagnosis system for one group of components in each case through logical combination with the layout information. In this case the diagnosis function of a subsystem is based on the standardized diagnosis functions of the automation components that it contains. In accordance with a further advantageous embodiment of the invention the components are elements of an installation layout and the diagnosis information is logically combined as a function of information contained in the installation layout. One object of the system diagnose is the detection of errors which arise from the interaction of the components of the installation. The installation manufacturer defines the interaction of the components through the layout planning of the installation. The proposed embodiment of the invention makes it possible to derive an installation diagnosis from the digital installation layout created during the installation planning phase by generating it automatically. In addition to shortening the engineering times, this also leads to a reduction in the probability of errors during creation of the diagnosis system. A novel method is thus proposed which makes it possible to automatically derive from layout information a diagnosis system, especially for a distributed automation system including its components, with this system having the attribute of fractality as regards its diagnosis functions. The installation components are collected in the installation layout into logically associated groups, known as diagnosis subsystems This process can for example correspond to the determination of the technological hierarchy often to be defined in the planning phase. In this case a specific definition of a hierarchy of diagnosis subsystems based on the layout is omitted. Ex ante however the diagnosis subsystems do not have to cover the same areas as the elements of the technological hierarchy required for operational control (subsystems, units, . . . ), in particular entirely different aspects, e.g. locality, can determine the structuring of the diagnosis hierarchy. These diagnosis subsystems encapsulate the automation components contained within them and thus reduce the complexity of the diagnosis of the overall system. In accordance with a further advantageous embodiment of the invention, tasks and networking of the components are also specified by the installation layout. Advantageously the membership of the groups in higher-ranking groups, i.e. of diagnosis subsystems in the next higher hierarchy level, can also be defined in the installation layout. This corresponds to the collection of the associated diagnosis subsystems into an encapsulating diagnosis subsystem at a higher level. In accordance with a further advantageous embodiment of the invention the diagnosis information is structured in a semantically similar manner. On the basis of the diagnosis hierarchy defined in the installation layout a semantically similar diagnosis function can be generated automatically for all elements of the hierarchy. This is based on the following principle: The generated diagnosis function of a component checks its own status when called. Depending on the result, the diagnosis function reports an error including description. At the level of the next-highest level the generated diagnosis function of a subsystem for example checks its own status and calls the diagnosis function of the associated component. Depending on the values obtained, the diagnosis function reports an error with description if necessary. This means that the purely logical diagnosis subsystems also possess a diagnosis function. This principle is applied recursively up to the highest level, i.e. the diagnosis function of the diagnosis subsystem is characterized so that it calls the diagnosis functions of the directly subordinate subsystems in each case. In addition to this propagation of diagnosis function calls from a higher level down to the respective subordinate level of the diagnosis hierarchy, higher-value diagnosis functionality can be generated automatically in the sense of induction by including the installation logic. Advantageously the diagnosis information includes functions which combine input variables—especially logically combining them—and provide at least one output variable as a result of the logical combination of the input variables. The applicable installation or system logic can be subdivided in this case into two categories. “Single Level Logic” maps the logic of an element of the diagnosis hierarchy. In this case internal information of the element concerned is logically combined. “Multi Level Logic” maps the logic of a subsystem, building on the subordinate elements “contained with in it”. For recursive generation of the diagnosis functions (these are for example characterized as a script) the rules are then incorporated into the characterization of the diagnosis functions. In the case of single level logic the defined roles are accepted directly into the diagnosis function. In the case of multi-level logic, the rule to be used in the given case is determined on the basis of the installation layout, since multi-level logic arises from the interaction between different components. Diagnosis information is thus generated by recursive application of a system of rules which logically combines standardized diagnosis interfaces with layout information. Consistency rules (“constraints”) can be defined for both categories or can already be present as type attribute of the components or also the subsystem classes used. These rules are generally already present when the invention is used as part of a component (e.g. as what is referred to as a facet) or diagnosis subsystems (e.g. for re-use of the planning information of parts of older installations). In accordance with a further advantageous embodiment of the invention classes are assigned to the components and the groups which define functions and properties of the relevant component or group. The definition of device classes (relative to components and subsystems) with defined functions and properties can be the basis for the creation of single-level and multi-level logic. By using the inherent rules or rules building on them and by including the installation layout, diagnosis functionality can be derived and generated automatically, as outlined above. The rules can be applied recursively because of the fractality and thus, starting from smaller component groups, a diagnosis system can be built up for the entire installation. The invention can advantageously be used to supply diagnosis information in a distributed, component-based automation system. Thus a method is proposed in particular for the automatic generation of a function-fractal installation diagnosis system for a distributed, component-based automation system from layout information. If, in accordance with a further advantageous embodiment of the invention, the components are PROFInet components, the automation functionality is produced by what are known as RT-Autos, so that diagnosis subsystems at the lowest level encapsulate the associated RT-Autos. Advantageously means are provided for the visualization of the diagnosis information on the basis of the installation layout. It is proposed that the inventive system be used for the diagnosis of a technical installation or a technical process.

20060228

20100810

20061116

73540.0

G06F1900

LE, TOAN M

SYSTEM AND METHOD FOR PROVIDING DIAGNOSIS INFORMATION

UNDISCOUNTED

ACCEPTED

G06F

ACCEPTED

Pharmaceutical products comprising bisphosphonates

A pharmaceutical product comprises a container containing a bisphosphonate solution, in which at least the internal surface of the container comprises a plastic material and in which the container is heat sterilisable, and which is in the form of a ready to use infusion solution, for administration of the bisphosphonate to a patient in need of bisphosphonate treatment.

1. A pharmaceutical product in the form of a ready to use solution comprising a container containing a bisphosphonate solution, in which at least the internal surface of the container comprises a plastic material and in which the container is heat sterilisable. 2. A product according to claim 1, in unit dose form having a volume of from about 20 ml up to about 500 ml. 3. A product according to claim 1 or comprising a buffering agent, preferably a basic buffering agent, more preferably an organic base buffering agent. 4. A product according to claim 3, adjusted with an organic base to a physiologically acceptable pH value of pH 5.5-8.0, preferably pH 6.0-7.5, most preferably pH 6.5. 5. A product according to claim 4, in which the organic base is sodium citrate 6. A product according to claim 4, in which the organic base is sodium acetate 7. A product according to claim 4, in which the base is sodium or potassium phosphate 8. A product according to claim 4, in which the base is sodium or potassium hydroxide 9. A product according to claim 1, comprising an isotonising agent, preferably a non-ionic isotonising agent, more preferably a sugar, ester or alcohol, e.g. mannitol, 1,2 propylene glycol, glycerol and sorbitol, of which mannitol is particularly preferred. 10. A product according to claim 9, in which the isotonising agent is a non-ionic isotonising agent and which is analysable with a limit of quantitation for the bisphophonate and its by- and degradation products of at least 0.1% related to the declared dose, preferably without applying a derivatization step. 11. A product according to claim 10, which is analysable by reversed phase chromatography with a complexation agent, e.g. EDTA, for determination of the bisphophonate and its by- and degradation products. 12. A pharmaceutical product comprising a container containing a bisphosphonate solution in the form of a ready to use solution, comprising a) a unit dose of a bisphosphonate; b) an organic base buffering agent, and c) a non-ionic isotonising agent in which at least the internal surface of the container comprises a plastic material and in which the filled container is terminally heat sterilisable. 13. A product according to claim 1, in which the container is a prefillable plastic syringe. 14. A product according to claim 1, in which the plastic material is transparent. 15. A product according to claim 1, in which the plastic material is a cycloolefinic polymer. 16. A product according to claim 15, in which the plastic material is is Daikyo CZ resin or a similar cycloolefinic polymer 17. A product according to claim 15, in which the plastic material is a Ticona TOPAS Polymer. 18. A product according to claim 15, in which the plastic material is a Schott TopPac vial or syringe. 19. A product according to claim 1 in which the container is an infusion bag. 20. A product according to claim 19, in which the infusion bag is made of polypropylene, polypropylene/Kraton blend, a multilayer bag with polypropylene or polyethylene at the product contacting side. 21. A product according to claim 19, in which the infusion bag is a Baxter Intravia container. 22. A product according to claim 19, in which the infusion bag is a Braun Ecoflac container. 23. A product according to claim 19, in which the infusion bag is a Braun PAB container. 24. A product according to claim 19, in which the infusion bag is made of a Cryovac M312 foil. 25. A product according to claim 1 in which the container is made by the Blow/Fill/Seal technology and the container material is selected from Polyethylene or Polypropylene. 26. A product according to claim 25 in which the container is made by the Blow/Fill/Seal technology and the container material is Polypropylene. 27. A product according to claim 25, in which the container is made by the Blow/Fill/Seal technology and the container material is Rexene 32M2 polypropylene. 28. A product according to claim 1, in which the bisphosphonate is an N-bisphosphonate or a pharmacologically acceptable salt thereof. 29. A product according to claim 28 in which the bisphosphonate is 2-(imidazol-1yl)-1-hydroxyethane-1,1-diphosphonic acid (zoledronic acid) or a pharmacologically acceptable salt thereof. 30. A product according to claim 28 in which the bisphosphonate is Disodium-3-amino-1-hydroxy-propylidene-1,1-bisphosphonate pentahydrate (pamidronic acid) or a pharmacologically acceptable salt thereof. 31. A process for the production of a ready to use bisphosphonate pharmaceutical product comprising a container containing a bisphosphonate solution, in which a bisphosphonate solution is provided within a container in which at least the internal surface of the container comprises a transparent plastic material and in which the container is heat sterilised, preferably moist heat sterilised. 32. A process according to claim 31, in which the container is terminally heat sterilized. 33. A process according to claim 31, in which heat sterilization is at a temperature of at least about 110° C. to about 130° C. or higher, e.g. at a temperature of at least 121° C. or higher, e.g. preferably at about 121-124° C. 34. A process according to claim 31, in which the dwell time is from about 15 minutes up to about 3 hours, conveniently from about 15 minutes to about 2 hours, e.g. preferably about 30 min. 35. A process according to claim 31, in which autoclaving conditions are applied to obtain a sterility assurance level of at least 10−6, e.g. by autoclaving (dwell time) at >121° C. for at least the 8-fold time of the D121 value of the solution. 36. A process according to claim 31, in which autoclaving conditions are applied to obtain a sterility assurance level of at least 10−12, e.g. by autoclaving (dwell time) at >121° C. for at least the 14-fold time of the D121 value of the solution. 37. A process according to claim 31, in which the container is depyrogenised before filling with the bisphosphonate solution, conveniently by washing with water, preferably under pressure. 38. A process according to claim 31, in which an endotoxin/pyrogen-free or substantially endotoxin/pyrogen-free container is obtained and is filled with the bisphosphonate solution. 39. A process according to claim 31, wherein the product comprises a non-ionic isotonising agent and in which ion chromatography, capillary electrophoresis, or high performance liquid chromatography (HPLC) is used for determination of the bisphophonate and its by- and degradation products 40. A process according to claim 26, wherein the product comprises a non-ionic isotonising agent and in which reversed phase chromatography, preferably with a complexation agent, e.g. EDTA, is used for determination of the bisphophonate and its by- and degradation products, advantageously with a limit of quantitation of at least 0.1% related to the declared dose, preferably without applying a derivatization step.

This invention relates to pharmaceutical products and processes for their production, in particular to pharmaceutical products comprising bisphosphonates and to processes for producing such bisphosphonate products. Bisphosphonates are widely used to inhibit osteoclast activity in a variety of both benign and malignant diseases which involve excessive or inappropriate bone resorption. These pyrophosphate analogs not only reduce the occurrence of skeletal related events but they also provide patients with clinical benefit and improve survival. Bisphosphonates are able to prevent bone resorption in vivo; the therapeutic efficacy of bisphosphonates has been demonstrated in the treatment of osteoporosis, osteopenia, Paget's disease of bone, tumour-induced hypercalcemia (TIH) and, more recently, bone metastases (BM) and multiple myeloma (MM) (for review see Fleisch H 1997 Bisphosphonates clinical. In Bisphosphonates in Bone Disease. From the Laboratory to the Patient. Eds: The Parthenon Publishing Group, New York/London pp 68-163). Customary bisphosphonate dosage forms, e.g. for the treatment of TIH, BM and MM, are intravenous infusion solutions. However, bisphosphonates solutions, although intrinsically stable, react with di- and polyvalent cations, especially calcium, barium, magnesium, aluminium, boron, and silicon present in glass to form insoluble precipitates giving rise to turbidity and possible loss of potency, neither of which can be tolerated in a pharmaceutical product. Further such precipitates may lead to blockage of blood vessels and thus could cause a thrombosis as serious complication of the medication. Thus long term storage of bisphosphonate solution formulations in standard glass vials, even of hydrolytic resistance class I quality is not possible. Also such solution in glass products cannot be terminally moist heat sterilized, and must be aseptically filled, because the leaching of cations is accelerated under the elevated temperature conditions of moist heat sterilization. It has been shown that at pH values acceptable for parenteral delivery, significant amounts of ions are leached out of commercially available glass containers (Farm. Vestnik. Vol 54, p. 331 (2003)). Consequently, for short term storage of solution in glass products it would be necessary to aseptically fill the solutions, although in view of their high chemical stability heat sterilisation of bisphosphonate solutions is inherently possible. Such aseptic filling does not comply with the currently accepted processing norms, as outlined in the document no. CPMP/QWP/054/98 corr., “Decision trees for the selection of sterilisation methods” issued by the European Agency for the Evaluation of Medicinal Products (EMEA). The same document also states that “the use of an inappropriate heat-labile packaging material cannot be in itself the sole reason for adoption of aseptic processing”. Consequently bisphosphonate products for iv infusion are typically provided in the form of solid lyophilisates, which do not show microbial growth promoting properties when compared with unpreserved bisphosphonate solutions at physiologically acceptable pHs. The lyophilisates are made up into the infusion solution with water for injection or other aqueous solvents shortly before use, e.g. Aredia® and Zometa®. In view of the low solubility of the precipitates formed with divalent and polyvalent cations, even the low levels of alkaline earth metal impurities present in all commercially available grades of sodium chloride and saline solutions could result in formation of such precipitates when diluting concentrated bisphosphonic acid solutions. Recently it has been proposed (WO 02/22136, F. H. Faulding & Co Ltd.) to provide a pharmaceutical product comprising a container containing a diphosphonate in solution, wherein the solution: (a) has a pH of between 5 and 8; and (b) is free of organic buffer and polyethylene glycol and wherein the container is a glass container in which the surface in contact with the solution has been pre-treated to protect against leaching of impurities from the glass by the solution or wherein the container consists of at least one component manufactured from a non-glass material, such as polyethylene, polypropylene and polymethylpentene. However, WO 02/22136 does not include any teaching as to how, when or if the product is sterilised. Further this reference does not give guidance on how to keep the pH value stable over storage time if highly potent low dosed bisphosphonates as e.g. zoledronic acid is formulated. It has now been found that bisphosphonate solutions may be formulated for long term storage in containers comprising polymeric materials which containers do not chemically interact with the bisphosphonate solution and which may be conveniently terminally sterilised. Accordingly the present invention provides a ready-to-use bisphosphonate pharmaceutical product comprising a container containing a bisphosphonate solution, in which at least the internal surface of the container comprises a plastic material and in which the container is heat sterilisable. The products of the present invention are advantageously solution products for parenteral administration which do not require reconstitution of a lyophilisate prior to use. Conveniently also the product may be heat sterilised in situ in the container during production, preferably terminally moist heat sterilised (e.g. by steam thus advantageously obtaining a Sterility Assurance Level of at least 10−6). Additionally, these ready-to-use solutions do not require dilution prior to use. The products of the invention may be administered orally, transdermally, or by injection, e.g. subcutaneously, arterially or intravenously. Most preferably the products of the invention are administered by intravenous infusion. The products of the invention comprise solutions which are ready to use, in which the bisphosphonate is present at a concentration suitable for direct administration without dilution and as such are referred to as “ready to use solutions”. Preferably the ready to use solution product is in the form of a unit dose ready to use solution, i.e. contains sufficient bisphosphonate for a single dose treatment. Such unit dose ready to use solution products for infusion typically have a volume in the range from about 20 up to about 500 ml, usually from about 50 to about 250 ml, preferably about 100 ml (wherein such volumes may additionally include up to about 20 ml, e.g. preferably about 2 ml, overfill to accommodate for liquid remaining in the container when the ready to use solution is infused to a patient.). Such ready to use solutions advantageously are brought to a physiologically acceptable pH value with bases. It has been found that with organic bases that have cation complexing properties slight hazes due to precipitates of the drug substance with cationic impurities of the excipients used can be avoided. It further has been found that compared to strong inorganic bases as sodium hydroxide, a slight buffering system is formed in situ with the bisphosphonate itself which enables more easily adjustment of the desired pH-value and ensures optimal stability of the pH value over the whole storage time. The pH of the solution is preferably in the region from about pH 4.5 up to about pH 8, more preferably in the range from about pH 5.5 up to about pH 7.5, e.g. about pH 6.5 or about pH 6.8 or about pH 7.2. Examples of suitable organic bases include the sodium or potassium salts of organic acids as acetic acid, citric acid, lactic acid, glutamic acid, tartaric acid, fumaric acid, maleic acid, or malic acid. Furthermore, basic forms of amino acids may be used, e.g. histidine or arginine. Examples of suitable anorganic bases are sodium or potassium phosphate, sodium hydrogen carbonate or sodium hydroxide. Also mixtures of the above bases, or mixtures of the bases with their corresponding acids may be used. For example, the formulation may comprise a base, e.g. sodium citrate, with an acid, e.g. hydrochloric acid. Preferably the base is a sodium or potassium salt. When using potassium salts, the physiological tolerability of such formulations however have to be carefully assessed, and it is recommended not to exceed the physiological concentration of potassium in blood serum which is approx. 4 milli-moles per litre. Such ready to use solutions may also typically comprise an isotonising agent. Preferably the tonicity of the solution is in the range from about 250 mOsm/kg up to about 400 mOsm/kg, more preferably from about 260 mOsm/kg up to about 350 mOsm/kg, e.g. about 300 mOsm/kg. Examples of suitable isotonising agents are: glycerol, polyethylene glycol, propylene glycol, ethanol, cyclodextrins, amino acids, sugars and sugar alcohols including: Glucose, fructose, mannose, mannitol, saccharose, lactose, trehalose, maltose, sorbitol, sodium chloride, sodium nitrate, potassium chloride, urea, ammonium chloride. Preferably the isotonising agent is a non-ionic isotonising agent, more preferably a sugar, ester, alcohol or polyol. Particularly preferred isotonising agents for use in the solution pre-concentrate are mannitol, 1,2 propylene glycol, glycerol and sorbitol, of which mannitol is particularly preferred. It has been found in accordance with the present invention that the use of non-ionic isotonising agents permits easy and reliable analysis, e.g. by ion chromatography, capillary electrophoresis, and high performance liquid chromatography (HPLC). It has been found, that with reversed phase HPLC using an ion pair reagent (e.g. tetrahexylammonium hydrogen sulfate) and a complexation reagent (e.g. ethylendiamintetraacetic acid, EDTA) and the UV detection mode a very low concentration of the bisphophonate and especially of potential by- and degradation products can be reliably determined. It is highly desirable to be able to detect such potential by- and degradation products at the low concentrations at which they are present in ready to use solution products. No derivatization step is necessary. For the ready to use solution product of the present invention a concentrations of 0.04 μg/ml can be reliably quantified. This corresponds to 0.1% related to the declared dose, which is the reporting limit, which has to be achieved in order to comply with international regulatory guidelines. In contrast, if one of the customary ionic isotonising agents, e.g. sodium chloride, is used, these interfere with the chromatographic measurements to an extent that potential by- and degradation products cannot be reliably quantified. Thus in particular embodiments the invention includes product as defined above, in which the isotonising agent is non-ionic: i) and in which the product is analysable with a limit of quantitation for the bisphophonate and its by- and degradation products of at least 0.1% related to the declared dose, preferably without applying a derivatization step, and ii) A product as defined above, which is analysable by reversed phase chromatography with a complexation agent, e.g. EDTA, for determination of the bisphophonate and its by- and degradation products with a limit of quantitation of at least 0.1% related to the declared dose, preferably without applying a derivatization step. Thus in a further preferred embodiment the invention provides a pharmaceutical product comprising a container containing a bisphosphonate solution in the form of a ready to use solution, comprising a) a unit dose of a bisphosphonate, b) an organic base, and c) a non-ionic isotonising agent in which at least the internal surface of the container comprises a transparent plastic material and in which the filled container is terminally heat sterilisable. Ready to use solution products may be provided in infusion bags; for instance as customarily used for infusion of other therapeutic infusion products, e.g. plastic infusion bags made of polyvinyl chloride, polyolefine copolymers, a Cryovac® M312 foil (Sealed Air Corporation), Baxter Intravia®, and B.Braun PAB (polypropylene with 10% of styrene ethylene-butylenes styrene (SEBS) thermoplastic elastomer) or similar infusion bags. The container for the product of the invention may comprise a glass container having a transparent plastic inner lining. Preferably, however, the container is made of plastic material and does not comprise a glass outer shell. Examples of plastic materials which may be used include: polysulfone, polycarbonate, polypropylene, polyethylene (LDPE or HDPE), ethylene/propylene copolymers, polyolefines, acrylic-imide copolymers, PVC, polyester (e.g. PET, PEN and the like), Teflon, Nylon, acetal (Delrin), polymethylpentene, PVDC, ethylvinylacetate, AN-copolymer etc. The plastic material used for either type of container is preferably a transparent plastic material, i.e. it is translucent and permits visual inspection of the contents. Furthermore the plastic material used is a plastic which is capable of withstanding heat sterilisation in the filled and unfilled state, preferably moist heat sterilisation e.g. steam sterilisation or superheated water showering sterilisation, at a temperature of at least about 110° C. to about 130° C. or higher, e.g. at a temperature of at least 121° C., e.g. at 121-124° C. Particularly preferred plastic materials for the container are transparent cycloolefinic polymers such as Daikyo CZ resin, thermoplastic olefin polymers of amorphous structure (e.g. TOPAS, manufactured by Ticona). Most preferred are Daikyo CZ resin and similar cycloolefinic polymers. Ready to use products may be provided in plastic or plastic-coated bottles having a volume from about 20 ml up to about 500 ml, e.g. about 100 ml. Bisphosphonate solutions may also be administered by slow intraveneous injection of a more concentrated form, e.g. with a concentration in the range from about 0.01 to about 0.5, more usually from about 0.05 up to about 0.2 mg bisphosphonate/ml. For this purpose the product may also be filled into prefillable syringes that can be terminally moist heat sterilized, e.g. in syringes made of Daikyo CZ resin or similar or of thermoplastic olefin polymers of amorphous structure (e.g. as sold by Schott under the trade name Schott Top Pac or similar) Commercially available plastic container materials like the Daikyo CZ resin further have a thermal deformation temperature according to ASTM D648 of 123° C., which would narrow down the acceptable sterilization temperature to at most 123° C. It has now been found that sterilization even at significantly higher temperatures of e.g. up to 130° C., lead neither to measurable deformations of the container nor to impaired container closure integrity. Preferably the bisphosphonates for use in the invention are the nitrogen containing bisphosphonates, including those having side chains which contain amino groups or especially those having side chains containing nitrogen-containing heterocycles, most especially containing aromatic nitrogen-containing heterocycles. Examples of suitable bisphosphonates for use in the invention may include the following compounds or a pharmaceutically acceptable salt thereof: 3-amino-1-hydroxypropane-1,1-diphosphonic acid (pamidronic acid), e.g. pamidronate (APD); 3-(N,N-dimethylamino)-1-hydroxypropane-1,1-diphosphonic acid, e.g. dimethyl-APD; 4-amino-1-hydroxybutane-1,1-diphosphonic acid (alendronic acid), e.g. alendronate; 1-hydroxy-ethidene-bisphosphonic acid, e.g. etidronate; 1-hydroxy-3-(methylpentylamino)-propylidene-bisphosphonic acid, ibandronic acid, e.g. ibandronate; 6-amino-1-hydroxyhexane-1,1-diphosphonic acid, e.g. amino-hexyl-BP; 3-(N-methyl-N-n-pentylamino)-1-hydroxypropane-1,1-diphosphonic acid, e.g. methyl-pentyl-APD(=BM 21.0955); 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid, e.g. zoledronic acid; 1-hydroxy-2-(3-pyridyl)ethane-1,1-diphosphonic acid (risedronic acid), e.g. risedronate, including N-methyl pyridinium salts thereof, for example N-methylpyridinium iodides such as NE-10244 or NE-10446; 1-(4-chlorophenylthio)methane-1,1-diphosphonic acid (tiludronic acid), e.g. tiludronate; 3-[N-(2-phenylthioethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonic acid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1,1-diphosphonic acid, e.g. EB 1053 (Leo); 1-(N-phenyl-aminothiocarbonyl)methane-1,1-diphosphonic acid, e.g. FR 78844 (Fujisawa); 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid tetraethyl ester, e.g. U-81581 (Upjohn); 1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethane-1,1-diphosphonic acid, e.g. YM 529; and 1,1-dichloromethane-1,1-diphosphonic acid (clodronic acid), e.g. clodronate. A particularly preferred bisphosphonate for use in the invention comprises a compound of Formula I wherein Het is an imidazole, oxazole, isoxazole, oxadiazole, thiazole, thiadiazole, pyridine, 1,2,3-triazole, 1,2,4-triazole or benzimidazole radical, which is optionally substituted by alkyl, alkoxy, halogen, hydroxyl, carboxyl, an amino group optionally substituted by alkyl or alkanoyl radicals or a benzyl radical optionally substituted by alkyl, nitro, amino or aminoalkyl; A is a straight-chained or branched, saturated or unsaturated hydrocarbon moiety containing from 1 to 8 carbon atoms; X is a hydrogen atom, optionally substituted by alkanoyl, or an amino group optionally substituted by alkyl or alkanoyl radicals, and R is a hydrogen atom or an alkyl radical, and the pharmacologically acceptable salts thereof. Examples of particularly preferred bisphophonates for use in the invention are: 2-(1-Methylimidazol-2-yl)-1-hydroxyethane-1,1-diphosphonic acid; 2-(1-Benzylimidazol-2-yl)-1-hydroxyethane-1,1-diphosphonic acid; 2-(1-Methylimidazol-4-yl)-1-hydroxyethane-1,1-diphosphonic acid; 1-Amino-2-(1-methylimidazol-4-yl)ethane-1,1-diphosphonic acid; 1-Amino-2-(1-benzylimidazol-4-yl)ethane-1,1-diphosphonic acid; 2-(1-Methylimidazol-2-yl)ethane-1,1-diphosphonic acid; 2-(1-Benzylimidazol-2-yl)ethane-1,1-diphosphonic acid; 2-(Imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid; 2-(Imidazol-1-yl)ethane-1,1-diphosphonic acid; 2-(4H-1,2,4-triazol-4-yl)-1-hydroxyethane-1,1-diphosphonic acid; 2-(Thiazol-2-yl)ethane-1,1-diphosphonic acid; 2-(Imidazol-2-yl)ethane-1,1-diphosphonic acid; 2-(2-Methylimidazol-4(5)-yl)ethane-1,1-diphosphonic acid; 2-(2-Phenylimidazol-4(5)-yl)ethane-1,1-diphosphonic acid; 2-(4,5-Dimethylimidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid, and 2-(2-Methylimidazol-4(5)-yl)-1-hydroxyethane-1,1-diphosphonic acid, and pharmacologically acceptable salts thereof. More preferred bisphosphonates for use in the invention are Disodium-3-amino-1-hydroxy-propylidene-1,1-bisphosphonate pentahydrate (pamidronic acid) and 2-(imidazol-1yl)-1-hydroxyethane-1,1-diphosphonic acid (zoledronic acid) or pharmacologically acceptable salts thereof. The most preferred bisphosphonate for use in the invention is 2-(imidazol-1yl)-1-hydroxyethane-1,1-diphosphonic acid (zoledronic acid) or a pharmacologically acceptable salt thereof. Particularly preferred ready to use products are in unit dose form and comprise from 2 to 10 mg of zoledronic acid or a pharmaceutically acceptable salt thereof. Most preferably the zoledronate unit dose product comprises an equivalent to 4 mg or 5 mg of anhydrous zoledronic acid, in particular as hereinafter described in the Examples. Pharmacologically acceptable salts are preferably salts with bases, conveniently metal salts derived from groups Ia, Ib, IIa and IIb of the Periodic Table of the Elements, including alkali metal salts, e.g. potassium and especially sodium salts, and also ammonium salts with ammonia or organic amines. Especially preferred pharmaceutically acceptable salts are those where one, two, three or four, in particular two or three, of the acidic hydrogens of the bisphosphonic acid are replaced by a pharmaceutically acceptable cation, in particular sodium, potassium or ammonium, in first instance sodium. A very preferred group of pharmaceutically acceptable salts is characterized by having at least one acidic hydrogen and one pharmaceutically acceptable cation, especially sodium, in each of the phosphonic acid groups. All the bisphosphonic acid derivatives mentioned above are well known from the literature. This includes their manufacture (see e.g. EP-A-513760, pp. 1348). For example, 3-amino-1-hydroxypropane-1,1-diphosphonic acid is prepared as described e.g. in U.S. Pat. No. 3,962,432 as well as the disodium salt as in U.S. Pat. Nos. 4,639,338 and 4,711,880, and 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid is prepared as described e.g. in U.S. Pat. No. 4,939,130. See also U.S. Pat. Nos. 4,777,163 and 4,687,767 and EP 0 275 821 B. The invention also includes processes for the production of the solution products of the invention, which processes typically comprise a terminal heat sterilization step. Accordingly in a further aspect the invention comprises a process for the production of a pharmaceutical product comprising a container containing a bisphosphonate solution, in which a bisphosphonate solution is provided within a container in which at least the internal surface of the container comprises a transparent plastic material and in which the container containing the bisphosphonate solution is terminally heat sterilised. Thus the container containing the bisphosphonate solution is heat sterilized, preferably moist heat sterilised e.g. by saturated steam, steam/air mixtures or superheated water showering sterilisation, at a temperature of at least about 110° C. to about 130° C. or higher, e.g. at a temperature of at least 121° C. or higher, e.g. preferably at about 121-124° C. The effective sterilization time depends on the D-value of test spores in the solution and should be dimensioned that an overall SAL of at least 10−6, preferably of at least 10−12 is obtained. The effective sterilization time (dwell time) may be from about 15 minutes up to about 3 hours, conveniently from about 15 minutes to about 2 hours, e.g. preferably about 30 min. Advantageously the heat sterilisation is terminal heat sterilisation, i.e. heat sterilisation which is carried out near to or at completion of the production process, after filling of the container with the bisphosphonate solution and preferably after closure of the container, e.g. with a suitable cap, stopper or other closure. Conveniently standard production equipment for processing of glass vials may be used. Suitable rubber stoppers are those which show only negligible leaching of metal ions like calcium, magnesium, zinc or silica when contacted with aqueous solutions, e.g. bisphosphonate solutions. Preferred stoppers have a low ash content and are coated on the product side with an impermeable and inert barrier, e.g. made of ETFE, Teflon or fluorinated elastomers. Suitable stoppers are e.g. Daikyo D-777-1, Daikyo D-777-3, Daikyo D-713, Daikyo D-21-7S, all coated on the product side with an ETFE layer, or Helvoet FM259/0 coated with a layer of a fluoropolymer (e.g. the Helvoet proprietary material Omniflex or Omniflex plus). The ready to use bisphosphonate solution may be prepared in bulk and delivered to the containers; for instance, using the customary art procedures. The bulk bisphosphonate solution may be in the form of a solution of the free bisphosphonic acid, e.g. zoledronic acid, or in the form of a salt thereof, e.g. the sodium salt. Bulk bisphosphonate salt solutions may be prepared by dissolving the salt in aqueous media, or may be prepared in situ in solution by reaction of a dispersion of the free bisphophonic acid with a base, e.g. neutralisation of the acid with sodium hydroxide to give the mono sodium salt, disodium salt, trisodium salt or tetra sodium salt as desired, e.g. disodium pamidronate or disodium zoledronate. According to GMP requirements, all container material used for parenteral products are to be subjected to a depyrogenization process ensuring an endotoxin reduction of at least 3 log units. Heat depyrogenisation is customarily used for glass vials. However, plastic vials generally cannot be processed on standard pharmaceutical sterile drug product filling lines, as such containers would not withstand the thermal stress applied in the heat depyrogenization tunnel. Therefore, plastic vials are usually processed without the necessary cleaning and depyrogenization steps, thus bearing the risk of contamination of the parenteral drug product with foreign matter present in the vials as well as with Endotoxins that may be dissolved from the vial material surface. Surprisingly it has been found in accordance with the present invention that some plastic containers can be processed on standard filling lines for glass vials, and that provided the washing process is suitably adjusted an endotoxin reduction by the factor of at least 1000 can be reproducibly obtained. Thus in addition to the sterilisation step, the containers, in particular the plastic containers, may be depyrogenised prior to filling with bisphosphonate solution. We have found that washing of the plastic vials with water under pressure gives satisfactory depyrogenisation, e.g. reduction in endotoxin concentration by a factor of at least 1000 or more, e.g. about 16000-100000. Such a depyrogenisation step is preferably included within the production processes of the invention. Alternatively endotoxin-free or substantially endotoxin-free plastic containers may be obtained from a supplier and such containers used without need for depyrogenisation. Furthermore the invention includes processes for preparation of the products of the invention as defined above in which reversed phase chromatography with a complexation agent, e.g. EDTA, is used for determination of the bisphophonate and its by- and degradation products, advantageously with a limit of quantitation of at least 0.1% related to the declared dose, preferably without applying a derivatization step. The particular mode of administration and the dosage for the products of the invention may be selected by the attending physician talking into account the particulars of the patient, especially age, weight, life style, activity level, hormonal status (e.g. post-menopausal) and bone mineral density as appropriate. Most preferably, however, the bisphosphonate is administered intravenously. Normally the dosage is such that a single dose of the bisphosphonate active ingredient from 0.002-20.0 mg/kg, especially 0.01-10.0 mg/kg, is administered to a warm-blooded animal weighing approximately 75 kg. If desired, this dose may also be taken in several, optionally equal, partial doses. “mg/kg” means mg drug per kg body weight of the mammal—including man—to be treated. Preferably, the bisphosphonates are administered in doses which are in the same order of magnitude as those used in the treatment of the diseases classically treated with bisphosphonic acid derivatives, such as Paget's disease, tumour-induced hypercalcemia or osteoporosis. In other words, preferably the bisphosphonic acid derivatives are administered in doses which would likewise be therapeutically effective in the treatment of Paget's disease, tumour-induced hypercalcaemia or osteoporosis, i.e. preferably they are administered in doses which would likewise effectively inhibit bone resorption. The following Examples illustrate the invention described hereinbefore. EXAMPLES Example 1 Zoledronic Acid 4 mg/100 mL Ingredient Amount [kg] per 1000 L Zoledronic acid monohydrate 0.04264 kg Corresponding to 0.0400 kg zoledronic acid anhydrous Mannitol 51.00 kg Sodium citrate 0.240 kg Water for injection Up to 1′015 kg = 1000 L Approx. 85-95% of the total amount of water for injection is filled into a stainless steel compounding vessel. The excipients mannitol and sodium citrate are added and dissolved under stirring. The drug substance zoledronic acid is added and dissolved under stirring. The preparation is adjusted to the final weight with water for injection. The amount of sodium citrate neutralizes the zoledronic acid to a pH value of 6.5. The bulk solution is passed to the filling line and filtered in-line through a filter of 0.2 μm pore size. Washed and dried 100 mL Daikyo CZ plastic vials are filled with 102.0 ml of bulk solution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers are inserted into the vials, and the stoppered vials are sealed with aluminium caps. The vials are sterilized with moist heat to obtain a Sterility Assurance Level of 10−12, i.e. at 121-123° C. for 30 minutes (effective dwell time). The product is stable and does not show any sign for degradation eve under severe stress conditions of 50° C./75% RH and 40° C./75% RH. 40° C./ 50° C./ 75% rel. humidity 75% rel. humidity Test Start 3 months 1 month Assay 99.5% 101.4% 98.8% Degradation products, <0.1% <0.1% <0.1% sum pH-value 6.7 6.6 6.6 Appearance clear, colorless clear, colorless clear, colorless particle-free solution particle-free solution particle-free solution Extractables <0.05 μg/mL <0.05 μg/mL <0.05 μg/mL Example 2 Zoledronic Acid 5 mg/100 mL Ingredient Amount [kg] per 1000 L Zoledronic acid monohydrate 0.0533 kg Corresponding to 0.0500 kg zoledronic acid anhydrous Mannitol 49.50 kg Sodium citrate 0.300 kg Water for injection Up to 1′014.5 kg = 1000 L Approx. 85-95% of the total amount of water for injection is filled into a stainless steel compounding vessel. The excipients mannitol and sodium citrate are added and dissolved under stirring. The drug substance zoledronic acid is added and dissolved under stirring. The preparation is adjusted to the final weight with water for injection. The amount of sodium citrate neutralizes the zoledronic acid to a pH value of 6.5. The bulk solution is passed to the filling line and filtered in-line through a filter of 0.2 μm pore size. Washed and dried 100 mL Daikyo CZ plastic vials are filled with 102.0 ml of bulk solution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers are inserted into the vials, and the stoppered vials are sealed with aluminium caps. The vials are sterilized with moist heat to obtain a Sterility Assurance Level of 10−12, i.e. at 121-123° C. for 30 minutes (effective dwell time). The product is stable and does not show any sign for degradation eve under severe stress conditions of 50° C./75% RH and 40° C./75% RH. 40° C./75% rel humidity 30° C./70% inverse rel. humidity storage Test Start 12 months 6 months Assay 99.8% 100.0% 99.9% Degradation products, <0.1% <0.1% <0.1% sum pH-value 6.6 6.6 6.4 Particulate ≧10 μm 10 10 5 matter ≧25 μm 0 0 0 (USP) Appearance clear, colorless clear, colorless clear, colorless solution solution solution Extractables <0.05 μg/mL <0.05 μg/mL <0.05 μg/mL Heavy Metals Ca <50 μg/L <50 μg/L <50 μg/L Mg <50 μg/L <50 μg/L <50 μg/L Al <100 μg/kg <100 μg/kg <100 μg/kg Cd <100 μg/kg <100 μg/kg <100 μg/kg Cr <100 μg/kg <100 μg/kg <100 μg/kg Cu <100 μg/kg <100 μg/kg <100 μg/kg Fe <100 μg/kg <100 μg/kg <100 μg/kg Ti <100 μg/kg <100 μg/kg <100 μg/kg Zn <100 μg/kg <100 μg/kg <100 μg/kg Example 3 Adjustment of pH Value in Zoledronic Acid Formulations with Different Bases 533.1 mg of zoledronic acid monohydrate (equivalent to 500 mg of zoledronic acid) and 480.0 g of mannitol are added to 7520 g of water for injection and stirred until a clear solution with a total weight of 8000 g is obtained. Each 800 g of this solution (equivalent to 50 mg of zoledronic acid) are titrated with (a) a solution of 0.500 g/100 mL trisodium citrate dihydrate in water for injection (b) a solution of 0.500 g/100 mL anhydrous sodium acetate in water for injection (c) a solution of 0.500 g/100 mL disodium tartrate dihydrate in water for injection (d) a solution of 0.500 g/100 mL trisodium phosphate hexahydrate in water for injection (e) a solution of 0.400 g/100 mL sodium hydroxide in water for injection The pH value after each addition of 200 μL of base solution is recorded potentiometrically. The data show that due to the pKa values of zoledronic acid of 5.9 and 8.28, a steep increase of the pH value in the physiologically most preferred pH range of pH 6 to 7.5 is seen when using sodium hydroxide as base. Compared to that with sodium phosphate and sodium citrate the dissociation of the zoledronic acid acidic groups is slightly buffered, and therefore the desired pH value of usually pH 6.0-7.5 easily can be adjusted. Example 4 Zoledronic Acid 5 mg/100 mL Formulated with Trisodium Citrate at Different pH Values Formulation 4A: Formulation 4B: Formulation 4C: Ingredient pH 6.0 pH 6.5 pH 7.0 Zoledronic acid 53.3 mg 53.3 mg 53.3 mg monohydrate Corresponding to 50 mg zoledronic acid anhydrous Mannitol 50.0 g 49.5 g 47.0 g Trisodium citrate dihydrate 0.115 g 0.300 g 1.00 g Water for injection Up to 1.00 L Up to 1.00 L Up to 1.00 L Example 5 Zoledronic Acid 5 mg/100 mL Formulated with Trisodium Phosphate at Different pH Values Formulation Formulation Formulation Formulation Ingredient 5A: pH 6.0 5B: pH 6.5 5C: pH 7.0 5D: pH 7.5 Zoledronic acid 53.3 mg 53.3 mg 53.3 mg 53.3 mg monohydrate Corresponding to 50 mg zoledronic acid anhydrous Mannitol 50.0 g 50.0 g 50.0 g 50.0 g Trisodium phosphate 0.038 g 0.050 g 0.065 g 0.085 g hexahydrate Water for injection Up to 1.00 L Up to 1.00 L Up to 1.00 L Up to 1.00 L Example 6 Zoledronic Acid 5 mg/100 mL Formulated with Sodium Acetate at Different pH Values Formulation 6A: Formulation 6B: Ingredient pH 5.5 pH 6.0 Zoledronic acid 53.3 mg 53.3 mg monohydrate Corresponding to 50 mg zoledronic acid anhydrous Mannitol 49.5 g 49.0 g Sodium acetate anhydrous 0.125 g 0.500 g Water for injection Up to 1.00 L Up to 1.00 L Example 7 Zoledronic Acid 4 mL/100 mL Ingredient Amount [kg] per 1000 L Zoledronic acid monohydrate 0.04264 kg Corresponding to 0.0400 kg zoledronic acid anhydrous Mannitol 51.00 kg Sodium citrate 0.240 kg Water for injection Up to 1′015 kg = 1000 L Approx. 85-95% of the total amount of water for injection are filled into a stainless steel compounding vessel. The excipients mannitol and sodium citrate are added and dissolved under stirring. The drug substance zoledronic acid is added and dissolved under stirring. The preparation is adjusted to the final weight with water for injection. The bulk solution is passed to the filling line and filter in-line through a filter of 0.2 μm pore size. Empty plastic infusion bags made of a Cryovac® M312 foil (Sealed Air Corporation), Baxter Intravia®, and B.Braun PAB® (polypropylene based foil) are filled with each 102.0 ml of bulk solution. The bags are hermetically sealed. The bags are sterilized with moist heat under a supportive pressure of at least 100 mbar above the water vapour pressure at the chamber temperature (superheated water showering or steam/air mixture) to obtain a Sterility Assurance Level of 10−12, i.e. at 121-123° C. for 30 minutes (effective dwell time). Example 8 Zoledronic Acid 5 mg/100 mL Ingredient Amount [g] per 1 L Zoledronic acid monohydrate 0.0533 g Corresponding to 0.0500 g zoledronic acid anhydrous Sorbitol crystalline 50.0 g Sodium citrate 0.300 g Water for injection Up to 1.00 L Approx. 800 g of water for injection are filled into the compounding vessel. The excipients Sorbitol and sodium citrate are added and dissolved under stirring. The drug substance zoledronic acid is added and dissolved under stirring. The preparation is adjusted to the final volume with water for injection. The solution is filtered into the vials through a filter of 0.2 μm pore size. Washed and dried Daikyo CZ plastic vials are filled with the bulk solution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers are inserted into the vials, and the stoppered vials are sealed with aluminium caps. The vials are sterilized with moist heat. As can be seen from the table below, the formulation is stable even after severe heat intake of 121° C./60 minutes after sterilization (121° C./60 min Test prior to sterilization effective dwel time) Color colorless colorless Clarity clear, particle free clear, particle free pH-value 6.3 6.1 No change in assay value is observed, and prior as well as after sterilization no degradation products at levels above the limit of detection could be found. Example 9 Zoledronic Acid 5 mg/100 mL Ingredient Amount [g] per 1 L Zoledronic acid monohydrate 0.0533 g Corresponding to 0.0500 g zoledronic acid anhydrous Glycerol water free 22.5 g Sodium citrate 0.300 g Water for injection Up to 1.00 L Approx. 800 g of water for injection are filled into the compounding vessel. The excipients glycerol and sodium citrate are added and dissolved under stirring. The drug substance zoledronic acid is added and dissolved under stirring. The preparation is adjusted to the final volume with water for injection. The solution is filtered into the vials through a filter of 0.2 μm pore size. Washed and dried Daikyo CZ plastic vials are filled with the bulk solution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers are inserted into the vials, and the stoppered vials are sealed with aluminium caps. The vials are sterilized with moist heat. As can be seen from the table below, the formulation is stable even after severe heat intake of 121° C./60 minutes after sterilization (121° C./60 min Test prior to sterilization effective dwell time) Color colorless colorless Clarity clear, particle free clear, particle free pH-value 6.4 6.2 No change in assay value is observed, and prior as well as after sterilization no degradation products at levels above the limit of detection could be found. Example 10 Zoledronic Acid 5 mg/100 mL Ingredient Amount [g] per 1 L Zoledronic acid monohydrate 0.0533 g Corresponding to 0.0500 g zoledronic acid anhydrous 1,2 propylene glycol 19.0 g Sodium citrate 0.300 g Water for injection Up to 1.00 L Approx. 800 g of water for injection are filled into the compounding vessel. The excipients Propylene glycol and sodium citrate are added and dissolved under stirring. The drug substance zoledronic acid is added and dissolved under stirring. The preparation is adjusted to the final volume with water for injection. The solution is filtered into the vials through a filter of 0.2 μm pore size. Washed and dried Daikyo CZ plastic vials are filled with the bulk solution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers are inserted into the vials, and the stoppered vials are sealed with aluminium caps. The vials are sterilized with moist heat. As can be seen from the table below, the formulation is stable even after severe heat intake of 121° C./60 minutes after sterilization (121° C./60 min Test prior to sterilization effective dwell time) Color colorless colorless Clarity clear, particle free clear, particle free pH-value 6.4 6.3 No change in assay value is observed, and prior as well as after sterilization no degradation products at levels above the limit of detection could be found. Example 11 Washing of Vials/Endotoxin Removal The plastic vials are processed on a conventional integrated automatic liquid filling processing line. Washing is performed in a conventional rotary vial washing machine (e.g. Bausch&Stroebel FAU 6000 or Bosch RRU 2020) as used for glass vials. The vials are put on the feeding belt of the washing machine. In a first instance the vials are submerged in a bath with hot water and treated by sonication. After that the vials are transported to the rotary washing station and are inverted. Cleaning is accomplished by a programmed process of air and water flushing through nozzles inserted into the vials. The vials are first washed with recycled hot Water for Injections (>70° C.), blown out with filtered air, then washed again with fresh hot Water for Injections and blown out with filtered air. Following washing, the vials are inverted again to their normal position, and then transferred by the conveyor to the belt of the hot air tunnel, where they are dried at 110° C. On a Bausch&Stroebel FAU 6000 washing machine, a washing speed of 84 vials/min is suitable. On a Bosch RRU 2020, a suitable washing speed is at a machine setting of 5.8-6.5 scale units. The efficiency of this process has been assessed by comparison of the endotoxin load of endotoxin-spiked vials prior and after the routine washing process. The results show more than 3 log reduction of the endotoxin challenge, i.e. the requirement of more than a 3 log reduction was met at each position tested during the washing process. Endotoxin Recovery from Treated Vials Endotoxin is spiked into the plastic vials and dried. The endotoxin spike recovery from five non washed vials is determined in duplicate (spike controls). The spike is 8538 EU (IU) per vial, i.e. the mean value of the results minus two times the standard deviation. Three qualification runs are performed. In each run 10 vials spiked with endotoxin are distributed into one batch of un-spiked vials and are washed in the washing machine. Results of Endotoxin Recovery: EU (IU)/vial Run 1 Run 2 Run 3 Vial 1 <0.63 <0.63 1.57 Vial 2 <0.63 <0.63 <0.63 Vial 3 <0.63 <0.63 <0.63 Vial 4 0.64 <0.63 <0.63 Vial 5 <0.63 <0.63 <0.63 Vial 6 <0.63 <0.63 <0.63 Vial 7 <0.63 <0.63 <0.63 Vial 8 <0.63 <0.63 <0.63 Vial 9 <0.63 <0.63 <0.63 Vial 10 <0.63 <0.63 <0.63 In all vials tested an endotoxin reduction of at least a factor 1000 is shown. Example 12 Sterilization of Zoledronic Acid 5 mg/100 mL Studies have shown that the solution for infusion is chemically and physically stable during autoclaving. Upon sterilisation of up to 150 minutes at ≧121° C. no degradation of the drug substance could be observed (please see results in the table below). This heat resistance allows an overkill sterilisation cycle yielding a sterility assurance level (SAL) of at least 10−12. Based on the spore reduction kinetics, expressed in the decimal reduction value (D-value) of Geobacillus stearothermophilus spores in the Zoledronic acid 5 mg/100 mL drug product solution, a sterilisation time (dwell time) of 30 minutes was derived to obtain the desired spore reduction rate. The chosen sterilization procedure is in line with the requirements of Ph. Bur. and USP. Stability of Zoledronic acid 5 mg/100 ml upon prolonged sterilization times Autoclaved for Autoclaved for Autoclaved 30 additional additional 2 times 60 min/ Parameter minutes/121° C. 60 min/124° C. 124° C. Overall dwell 30 min. 90 min. 150 min. time at >121° C. Appearance of 100 ml colourless 100 ml colourless 100 ml colourless the container plastic vials, grey plastic vials, grey plastic vials, grey rubber-stopper, rubber-stopper, rubber-stopper, aluminium cap with aluminium cap with aluminium cap with plastic flip component plastic flip component plastic flip component Appearance of clear, colourless clear, colourless clear, colourless the solution solution solution solution Absorbance of 0.00 0.00 0.00 the solution* pH value 6.6 6.6 6.6 Particulate matter: >25 μm 0 (USP) 0 (USP) 0 (USP) 3 (Ph. Eur.) 0 (Ph. Eur.) 7 (Ph. Eur.) >10 μm 20 (USP) 10 (USP) 0 (USP) 13 (Ph. Eur). 3 (Ph. Eur). 10 (Ph. Eur). Degradation <0.1% <0.1% <0.1% products Assay of 98.7% 99.6% 99.3% zoledronic acid Bacterial <0.025 EU (IU)/mL <0.025 EU (IU)/mL <0.025 EU (IU)/mL endotoxins Container/ Complies: no unit out Complies: no unit out Complies: no unit out closure of 40 vials tested shows of 40 vials tested shows of 40 vials tested shows tightness by sign for dye ingress sign for dye ingress sign for dye ingress dye intrusion Compared to multiple sterilization in glass vials, no increase in particulate matter is detected. The formulation is stable even after a total sterilization time of 150 minutes at >121° C. Example 13 Evaluation of Plastic Vials Under Worst Case Sterilization Conditions During processing, the vials are exposed to dry heat (drying after washing) of up to 120° C. and moist heat (during autoclaving) of up to 124° C. To assess any potential risk for damage of the vial and the container closure integrity, a heat resistance study has been performed. 20 empty vials as used for Example 2 are subjected to dry heat at 125° C. for 10 hours, which is above the temperature of a drying process which is normally set to 100-120° C. Prior and after heat treatment the inner diameter and the ovality of the vial neck were determined as these dimensions are considered to be the most critical parameters for vial tightness. A negligible reduction of the inner diameter of the vial neck by 0.03 mm (range 0.02-0.05 mm) is observed. The apparent ovality, given as the difference of two perpendicular diameters of the vial opening divided by the sum of these diameters, remained unchanged and is 0.18% in the selected samples (prior to treatment: range 0.05-0.45%; after treatment: range 0.00-0.50%). Vials from Example 2 are subjected to a worst case steam sterilization cycle of 60 minutes in saturated steam at 124.5° C., which is above the thermal deformation temperature of the vial of 123° C. according to ASTM D648). Supporting overpressure is not applied during the sterilisation phase. Sterilized as well as not-sterilized reference samples are tested for dimensional changes as well as for tightness by dye intrusion and weight loss. Results of the evaluation of vials in worst case sterilization After sterilization Before sterilization (124.5° C./60 min) Weight loss (2 weeks, 40° C.), 21 mg 22 mg n = 20 (range: 20-22 mm) (range: 21-23 mm) Inner diameter of vial mouth, 22.0 mm 22.1 mm n = 20 (range: 21.96-22.04 mm) (range: 22.09-22.18 mm) Apparent ovality of inner 0.11% 0.20% diameter of vial mouth, n = 8 (range: 0.00-0.23%) (range: 0.00-0.41%) Container closure tightness by tight tight dye intrusion, n = 40 Sterilization at worst case conditions does not have any detectable influence on vial tightness as expressed by weight loss and resistance to dye intrusion. A very slight change is observed in the inner diameter of the vial mouth, but the values are within the specifications of 22.0+/−0.2 mm. Example 14 Analytics of Zoledronic Acid 4 mg/100 mL Solutions Column Luna, RP-C18 (2), 5 μm (in steel), Phenomenex Length 250 mm, internal diameter 4.6 mm, or equivalent column Stock solution EDTA Accurately weigh to 0.001 g 0.365 g of EDTA into a 100 ml volumetric flask, dissolve with 5 ml 2 M NaOH and fill up to the mark with water Mobile phase Accurately weigh to 0.1 g 6.2 g of disodium hydrogen phosphate dihydrate (35 mM) and 4.5 g of tetrahexyl- ammonium hydrogen sulfate (10 mM) into a flask, add 900 ml of water, 100 ml of acetonitrile dissolve and add 2 ml of EDTA stock solution and mix thoroughly. Adjust the pH to 7.9 with 2 M sodium hydroxide solution. Flow rate 1.2 ml/min Detection 215 nm Temperature 30° C. Injection volume 160 μl Run time Approx. 80 min Important remarks PEEK capillaries are recommended at least between column and detector In order to avoid adsorption on glass surfaces use plastic auto sampler vials and pasteur pipettes made from plastic. Reference solutions have to be prepared with volumetric flasks of frequently used glassware or of plastic and stored in plastic flasks. Example 15 Ready-to Use Formulations of Pamidronic Acid Composition per unit dose pack of 100.0 mL equivalent to 101.5 g: 15 mg/100 mL 30 mg/100 mL 60 mg/100 mL 90 mg/100 mL Ingredient strength strength strength strength Pamidronic acid disodium salt 19.79 mg 39.58 mg 79.16 mg 118.74 mg pentahydrate equivalent to pamidronic acid 15 mg 30 mg 60 mg 90 mg Citric acid Ph. Eur. approx. 1.5 mg approx. 3 mg approx. 6 mg approx. 9 mg up to pH 6.5 Mannitol Ph. Eur. 5185 mg 5170 mg 5140 mg 5110 mg Water for injection 96.29 g 96.28 g 96.27 g 96.26 g Based on the basic composition of one dosage form unit given in the table above, the amount needed for the batch to be manufactured is calculated. A typical batch size is approx. 5 L for a lab scale batch, 100 L for a pilot scale batch and 1000 L for a production scale batch. Approx. 85-95% of the total amount of water for injection are filled into a stainless steel compounding vessel. Mannitol is added and dissolved under stirring. The drug substance pamidrionic acid disodium salt pentahydrate is added and dissolved under stirring. The pH value is adjusted with a 5% solution of citric acid in water for injection. The preparation is adjusted to the final weigh with water for injection. The bulk solution is passed to the filling line and filter in-line through a filter of 0.2 μm pore size. Washed and dried Daikyo CZ 100 mL plastic vials are filled with each 102 mL of the bulk solution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers are inserted into the vials, and the stoppered vials are sealed with aluminium caps. The vials are sterilized with moist heat at >121° C. for at least 15 minutes (effective dwell time). Example 16 Ready-to Use Formulations of Pamidronic Acid Composition per unit dose pack of 100.0 mL equivalent to 101.5 g: 15 mg/100 mL 30 mg/100 mL 60 mg/100 mL 90 mg/100 mL Ingredient strength strength strength strength Pamidronic acid disodium salt 19.79 mg 39.58 mg 79.16 mg 118.74 mg pentahydrate equivalent to pamidronic acid 15 mg 30 mg 60 mg 90 mg Phosphoric acid 85% approx. 2.35 mg approx. 4.7 mg approx. 9.4 mg approx. 14.1 mg up to pH 6.3 Mannitol Ph. Eur. 5185 mg 5170 mg 5140 mg 5110 mg Water for injection 96.29 g 96.28 g 96.27 g 96.26 g Based on the basic composition of one dosage form unit given in the table above, the amount needed for the batch to be manufactured is calculated. A typical batch size is approx. 5 L for a lab scale batch, 100 L for a pilot scale batch and 1000 L for a product-ion scale batch. Approx. 85-95% of the total amount of water for injection are filled into a stainless steel compounding vessel. Mannitol is added and dissolved under stirring. The drug substance pamidrionic acid disodium salt pentahydrate is added and dissolved under stirring. The pH value of pH 6.3 is adjusted with a 5% solution of phosphoric acid in water for injection. The preparation is adjusted to the final weight with water for injection. The bulk solution is passed to the filling line and filter in-line through a filter of 0.2 μm pore size. Washed and dried Daikyo CZ 100 mL plastic vials are filled with each 102 mL of the bulk solution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers are inserted into the vials, and the stoppered vials are sealed with aluminium caps. The vials are sterilized with moist heat at >121° C. for at least 15 minutes (effective dwell time). Example 17 Ready-to Use Formulations of Pamidronic Acid Composition per unit dose pack of 100.0 mL equivalent to 101.5 g: 15 mg/100 mL 30 mg/100 mL 60 mg/100 mL 90 mg/100 mL Ingredient strength strength strength strength Pamidronic acid disodium salt 19.79 mg 39.58 mg 79.16 mg 118.74 mg pentahydrate equivalent to pamidronic acid 15 mg 30 mg 60 mg 90 mg Acetic acid glacial Ph. Eur. approx. 1.25 mg approx. 2.5 mg approx. 5.0 mg approx. 7.5 mg up to pH 6.5 Mannitol Ph. Eur. 5185 mg 5170 mg 5140 mg 5110 mg Water for injection 96.29 g 96.28 g 96.27 g 96.26 g Based on the basic composition of one dosage form unit given in the table above, the amount needed for the batch to be manufactured is calculated. A typical batch size is approx. 5 L for a lab scale batch, 100 L for a pilot scale batch and 1000 L for a production scale batch. Approx. 85-95% of the total amount of water for injection are filled into a stainless steel compounding vessel. Mannitol is added and dissolved under stirring. The drug substance pamidrionic acid disodium salt pentahydrate is added and dissolved under stirring. The pH value of pH 6.3 is adjusted with a 5% solution of acetic acid in water for injection. The preparation is adjusted to the final weight with water for injection. The bulk solution is passed to the filling line and filter in-line through a filter of 0.2 μm pore size. Washed and dried Daikyo CZ 100 mL plastic vials are filled with each 102 mL of the bulk solution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers are inserted into the vials, and the stoppered vials are sealed with aluminium caps. The vials are sterilized with moist heat at >121° C. for at least 15 minutes (effective dwell time). Example 18 Ready-to Use Formulations of Pamidronic Acid Composition per unit dose pack of 100.0 mL equivalent to 101.5 g: 15 mg/100 mL 30 mg/100 mL 60 mg/100 mL 90 mg/100 mL Ingredient strength strength strength strength Pamidronic acid disodium salt 19.79 mg 39.58 mg 79.16 mg 118.74 mg pentahydrate equivalent to pamidronic acid 15 mg 30 mg 60 mg 90 mg Lactic acid Ph. Eur. approx. 2.5 mg approx. 5.0 mg approx. 10.0 mg approx. 15.0 mg up to pH 6.5 Mannitol Ph. Eur. 5185 mg 5170 mg 5140 mg 5110 mg Water for injection 96.29 g 96.28 g 96.27 g 96.26 g Based on the basic composition of one dosage form unit given in the table above, the amount needed for the batch to be manufactured is calculated. A typical batch size is approx. 5 L for a lab scale batch, 100 L for a pilot scale batch and 1000 L for a production scale batch. Approx. 85-95% of the total amount of water for injection are filled into a stainless steel compounding vessel. Mannitol is added and dissolved under stirring. The drug substance pamidrionic acid disodium salt pentahydrate is added and dissolved under stirring. The pH value of pH 6.3 is adjusted with a 5% solution of lactic acid in water for injection. The preparation is adjusted to the final weight with water for injection. The bulk solution is passed to the filling line and filter in-line through a filter of 0.2 μm pore size. Washed and dried Daikyo CZ 100 mL plastic vials are filled with each 102 mL of the bulk solution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers are inserted into the vials, and the stoppered vials are sealed with aluminium caps. The vials are sterilized with moist heat at >121° C. for at least 15 minutes (effective dwell time). Example 19 Ready-to Use Formulations of Pamidronic Acid Composition per unit dose pack of 100.0 mL equivalent to 101.5 g: 15 mg/100 mL 30 mg/100 mL 60 mg/100 mL 90 mg/100 mL Ingredient strength strength strength strength Pamidronic acid disodium salt 19.79 mg 39.58 mg 79.16 mg 118.74 mg pentahydrate equivalent to pamidronic acid 15 mg 30 mg 60 mg 90 mg Tartaric acid Ph. Eur. approx. 1.5 mg approx. 3.0 mg approx. 6.0 mg approx. 9.0 mg up to pH 6.5 Mannitol Ph. Eur. 5185 mg 5170 mg 5140 mg 5110 mg Water for injection 96.29 g 96.28 g 96.27 g 96.26 g Based on the basic composition of one dosage form unit given in the table above, the amount needed for the batch to be manufactured is calculated. A typical batch size is approx. 5 L for a lab scale batch, 100 L for a pilot scale batch and 1000 L for a production scale batch. Approx. 85-95% of the total amount of water for injection are filled into a stainless steel compounding vessel. Mannitol is added and dissolved under stirring. The drug substance pamidrionic acid disodium salt pentahydrate is added and dissolved under stirring. The pH value of pH 6.3 is adjusted with a 5% solution of tartaric acid in water for injection. The preparation is adjusted to the final weight with water for injection. The bulk solution is passed to the filling line and filter in-line through a filter of 0.2 μm pore size. Washed and dried Daikyo CZ 100 mL plastic vials are filled with each 102 mL of the bulk solution. Sterilized Helvoet FM259/0 Omniflex plus coated stoppers are inserted into the vials, and the stoppered vials are sealed with aluminium caps. The vials are sterilized with moist heat at >121° C. for at least 15 minutes (effective dwell time).

20060811

20110426

20070118

91655.0

A61K31663

HENLEY III, RAYMOND J

PHARMACEUTICAL PRODUCTS COMPRISING BISPHOSPHONATES

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Method and apparatus for press forming sheet material

[Problem to be Solved] An object of the present invention is to obtain a component, such as an end plate of a silencer by one cycle of pressing operation for a sheet material. [Solution] A press forming apparatus comprises an upper die 10 provided with an upper drawing die 13, a punch 12, an upper movable blank holder 14, and a trimming member 15 and a lower die 20 provided with a lower drawing die 23, a die 22, an outer periphery drawing die 24, and a lower movable blank holder 25. The upper die is lowered with respect to the lower die, and the outer periphery portion of a blank B is held by the trimming member and the upper blank holder. Then, the central portion of the blank is drawn by the upper and lower drawing dies. Next, the outer periphery portion of the blank is trimmed by the trimming member and the outer periphery drawing die, and then drawing of the outer periphery portion of the blank is started by the upper drawing die and the outer periphery drawing die. Next, the blank is pierced by the punch and the die, and burring around the pierced hole is started. Next, the outermost periphery portion of the blank is bent by the trimming member and the outer periphery drawing die, thereby obtaining an end plate.

1. A press forming method for a sheet material, in which an upper die provided with one of dies for drawing a sheet material and one of a plurality of secondary working members separate from the dies, which perform secondary working, such as trimming, piercing, burring, bending, or coining of the sheet material, is lowered with respect to a lower die provided with the other of the dies and the other of the secondary working members, wherein a plurality of secondary working operations, such as trimming, piercing, burring, bending, or coining are performed in the same process while shape forming is performed by drawing operation for the sheet material. 2. The press forming method for a sheet material according to claim 1, in which an upper die provided with an upper drawing die, a punch, and a trimming member also used as a blank holder and a bending die is lowered with respect to a lower die provided with a lower drawing die, a die, an outer periphery drawing die also used as a trimming member and a bending die, and a blank holder, wherein the outer periphery portion of a blank placed on the blank holder is held by the blank holder and the trimming member, successively, the central portion of the blank is drawn by the lower drawing die and the upper drawing die by moving the lower drawing die upward under pressure, successively, the outer periphery portion of the blank is trimmed by the trimming member and the outer periphery drawing die, successively, overall forming by drawing of the outer periphery portion of the blank performed by the upper drawing die and the outer periphery drawing die is started, and at the same time, piercing of the blank is performed by the punch and the die, and burring around an opened pierced hole is started, successively, bending of the outermost periphery portion of the blank is started by the trimming member and the outer periphery drawing die, and as the upper die reaches the bottom dead center, the overall forming, burring, and bending of the outermost periphery portion of the blank are completed. 3. The press forming method for a sheet material according to claim 1, in which an upper die provided with an upper drawing die, a punch, a blank holder, and a trimming member is lowered with respect to a lower die provided with a lower drawing die, a die, and an outer periphery drawing die also used as a blank holder and a trimming member, wherein the outer periphery portion of a blank placed on the outer periphery drawing die is held by the outer periphery drawing die and the blank holder, successively, the central portion of the blank is pressed between the upper drawing die and the lower drawing die, and the outer periphery portion of the blank is trimmed by the trimming member and the outer periphery draw ing die, successively, drawing of the outer periphery portion of the blank is started by the upper drawing die and the outer periphery drawing die, successively, the blank is pierced by the punch and the die, and burring around an opened pierced hole is started, and as the upper die reaches the bottom dead center, the drawing of the outer periphery portion of the blank and the burring are completed. 4. The press forming method for a sheet material according to claim 1, in which an upper die provided with an upper drawing die, a pierced hole periphery die having a concave portion for coining, a punch, and an upper blank holder is lowered with respect to a lower die provided with a lower drawing die having a punch housing hole, a coining punch, a lower blank holder, and a trimming member also used as a blank holder, wherein the outer periphery portion of a blank placed on the trimming member is held by the trimming member and the upper blank holder, successively, the outer periphery portion of the blank is trimmed by the upper drawing die and the lower blank holder, successively, overall forming by drawing of the blank is started in cooperation by the upper drawing die and the lower drawing die, successively, the pierced hole periphery portion of the blank is drawn in cooperation by the pierced hole periphery die and the lower drawing die by moving the pierced hole periphery die downward under pressure, successively, the blank is pierced by the punch and the punch housing hole, successively, coining of the blank is started by the coining punch and the concave portion for coining, and as the upper die reaches the bottom dead center, the overall forming and coining of the blank are completed. 5. A press forming apparatus for a sheet material comprising upper and lower dies wherein the upper die is lowered with respect to the lower die, in which the upper die is provided with one of dies for drawing a sheet material and one of a plurality of secondary working members separate from the dies, which perform secondary working, such as trimming, piercing, burring, bending, or coining of the sheet material, and the lower die is provided with the other of the dies and the other of the secondary working members, and shape forming by drawing operation for the sheet material and a plurality of shape forming operations, such as trimming, piercing, burring, bending, or coining can be performed by one cycle of pressing operation. 6. The press forming apparatus for a sheet material according to claim 5, in which the upper die comprises an upper drawing die fixed to an upper die body; a punch which passes through the upper drawing die and is fixed to the upper die body; an upper movable blank holder which is arranged at the outer periphery of the upper drawing die so as to be movable in the vertical direction and is urged downward with respect to the upper die body; and a trimming member which is arranged at the outer periphery of the upper movable blank holder and is fixed to the upper die body, and is also used as a blank holder and a bending die, and the lower die comprises a lower drawing die which is arranged in a lower die body so as to be movable in the vertical direction and is urged upward with respect to the lower die body and be capable of applying pressure in the upward direction, and draws the central portion of a blank in cooperation with the upper drawing die; a die which passes through the lower drawing die and is fixed to the lower die body, and performs piercing of the blank in cooperation with the punch and performs burring around an opened pierced hole; wherein an outer periphery drawing die, also used as a trimming member and a bending die, which is arranged at the outer periphery of the lower drawing die and is fixed to the lower die body, performs overall forming by drawing of the outer periphery portion of the blank in cooperation with the upper drawing die, and trims the outer periphery portion of the blank in cooperation with the trimming member and further bends the outermost periphery portion of the blank in cooperation with the upper movable blank holder; and a lower movable blank holder which is arranged at the outer periphery of the outer periphery drawing die so as to be movable in the vertical direction and is urged upward with respect to the lower die body, on which the blank is placed, and which holds the outer periphery portion of the blank in cooperation with the trimming member. 7. The press forming apparatus for a sheet material according to claim 5, in which the upper die comprises an upper drawing die fixed to an upper die body; a punch which passes through the upper drawing die and is fixed to the upper die body; a movable blank holder which is arranged at the outer periphery of the upper drawing die so as to be movable in the vertical direction and is urged downward with respect to the upper die body; and a trimming member which is arranged at the outer periphery of the movable blank holder and is fixed to the upper die body, and the lower die comprises a lower drawing die which is arranged in a lower die body so as to be movable in the vertical direction and is urged upward with respect to the lower die body, and presses the central portion of a blank between the upper drawing die and the lower drawing die; a die which passes through the lower drawing die and is fixed to the lower die body, and performs piercing of the blank in cooperation with the punch and performs burring around an opened pierced hole; and an outer periphery drawing die, also used as a blank holder and a trimming member, which is arranged at the outer periphery of the lower drawing die and is fixed to the lower die body, holds the outer periphery portion of the blank between the movable blank holder and the outer periphery drawing die, and trims the outer periphery portion of the blank in cooperation with the trimming member and further draws the outermost periphery portion of the blank in cooperation with the upper drawing die. 8. The press forming apparatus for a sheet material according to claim 5, in which the upper die comprises an upper drawing die fixed to an upper die body; a pierced hole periphery die having a concave portion for coining, which passes through the upper drawing die and is arranged in the upper die body so as to be movable in the vertical direction and can be moved downward under pressure; a punch which passes through the pierced hole periphery die and is fixed to the upper die body; and an upper movable blank holder which is arranged at the outer periphery of the upper drawing die so as to be movable in the vertical direction and is urged downward with respect to the upper die body, the lower die comprises a lower drawing die which is arranged in a lower die body so as to be movable in the vertical direction and is urged upward with respect to the lower die body, and performs overall forming by drawing of the blank in cooperation with the upper drawing die and performs drawing of the periphery portion of the pierced hole of the blank in cooperation with the pierced hole periphery die; a punch housing hole formed in the lower drawing die to pierce the blank in cooperation with the punch; a coining punch which passes through the lower drawing die and is arranged in the lower die body so as to be movable in the vertical direction, and performs coining of the blank in cooperation with the concave portion for coining; a lower movable blank holder which is arranged at the outer periphery of the lower drawing die so as to be movable in the vertical direction and is urged downward with respect to the lower die body, and holds the outer periphery portion of the blank in cooperation with the upper drawing die; and a trimming member, also used as a blank holder, which is arranged at the outer periphery of the lower movable blank holder and is fixed to the lower die body, and presses the outer periphery of the blank between the upper movable blank holder and the trimming member and also trims the outer periphery of the blank in cooperation with the upper drawing die, wherein the lower die body is provided further with a coining punch driving mechanism comprised of a trapezoidal horizontally movable member which is supported so as to be movable in the horizontal direction, a receiving member which has an inclined surface abutting on an inclined surface at one end of the horizontally movable member and is moved downward by receiving a pressing force due to the lowering of the upper die, and a vertically movable member which has an inclined surface abutting on an inclined surface at the other end of the horizontally movable member and is moved upward by receiving a pressing force due to the horizontal movement of the horizontally movable member. 9. The press forming apparatus for a sheet material according to claim 8, in which the upper die body is comprised of a top plate and a holder arranged under the top plate, the upper drawing die is fixed to the holder, the pierced hole periphery die is installed to a connecting body capable of applying pressure in the downward direction, which passes through the upper drawing die and the holder and is hung from the holder, the punch passes through the pierced hole periphery die and the holder and is fixed to the top plate, the upper movable blank holder passes through the holder and is fixed to the top plate, the holder is urged downward by a spring member installed to the top plate, and the lower surface thereof is supported by the lower end of a retainer which passes through the holder and is installed to the top plate, when the upper die is lowered, the lowering of the holder is stopped by the resistance force at the time of trimming of the outer periphery portion of the blank and only the top plate is lowered until a pressurizing tool provided on the lower surface of the top plate abuts on the holder, and subsequently, after the pressurizing tool has abutted on the holder, the whole of the upper die has lowered to the bottom dead center, and the forming of the blank has been completed, when the upper die is raised, the rising of the holder is prevented from occurring until the lower end of the retainer abuts on the lower surface of the holder.

TECHNICAL FIELD The present invention relates to a method and apparatus for press forming a sheet material, in which, other secondary working operations can be performed while shape forming operation for a sheet material is performed in one cycle of pressing operation. BACKGROUND ART A component constituting an automotive silencer, for example, an end plate is manufactured by press forming of a sheet material. The conventional typical method consists of four processes: the outer periphery portion of a sheet material is cut (trimmed) to form a predetermined blank, a predetermined formed surface in the central portion of the blank is drawn, a predetermined non-formed surface in the central portion of the blank is pierced to form a pierced hole (pipe mounting hole), and finally burring around the pierced hole in the blank and bending of the outermost portion of the blank are performed, thereby obtaining an end plate product. As a press forming method for a sheet material, a press forming method in which the drawing and the secondary working of a sheet material are performed by one cycle of pressing operation has been known (for example, refer to FIG. 1 of Patent Document 1). In the forming method described in this publication, an upper die to which a punch is installed via an elastic means is lowered with respect to a lower die on which a blank is set, by which a sheet material is drawn by the upper and lower dies. Then, an upper cutting blade mounted on the upper die is projected downward by the lowering of the upper die, whereby the outer periphery portion of the sheet material is trimmed or trimmed and downwardly bent by the upper cutting blade and a lower cutting blade mounted on the lower die. Next, the lower cutting blade is projected upward by the lowering of the upper die, whereby the outer periphery portion of the sheet material is upwardly bent by the upper cutting blade and the lower cutting blade. With this forming method, three processes of drawing, and outer periphery trimming and outer periphery bending, which are secondary working operations, can be performed by one pressing operation, but further secondary working operations cannot be performed simultaneously by this pressing operation. Therefore, for example, in the case where the above-mentioned silencer end plate is manufactured, piercing and burring must be performed separately, so that the shortening of pressing operation time is limited. Also, an independent die for piercing operation etc. is required. Therefore, the reduction in die cost is not so big. Also, since the outer periphery trimming operation and the outer periphery bending operation are performed in succession after the drawing operation has been finished, this method has a drawback in that the working stroke is long. Furthermore, since the cutting blades for cutting the outer periphery are not fixed to the upper and lower die set and are movable, there arises a problem in that a backup mechanism (guide mechanism) is needed. Patent Document 1: Japanese Patent Laid-Open No. H08-290219 DISCLOSURE OF INVENTION Problems to be Solved by the Invention Accordingly, an object of the present invention is to provide a method and apparatus for press forming a sheet material, in which a plurality of secondary working operations, such as trimming, piercing, burring, bending, and coining can be performed while a shape forming operation is performed for a sheet material, whereby a component, such as an end plate of a silencer can be obtained by on cycle of pressing operation for the sheet material. Means for Solving the Problems To achieve the above object, the invention described in claim 1 of the application concerned provides a press forming method for a sheet material, in which an upper die provided with one of dies for drawing a sheet material and one of a plurality of secondary working members separate from the dies, which perform secondary working, such as trimming, piercing, burring, bending, or coining of the sheet material, is lowered with respect to a lower die provided with the other of the dies and the other of the secondary working members, wherein a plurality of secondary working operations, such as trimming, piercing, burring, bending, or coining are performed in the same process while shape forming is performed by drawing operation for the sheet material. The invention described in claim 2 of the application concerned provides the press forming method for a sheet material according to claim 1, in which an upper die provided with an upper drawing die, a punch, and a trimming member also used as a blank holder and a bending die is lowered with respect to a lower die provided with a lower drawing die, a die, an outer periphery drawing die also used as a trimming member and a bending die, and a blank holder, wherein the outer periphery portion of a blank placed on the blank holder is held by the blank holder and the trimming member, successively, the central portion of the blank is drawn by the lower drawing die and the upper drawing die by moving the lower drawing die upward under pressure, successively, the outer periphery portion of the blank is trimmed by the trimming member and the outer periphery drawing die, successively, overall forming by drawing of the outer periphery portion of the blank performed by the upper drawing die and the outer periphery drawing die is started, and at the same time, piercing of the blank is performed by the punch and the die, and burring around an opened pierced hole is started, successively, bending of the outermost periphery portion of the blank is started by the trimming member and the outer periphery drawing die, and as the upper die reaches the bottom dead center, the overall forming, burring, and bending of the outermost periphery portion of the blank are completed. The invention described in claim 3 of the application concerned provides the press forming method for a sheet material according to claim 1, in which an upper die provided with an upper drawing die, a punch, a blank holder, and a trimming member is lowered with respect to a lower die provided with a lower drawing die, a die, and an outer periphery drawing die also used as a blank holder and a trimming member, wherein the outer periphery portion of a blank placed on the outer periphery drawing die is held by the outer periphery drawing die and the blank holder, successively, the central portion of the blank is pressed between the upper drawing die and the lower drawing die, and the outer periphery portion of the blank is trimmed by the trimming member and the outer periphery drawing die, successively, drawing of the outer periphery portion of the blank is started by the upper drawing die and the outer periphery drawing die, successively, the blank is pierced by the punch and the die, and burring around an opened pierced hole is started, and as the upper die reaches the bottom dead center, the drawing of the outer periphery portion of the blank and the burring are completed. The invention described in claim 4 of the application concerned provides the press forming method for a sheet material according to claim 1, in which an upper die provided with an upper drawing die, a pierced hole periphery die having a concave portion for coining, a punch, and an upper blank holder is lowered with respect to a lower die provided with a lower drawing die having a punch housing hole, a coining punch, a lower blank holder, and a trimming member also used as a blank holder, wherein the outer periphery portion of a blank placed on the trimming member is held by the trimming member and the upper blank holder, successively, the outer periphery portion of the blank is trimmed by the upper drawing die and the lower blank holder, successively, overall forming by drawing of the blank is started in cooperation by the upper drawing die and the lower drawing die, successively, the pierced hole periphery portion of the blank is drawn in cooperation by the pierced hole periphery die and the lower drawing die by moving the pierced hole periphery die downward under pressure, successively, the blank is pierced by the punch and the punch housing hole, successively, coining of the blank is started by the coining punch and the concave portion for coining, and as the upper die reaches the bottom dead center, the overall forming and coining of the blank are completed. The invention described in claim 5 of the application concerned provides a press forming apparatus for a sheet material including upper and lower dies wherein the upper die is lowered with respect to the lower die, in which the upper die is provided with one of dies for drawing a sheet material and one of a plurality of secondary working members separate from the dies, which perform secondary working, such as trimming, piercing, burring, bending, or coining of the sheet material, and the lower die is provided with the other of the dies and the other of the secondary working members, and shape forming by drawing operation for the sheet material and a plurality of shape forming operations, such as trimming, piercing, burring, bending, or coining can be performed by one cycle of pressing operation. The invention described in claim 6 of the application concerned provides the press forming apparatus for a sheet material according to claim 5, in which the upper die comprises an upper drawing die fixed to an upper die body; a punch which passes through the upper drawing die and is fixed to the upper die body; an upper movable blank holder which is arranged at the outer periphery of the upper drawing die so as to be movable in the vertical direction and is urged downward with respect to the upper die body; and a trimming member which is arranged at the outer periphery of the upper movable blank holder and is fixed to the upper die body, and is also used as a blank holder and a bending die, and the lower die comprises a lower drawing die which is arranged in a lower die body so as to be movable in the vertical direction and is urged upward with respect to the lower die body and be capable of applying pressure in the vertical direction, and draws the central portion of a blank in cooperation with the upper drawing die; a die which passes through the lower drawing die and is fixed to the lower die body, and performs piercing of the blank in cooperation with the punch and performs burring around an opened pierced hole; wherein an outer periphery drawing die, also used as a trimming member and a bending die, which is arranged at the outer periphery of the lower drawing die and is fixed to the lower die body, performs overall forming by drawing of the outer periphery portion of the blank in cooperation with the upper drawing die, and trims the outer periphery portion of the blank in cooperation with the trimming member and further bends the outermost periphery portion of the blank in cooperation with the upper movable blank holder; and a lower movable blank holder which is arranged at the outer periphery of the outer periphery drawing die so as to be movable in the vertical direction and is urged upward with respect to the lower die body, on which the blank is placed, and which holds the outer periphery portion of the blank in cooperation with the trimming member. The invention described in claim 7 of the application concerned provides the press forming apparatus for a sheet material according to claim 5, in which the upper die comprises an upper drawing die fixed to an upper die body; a punch which passes through the upper drawing die and is fixed to the upper die body; a movable blank holder which is arranged at the outer periphery of the upper drawing die so as to be movable in the vertical direction and is urged downward with respect to the upper die body; and a trimming member which is arranged at the outer periphery of the movable blank holder and is fixed to the upper die body, and the lower die comprises a lower drawing die which is arranged in a lower die body so as to be movable in the vertical direction and is urged upward with respect to the lower die body, and presses the central portion of a blank between the upper drawing die and the lower drawing die; a die which passes through the lower drawing die and is fixed to the lower die body, and performs piercing of the blank in cooperation with the punch and performs burring around an opened pierced hole; and an outer periphery drawing die, also used as a blank holder and a trimming member, which is arranged at the outer periphery of the lower drawing die and is fixed to the lower die body, holds the outer periphery portion of the blank between the movable blank holder and the outer periphery drawing die, and trims the outer periphery portion of the blank in cooperation with the trimming member and further draws the outermost periphery portion of the blank in cooperation with the upper drawing die. The invention described in claim 8 of the application concerned provides the press forming apparatus for a sheet material according to claim 5, in which the upper die comprises an upper drawing die fixed to an upper die body; a pierced hole periphery die having a concave portion for coining, which passes through the upper drawing die and is arranged in the upper die body so as to be movable in the vertical direction and can be moved downward under pressure; a punch which passes through the pierced hole periphery die and is fixed to the upper die body; and an upper movable blank holder which is arranged at the outer periphery of the upper drawing die so as to be movable in the vertical direction and is urged downward with respect to the upper die body, the lower die comprises a lower drawing die which is arranged in a lower die body so as to be movable in the vertical direction and is urged upward with respect to the lower die body, and performs overall forming by drawing of the blank in cooperation with the upper drawing die and performs drawing of the periphery portion of the pierced hole of the blank in cooperation with the pierced hole periphery die; a punch housing hole formed in the lower drawing die to pierce the blank in cooperation with the punch; a coining punch which passes through the lower drawing die and is arranged in the lower die body so as to be movable in the vertical direction, and performs coining of the blank in cooperation with the concave portion for coining; a lower movable blank holder which is arranged at the outer periphery of the lower drawing die so as to be movable in the vertical direction and is urged downward with respect to the lower die body, and holds the outer periphery portion of the blank in cooperation with the upper drawing die; and a trimming member, also used as a blank holder, which is arranged at the outer periphery of the lower movable blank holder and is fixed to the lower die body, and presses the outer periphery of the blank between the upper movable blank holder and the trimming member and also trims the outer periphery of the blank in cooperation with the upper drawing die, wherein the lower die body is provided further with a coining punch driving mechanism comprised of a trapezoidal horizontally movable member which is supported so as to be movable in the horizontal direction, a receiving member which has an inclined surface abutting on an inclined surface at one end of the horizontally movable member and is moved downward by receiving a pressing force due to the lowering of the upper die, and a vertically movable member which has an inclined surface abutting on an inclined surface at the other end of the horizontally movable member and is moved upward by receiving a pressing force due to the horizontal movement of the horizontally movable member. The invention described in claim 9 of the application concerned provides the press forming apparatus for a sheet material according to claim 8, in which the upper die body is comprised of a top plate and a holder arranged under the top plate, the upper drawing die is fixed to the holder, the pierced hole periphery die is installed to a connecting body capable of applying pressure in the downward direction, which passes through the upper drawing die and the holder and is hung from the holder, the punch passes through the pierced hole periphery die and the holder and is fixed to the top plate, the upper movable blank holder passes through the holder and is fixed to the top plate, the holder is urged downward by a spring member installed to the top plate, and the lower surface thereof is supported by the lower end of a retainer which passes through the holder and is installed to the top plate, when the upper die is lowered, the lowering of the holder is stopped by the resistance force at the time of trimming of the outer periphery portion of the blank and only the top plate is lowered until a pressurizing tool provided on the lower surface of the top plate abuts on the holder, and subsequently, after the pressurizing tool has abutted on the holder, the whole of the upper die has lowered to the bottom dead center, and the forming of the blank has been completed, when the upper die is raised, the rising of the holder is prevented from occurring until the lower end of the retainer abuts on the lower surface of the holder. According to the present invention, a plurality of secondary working operations of two or more processes, such as trimming, piercing, burring, bending, or coining can be performed while shape forming by drawing of a sheet material (blank) is performed, so that a component, such as an end plate of a silencer can be obtained by one cycle of pressing operation of the sheet material. Also, since the working operations are finished by one cycle of pressing operation, the position accuracy of hole, coining, etc. with respect to the shape, the height accuracy etc. of burring, and the product accuracy are improved. Also, since some of the plurality of processes start at the same time, or during one process, other processes are started, the working stroke does not become long. Furthermore, since the trimming member for trimming the outer periphery portion of the sheet material is fixed to the upper die body or the lower die body, a backup mechanism (guide mechanism) or the like for the trimming member is not needed. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a construction view showing one example of a press forming apparatus in accordance with the present invention; FIG. 2 is an explanatory view showing a pressing operation of the apparatus shown in FIG. 1; FIG. 3 is an explanatory view showing the continuation of FIG. 2; FIG. 4 is an explanatory view showing the continuation of FIG. 3; FIG. 5 is a construction view showing another example of a press forming apparatus in accordance with the present invention; FIG. 6 is an explanatory view showing a pressing operation of the apparatus shown in FIG. 5; FIG. 7 is an explanatory view showing the continuation of FIG. 6; FIG. 8 is an explanatory view showing the continuation of FIG. 7; FIG. 9 is a construction view showing still another example of a press forming apparatus in accordance with the present invention; FIG. 10 is an explanatory view showing a pressing operation of the apparatus shown in FIG. 9; FIG. 11 is an explanatory view showing the continuation of FIG. 10; FIG. 12,is an explanatory view showing the continuation of FIG. 11; FIG. 13 is an explanatory view showing the continuation of FIG. 12; FIG. 14 is an explanatory view showing the continuation of FIG. 13; FIG. 15 is an explanatory view showing the continuation of FIG. 14; FIG. 16 is an explanatory view showing a pressing operation of the apparatus shown in FIG. 15; FIG. 17 is an explanatory view showing the continuation of FIG. 16; FIG. 18 is an explanatory view showing the continuation of FIG. 17; and FIG. 19 is an explanatory view showing the continuation of FIG. 18. BEST MODE FOR CARRYING OUT THE INVENTION Examples of the present invention will now be described in detail. FIG. 1 is a construction view showing one example of a press forming apparatus for a sheet material in accordance with the present invention. The press forming apparatus of this example is a press forming apparatus for manufacturing an end plate or a front plate of a vehicular silencer. This press forming apparatus comprises an upper die 10 in which an upper drawing die 13 provided with a punch 12, an upper movable blank holder 14, and a trimming member 15 are provided on an upper die body 11, and a lower die 20 in which a lower drawing die 23 provided with a die 22, an outer periphery drawing die 24, and a lower movable blank holder 25 are provided on a lower die body 21, and therefore press forms a sheet material by the lowering of the upper die 10 that is provided so as to be movable vertically with respect to the lower die 20 that is provided so as to be stationary. The upper die body 11 has a holder 11a in the lower part and a top plate 11b in the upper part, and the upper drawing die 13 is fixedly provided in the central portion of the holder 11a. The left-hand side of the lower surface of the upper drawing die 13 corresponds to the curved outer surface shape in the inside portion of the end plate, and is formed into a forming shape having a predetermined curved shape that has a flat portion in the outer peripheral portion and is upwardly convex. The right-hand side of the lower surface of the upper drawing die 13 corresponds to the flat outer surface shape in the inside portion of the end plate, and is formed into a flat forming shape. The punch 12 is installed in a concave hole 13a provided at a predetermined position of the flat forming surface on the right-hand side of the upper drawing die 13, and the tip end thereof is positioned at the same height as that of the flat forming surface of the upper drawing die 13. The upper movable blank holder 14 is arranged at the outer periphery of the upper drawing die 13 so as to be movable in the vertical direction, and is installed to a damper 14a provided on the top plate 11b so as to pass through the holder 11a, by which the upper movable blank holder 14 is urged downward with respect to the upper die body 11. The trimming member 15 is arranged at the outer periphery of the movable blank holder 14, and is fixed to the holder 11a. This trimming member 15 is constructed so that the lower end thereof is used as a blank holder, and is provided with a downwardly projecting bending portion 15a in the step portion on the inside at the lower end thereof so that the trimming member 15 is also used as a bending die. The edge on the inside at the lower end of the trimming member 15 is formed into a cutting blade. The lower die body 21 has a holder 21a in the upper part and a base 21b in the lower part. The lower drawing die 23 is arranged so as to be movable in the vertical direction with respect to the lower die body 21, and the lower surface of the lower drawing die 23 is supported by a plurality of dampers 27 of a gas spring type, hydraulic type, or the like which are installed on the base 21b and project from the holder 21a, by which the lower drawing die 23 is urged upward so as to be capable of applying pressure in the upward direction. The upper surface of the lower drawing die 23 is formed into a forming surface corresponding to the forming surface of the upper drawing die 13. The die 22 passes through a through hole 23a provided in the flat portion on the right-hand side of the lower drawing die 23 and is fixed to the holder 21a, and the tip end of the die 22 is flush with the flat forming surface of the lower drawing die 23 in the through hole 23a. In the outer periphery portion of the lower drawing die 23, an upwardly urged work delivery element 28 is planted. The outer periphery drawing die 24 is arranged at the outer periphery of the lower drawing die 23, and is fixed to the holder 21. The edge on the outside at the upper end of the outer periphery drawing die 24 is formed into a cutting blade so that the outer periphery drawing die 24 plays a role of a trimming member, and a downwardly concaved bending portion 24a is provided at the upper end of the outer periphery drawing die 24 so that the outer periphery drawing die 24 also has a function of a bending die. The lower movable blank holder 25 is fitted on a guide 25b erected on the holder 21a, and thereby is arranged so as to be movable in the vertical direction along the outer periphery of the outer periphery drawing die 24. Also, the lower movable blank holder 25 is installed to a damper 25a that is provided on the base 21b and passes through the holder 21a, and thereby is urged upward with respect to the lower die body 21. In the outermost portions of the holder 11a of the upper die body 11 and the holder 21a of the lower die body 21, guides 17 and 29, which are fitted to each other by the lowering of the upper die 10 to guide the straight lowering of the upper die 10, are provided, respectively. An operation for press forming an end plate from a blank B of a sheet material by using the press forming apparatus will be explained with reference to FIGS. 2 to 4. The blank B is placed on the lower movable blank holder 25 of the lower die 20 shown in FIG. 1. When the upper die 10 located at the top dead center is lowered with respect to the lower die 20, the trimming member 15 of the upper die 10 abuts on the lower blank holder 25 of the lower die 20 via the blank B, whereby the outer periphery portion of the blank B is pressed by the trimming member 15 and the lower blank holder 25. When the upper die 10 is further lowered, as shown in FIG. 2, the upper movable blank holder 14 and the outer periphery drawing die 24 of the lower die 20 hold a portion close to the inside of the outer periphery portion of the blank B, and in this state, the upper drawing die 13 abuts on the lower drawing die 23 under low pressure via the blank B. At this time of abutment, the lower drawing die 23 is moved upward under pressure by the damper 27 to draw the central portion of the blank B by the forming surface of the upper drawing die 13 and the forming surface of the lower drawing die 23, by which the left portion of the blank B is formed into a predetermined upwardly curved shape. Owing to this pre-forming of the central portion of the blank B, the lower drawing die 23 plays a role of a shape pad at the time of subsequent overall forming. On the other hand, while the trimming member 15 lowers and pushes the lower blank holder 25 downward, the outer periphery portion of the blank B is cut by the edge (cutting blade) on the inside at the lower end of the trimming member 15 and the edge (cutting blade) on the outside at the upper end of the outer periphery drawing die 24, so that the outer periphery portion of the blank B is trimmed into a predetermined shape. Then, when the upper die 10 is further lowered, the upper drawing die 13 lowers and pushes the lower drawing die 23 downward against the damper 27, and as shown in FIG. 3, the inside of the outer periphery portion of the blank B held by the upper blank holder 14 and the outer periphery drawing die 24 is drawn by the upper drawing die 13 and the outer periphery drawing die 24, by which the overall forming of the blank B is started. At the same time, the tip end of the punch 12 enters the inside of the die 22 to punch out the blank B, by which a pierced hole is formed at a predetermined position on the right-hand side of the blank B. Furthermore, as the upper die 10 lowers, a gap around the tip end portion of the punch 12 receives the tip end portion of the die 22, and a portion around the pierced hole in the blank B is drawn between the inner wall surface defining the concave hole 13a in the upper drawing die 13 and the outer wall surface of the die 22, by which an upward burring operation around the pierced hole is started. When the upper die 10 is further lowered, as shown in FIG. 4, the bending portion 15a of the trimming member 15 abuts on and presses the bending portion 24a of the outer periphery drawing die 24 via the outermost portion of the blank B, by which the outermost portion of the blank B is upwardly bent to a small extent. By the time when the upper die 10 reaches the bottom dead center, the bending operation of the outermost portion of the blank B is finished. Also, the overall forming operation of the blank B and the burring operation around the pierced hole are also finished, and thus an end plate product is completed. When the upper die 10 is raised and the pressure is relieved, the obtained product is raised by the work delivery element 28 of the lower drawing die 23, and can be taken out of the press forming apparatus. As described above, according to this example, while shape forming of a sheet material (blank) is performed by drawing, shape forming of secondary working of trimming, bending, piercing and burring is performed, so that an end plate of a silencer can be manufactured by one cycle of pressing operation of a sheet material. Also, some of a plurality of processes are started at the same time, or during one process, other processes are started, so that the working stroke does not become long. Furthermore, since the trimming member for trimming the outer periphery portion of the sheet material is fixed to the upper die body and the lower die body, a backup mechanism (guide mechanism) for the trimming member or the like mechanism is not needed. Another example of the present invention is shown in FIGS. 5 to 8. In this example, press forming of a separator of a silencer is described. FIG. 5 is a construction view showing a press forming apparatus for forming the separator, and FIGS. 6 to 8 are views showing a press forming operation for the separator performed by using the apparatus shown in FIG. 5. This press forming apparatus comprises an upper die 30 in which an upper drawing die 33 provided with a punch 32, a movable blank holder 34, and a trimming member 35 are provided on an upper die body 31, and a lower die 40 in which a lower drawing die 43 provided with a die 42 and an outer periphery drawing die 44a are provided on a lower die body 41. The upper drawing die 33 is fixedly provided in the central portion of a holder 31a in the lower part of the upper die body 31, and the lower surface of the upper drawing die 33 is formed into a flat forming surface. The punch 32 passes through a through hole 33a provided at a predetermined position on the right-hand side of the upper drawing die 33 and is installed to the holder 31a, and the tip end thereof is positioned at the same height as that of the forming surface of the upper drawing die 33. The upper movable blank holder 34 is arranged at the outer periphery of the upper drawing die 33 so as to be movable in the vertical direction, and is installed to a damper 34a provided on a top plate 31b so as to pass through the holder 31a, by which the upper movable blank holder 34 is urged downward with respect to the upper die body 31. The trimming member 35 is arranged at the outer periphery of the movable blank holder 34, and is fixed to the holder 31a. The edge on the inside at the lower end of the trimming member 35 is formed into a cutting blade. The lower drawing die 43 is supported by a guide 45b passing through a holder 41a of the lower die body 41, and is provided so as to be movable in the vertical direction. Also, the lower drawing die 43 is installed to a damper 45a that passes through the holder 41a and is provided on a base 41b, and thereby is urged upward with respect to the lower die body 41. The upper surface of the lower drawing die 43 is formed into a flat forming surface as the forming surface of the upper drawing die 33. The die 42 passes through a through hole 42a provided at a predetermined position on the right-hand side of the lower drawing die 43 and is fixed to the base 41b, and the tip end of the die 42 is flush with the forming surface of the lower drawing die 43 in the through hole 42a. The outer periphery drawing die 44 is arranged at the outer periphery of the lower drawing die 43, and is fixed to the holder 41b. The upper end of the outer periphery drawing die 44 is also used as a blank holder, and the edge on the outside at the upper end of the outer periphery drawing die 44 is formed into a cutting blade so as to be also used as a trimming member. At the outer periphery of the outer periphery drawing die 44 on the holder 41a, a scrap cutter 46 is provided at two or more locations so that an annular scrap produced at the outer periphery of the die 44 by the trimming operation of a blank B is divided into pieces to prevent the scrap from remaining in the die. By using the above-mentioned press forming apparatus, a separator of a silencer is press formed from a blank B of a sheet material as described below. A blank B is placed on the outer periphery drawing die 44 of the lower die 40 shown in FIG. 5. When the upper die 30 is lowered with respect to the lower die 40, the movable blank holder 34 of the upper die 30 abuts on the outer periphery drawing die 44 via the blank B, and the outer periphery portion of the blank B is held by the movable blank holder 34 and the outer periphery drawing die 44. When the upper die 30 is further lowered, as shown in FIG. 6, the movable blank holder 34 and the outer periphery drawing die 44 hold a portion close to the inside of the outer periphery portion of the blank B, and in this state, the trimming member 35 lowers to cut the outer periphery portion of the blank B by means of the edge (cutting blade) of the trimming member 35 and the edge (cutting blade) of the outer periphery drawing die 44, by which the outer periphery portion of the blank B is trimmed into a predetermined shape. The upper drawing die 33 abuts on the lower drawing die 43 via the blank B, and the central portion of the blank B is pressed by the drawing dies 33 and 43 that play a role of a shape pad. Then, when the upper die 30 is further lowered, the upper drawing die 33 lowers and pushes the lower drawing die 43 downward against the damper 45a, and as shown in FIG. 7, while the outer periphery portion of the blank B held by the movable blank holder 34 and the outer periphery drawing die 44 is pulled out, the outer periphery portion of the blank B is drawn by the upper drawing die 33 and the outer periphery drawing die 44 so as to be drawn up, by which the -outer periphery portion of the blank B begins to be formed into a bend erected perpendicularly to the surface in the central portion of the blank B. When the upper die 30 is further lowered, as shown in FIG. 8, the tip end of the punch 32 enters the inside of the die 42 to punch out the blank B, by which a pierced hole is formed at a predetermined position on the right-hand side of the blank B. Furthermore, as the upper die 30 lowers, a gap around the tip end portion of the punch 32 receives the tip end portion of the die 42, and a portion around the pierced hole in the blank B is drawn between the inner wall surface of the tip end portion of the through hole 33a in the upper drawing die 33 and the outer wall surface of the die 42, by which an upward burring operation around the pierced hole is started. By the time when the upper die 30 reaches the bottom dead center, the burring operation around the pierced hole and the bending operation of the outer periphery portion in the blank B are finished. Thus, a separator product is completed. As described above, according to this example, a separator of a silencer can be manufactured by one cycle of pressing operation from a sheet material, and the same effect as that of the above-mentioned example can be achieved. Still another example of the present invention is explained with reference to FIGS. 9 to 19. This example is an example in which a pump impeller of a torque converter or a shell of a turbine runner is press formed. FIG. 9 is a construction view showing a press forming apparatus for forming the shell, and FIGS. 10 to 13 are explanatory views showing a press forming operation for the shell performed by using the apparatus shown in FIG. 9. The press forming apparatus of this example comprises an upper die 50 in which a pierced hole periphery die 52, an upper drawing die 54 provided with a punch 53, and an upper movable blank holder 55 are provided on an upper die body 51, and a lower die 60 in which a lower drawing die 64 provided with a coining punch 62, a lower movable blank holder 65, and an outer periphery die 66 are provided on a lower die body 61. The upper die body 51 has a rectangularly shaped top plate 51b and a rectangularly shaped holder 51a which is arranged under the top plate 51b and is slightly smaller than the top plate 51b. On the lower surface of the holder 51a, a four-side thick plate shaped pressurizing tool 51c is provided at the periphery, and a cylindrical pressurizing tool 51d is provided in the center. On the inside of the pressurizing tool 51c, there are provided a spring member 57a for urging the holder 51a downward and a retainer 57b which passes through the holder 51a and supports the lower surface of the holder 51a by means of a supporting portion 57b1 at the lower end thereof. The holder 51a supported by the retainer 57b is hung from the top plate 51b so that a predetermined gap is provided between the holder 51a and the pressurizing tools 51c and 51d. The upper drawing die 54 consists of an annular body, and the lower surface thereof is formed into a forming surface of a basin shape that is convex upward so as to correspond to the outer surface shape of the shell including the outer peripheral flange. The upper drawing die 54 is fixed to the holder 51a via a spacer 54a. The pierced hole periphery die 52 consists of an annular body, and the lower surface thereof is formed into a forming surface corresponding to the pierced hole periphery portion of the shell which is continued to the forming surface of the upper drawing die 54. The pierced hole periphery die 52 is arranged concentrically on the inside of the upper drawing die 54, and is installed at the lower ends of a plurality of connecting shafts 52b arranged in the circumferential direction with intervals being provided so as to be movable in the vertical direction. The connecting shafts 52b pass through the holder 51a and are hung by the holder 51a by hooking a ring 52b1 connecting the upper ends of the connecting shafts 52b on to the upper surface of the holder 51a. In the pressurizing tool 51d, a plurality of spring members 58 are installed along the circumferential direction, which spring members 58 press down the rising connecting shafts 52b via the ring 52b1 in the head portion to allow the connecting shafts 52b to operate as a damper. The spring members 58 are installed on the lower surface of the top plate 51b. The configuration may be such that the spring members 58 are not provided, and the connecting shafts 52b are formed by a damper so that the connecting shaft itself has a damper function. The pierced hole periphery die 52 projects in a curved portion on the lower surface of the upper drawing die 54 in a free state in which the connecting shafts 52b are hung by the holder 51a. At a position close to the center of the forming surface of the pierced hole periphery die 52, a plurality of small concave portions 52a for coining are provided. The punch 53 is arranged concentrically on the inside of the pierced hole periphery die 52, and passes through the holder 51a and is fixed to the pressuring tool 51d with a bolt. The tip end of the punch 53 is flush with the lower surface of the pierced hole periphery die 52 at the same height as that of the forming surface of the upper drawing die 54. The upper movable blank holder 55 consists of an annular body arranged at the outer periphery of the upper drawing die 54, and is installed at the lower ends of a plurality of dampers 55a urging downward so as to be movable in the vertical direction. In this state, the upper movable blank holder 55 projects downward from the upper drawing die 54. The dampers 55a pass through the holder 51a and are installed on the lower surface of the top plate 51b. At four corners of the lower surface of the holder 51a, there is provided a guide cylinder which fits on a guide rod 73 of the lower die 60 to guide the straight lowering of the upper die 50. Also, on both right and left sides of the lower surface of the holder 51b, a push arm 56 for operating a coining punch driving mechanism 72 of the lower die 60 is installed. The lower die body 61 comprises a holder 61a in an upper part and a base 61b in a lower part, and the holder 61a is fixed to the base 61b via a supporting tool 61c. The lower drawing die 64 consists of an annular body, and the upper surface thereof is formed into a brimless basin-shaped forming surface that is convex upward so as to correspond to the outer surface shape of the shell excluding the outer peripheral flange thereof. The inner periphery portion of the forming surface of the lower drawing die 64 is formed into a shallow concave shape corresponding to the pierced hole periphery portion of the shell, and a through hole 63 corresponding to the punch 53 is formed in the central portion of the lower drawing die 64. The lower drawing die 64 is fixed on a support 67 provided on the upper surface of the holder 61a. The coining punch 62 is provided so that the lower end of the punch 62 is installed to a vertically movable member 69, which passes through the holder 61a and is movable in the vertical direction, so as to be movable in the vertical direction in a through hole 62a formed in the lower drawing die 64, and the tip end of the punch 62 is flush with the upper surface of the inner periphery portion of the lower drawing die 64. The vertically movable member 69 constitutes a driving mechanism 72 for the coining punch 62. The lower movable blank holder 65 consists of an annular body arranged at the outer periphery of the lower drawing die 64, and is installed at the upper ends of a plurality of dampers 65a urging upward so as to be movable in the vertical direction. In this state, the upper end of the lower movable blank holder 65 is positioned slightly above the lower drawing die 64. The dampers 65a pass through the holder 61a and are fixed to a supporting tool 61d of the lower die body 61. The trimming member 66 is an annular member in which the inside edge at the upper end plays a role of a cutting blade, and which is also used as a lower blank holder, and is arranged at the outer periphery of the lower movable blank holder 65 and fixed on the holder 61a. The guide rod 73 is provided at four corners of the holder 61a so as to correspond to the guide cylinder 59 of the upper die 50. The coining punch driving mechanism 72 is a kind of cam mechanism, and is provided on both right and left sides of the lower die body. The coining punch driving mechanism 72 comprises a receiving member 70 in the vertical direction, a horizontally movable member 71 in the horizontal direction, and the above-mentioned vertically movable member 69 in the vertical direction. The trapezoidal horizontally movable member 71 is disposed on the base 61b so as to be movable horizontally to the right and left. The receiving member 70 passes through the holder 61a at the lower position of the push arm 56 of the upper die 50 so as to be movable in the vertical direction, and abuts on the side surface of the vertical member 61c provided in the lower die body 61 so as to be guided. An inclined surface 70a at the lower end of the receiving member 70 abuts on an inclined surface 71a at one end of the horizontally movable member 71, and an inclined surface 69a at the lower end of the vertically movable member 69 abuts on the inclined surface 71a at the other end of the horizontally movable member 71, by which the cam mechanism is formed. The vertically movable member 69 is urged downward by a return spring 74 provided in the supporting tool 61d of the lower die body 61. The push arm 56 is allowed to abut on the receiving member 70 by the lowering of the upper die 50, and the receiving member 70 is pushed to lower. Then, the horizontal movable member 71 is-pushed by the receiving member 70 and is moved to the inside in the horizontal direction, and the vertical movable member 69 is pushed upward against the spring 74 by the horizontally movable member 71, so that the coining punch 62 installed to the vertically movable member 69 projects from the tip end of the through hole 62a in the upper drawing die 64. The shell is formed as described below by this press forming apparatus. As shown in FIG. 9, in a state in which the upper die 50 is located at the top dead center, a blank B is placed on the lower movable blank holder 65 and the trimming member 66 of the lower die 60. When the top plate 51b is lowered by an elevating means, not shown, installed to the top plate 51b of the upper die 50, the whole of the upper die 50 including the holder 51a pressed by the spring member 57 lowers with respect to the lower die 60. As shown in FIG. 10, the upper movable blank holder 55 of the upper die 50 abuts on the trimming member 66 via the blank B so that the outer periphery portion of the blank B is pressed by the upper movable blank holder 55 and the trimming member 66. Then, the flat outer periphery portion of the upper drawing die 54 abuts on the lower movable blank holder 65 via the inside portion of the outer periphery portion of the blank B. Thus, the lowering of the holder 51a is once stopped by the resistance force of the blank B the outer periphery portion of which is cut by the edge (cutting blade) at the outer periphery of the upper drawing die 54 and the edge (cutting blade) at the inner periphery of the trimming member 66, and only the top plate 51b lowers. As shown in FIG. 11, the pressurizing tools 51c and 51d installed on the top plate 51b abut on the holder 51a, by which the holder 51a is pressed and lowered. Therefore, the flat outer periphery portion of the upper drawing die 54 pushes the lower movable blank holder 65 downward, and the edge (cutting blade) at the outer periphery of the upper drawing die 54 and the edge (cutting blade) at the inner periphery of the trimming member 66 cut the outer periphery portion of the blank B, so that the outer periphery portion of the blank B is trimmed into a predetermined circular shape. Also, a push pad 58a of the spring member 58 abuts on the ring 52b1 of the connecting shafts 52b, and presses down the connecting shafts 52b downward. When the upper die 50 is further lowered, as shown in FIG. 12, the outer periphery portion of the upper drawing die 54 further pushes the lower movable blank holder 65 downward, and the outer periphery portion of the blank B is held between the outer periphery portion of the upper drawing die 54 and the blank holder 65. In this state, the overall forming operation in which the blank B is drawn along the lower drawing die 64 by the upper drawing die 54 and the lower drawing die 64 is started. At the same time, the pierced hole periphery die 52 at the lower ends of the connecting shafts 52b abuts on the inner periphery portion of the lower drawing die 64 via the blank B. The pierced hole periphery die 52 applies downward pressure to the blank B to draw the inner periphery portion of the blank B into a predetermined shape, by which working around the pierced hole is completed. Owing to this pre-forming operation around the pierced hole of the blank B, the pierced hole periphery die 52 plays a role of a shape pad at the time of pierced hole forming and at the time of overall forming. When the upper die 50 is further lowered, as shown in FIG. 13, the push pad 58a of the spring member 58 of the upper die 50 is retreated by a reaction force from the blank B, and only the punch 53 and the upper drawing die 54 lower. Therefore, the tip end portion of the punch 53 enters the inside of the hole 63 in the lower drawing die 64 to punch out the blank B, by which a pierced hole is formed in the center of the blank B. Also, the outer periphery portion of the upper drawing die 54 further pushes the lower movable blank holder 65 downward, so that the drawing of the central portion of the blank B, namely, the overall forming progresses. At this time, the push arm 56 of the upper die 50 abuts on the receiving member 70 of the lower die 60. When the upper die 50 is further lowered, as shown in FIG. 14, the receiving member 70 of the coining punch driving mechanism 72 moves downward, the horizontal movable member 71 moves to the inside in the horizontal direction, and the vertically movable member 69 moves upward, whereby the coining punch 62 is pushed up, and the tip end of the punch 62 projects from the tip end of the through hole 62a in the lower drawing die 64 and is pressed into the concave portion 52a of the pierced hole periphery die 52 via the blank B, by which coining, namely, the forming of a groove for blade positioning is started around the pierced hole in the blank B. As shown in FIG. 15, when the upper die 50 reaches the bottom dead center, the overall forming (curved shape of shell and outer peripheral flange) and coining around the pierced hole are finished, by which a shell S is completed. When the upper die 50 is raised from the bottom dead center after the shell has been completed, the shell can be taken out. If the outer periphery portion of the upper drawing die 54, which abuts on, from the upside, on the flange of the shell S, is raised by raising the upper die 50 while the pierced hole periphery portion of the shell S is pressed from the upside by the pierced hole periphery die 52, the flange of the shell S is pressed upward by the lower movable blank holder 65 of the lower die 60, so that there is a fear that the flange may be deformed. In this example, the holder 51a and the top plate 51b of the upper die 50 are not fixed, and only the top plate 51b and attached members thereof, such as the pressurizing tool 51c are first raised from the upper die 50 located at the bottom dead center by the spring member 57a and the retainer 57b provided on the top plate 51b. Therefore, the deformation of the flange of the shell S can surely be prevented in the rising process of the upper die 50. This process is explained below. When the top plate 51b of the upper die 50 located at the bottom dead center is raised by the elevating means, not shown, as shown in FIG. 16, the holder 51a urged downward by the spring member 57a of the top plate 51b does not move, so that the supporting portion 57b1 of the retainer 57b installed on the top plate 51b abuts on the lower surface of the holder 51b and is hooked on to the holder 51b. The connecting shafts 52b fitted with the pierced hole periphery die 52 are pressed downward by the extending push portion 58a of the spring member 58 of the top plate 51b, so that the pierced hole periphery die 52 that abuts on the pierced hole periphery portion of the shell S still presses the shell S. Since the holder 51a does not rise, the upper drawing die 50 still presses the shell S. When the top plate 51b is further raised, as shown in FIG. 17, the holder 51a is hung by the retainer 57b, by which the whole of the upper die 50 is raised. The whole of the shell S including the flange is raised by the lower movable blank holder 65 of the lower die 60, which pushes the flange of the shell S, while being pressed by the upper drawing die 54 and the pierced hole periphery die 52. Therefore, at the time when the upper die 50 rises, the flange is not deformed by the lower movable blank 65 that pushes the flange of the shell S. Also, the push arm 56 of the holder 51a separates from the receiving member 70 of the coining punch driving mechanism 72, the vertically movable member 69 is lowered by the return spring 74, and the coining punch 62 of the vertically movable member 69 lowers. Also, the horizontally movable member 71 is moved to the outside in the horizontal direction by the vertically movable member 69, and the receiving member 70 is raised by the horizontally movable member 71, so that the coining punch driving mechanism 72 returns to the initial position. When the upper die 50 is further raised, as shown in FIG. 18, the lower movable blank holder 65 extends to the initial upper end position, and the shell S is not pushed up further. Therefore, when the upper die 50 is further raised, as shown in FIG. 19, the shell S drops onto the lower movable blank holder 65 by its gravity, and the shell S is taken out from between the upper die 50 having reached the top dead center and the lower die 60. As described above, according to this example, a pump impeller of a torque converter or a shell product of a turbine runner can be manufactured by one cycle of pressing operation from a sheet material, and the same effect as that of the above-mentioned examples can be achieved.

<SOH> BACKGROUND ART <EOH>A component constituting an automotive silencer, for example, an end plate is manufactured by press forming of a sheet material. The conventional typical method consists of four processes: the outer periphery portion of a sheet material is cut (trimmed) to form a predetermined blank, a predetermined formed surface in the central portion of the blank is drawn, a predetermined non-formed surface in the central portion of the blank is pierced to form a pierced hole (pipe mounting hole), and finally burring around the pierced hole in the blank and bending of the outermost portion of the blank are performed, thereby obtaining an end plate product. As a press forming method for a sheet material, a press forming method in which the drawing and the secondary working of a sheet material are performed by one cycle of pressing operation has been known (for example, refer to FIG. 1 of Patent Document 1). In the forming method described in this publication, an upper die to which a punch is installed via an elastic means is lowered with respect to a lower die on which a blank is set, by which a sheet material is drawn by the upper and lower dies. Then, an upper cutting blade mounted on the upper die is projected downward by the lowering of the upper die, whereby the outer periphery portion of the sheet material is trimmed or trimmed and downwardly bent by the upper cutting blade and a lower cutting blade mounted on the lower die. Next, the lower cutting blade is projected upward by the lowering of the upper die, whereby the outer periphery portion of the sheet material is upwardly bent by the upper cutting blade and the lower cutting blade. With this forming method, three processes of drawing, and outer periphery trimming and outer periphery bending, which are secondary working operations, can be performed by one pressing operation, but further secondary working operations cannot be performed simultaneously by this pressing operation. Therefore, for example, in the case where the above-mentioned silencer end plate is manufactured, piercing and burring must be performed separately, so that the shortening of pressing operation time is limited. Also, an independent die for piercing operation etc. is required. Therefore, the reduction in die cost is not so big. Also, since the outer periphery trimming operation and the outer periphery bending operation are performed in succession after the drawing operation has been finished, this method has a drawback in that the working stroke is long. Furthermore, since the cutting blades for cutting the outer periphery are not fixed to the upper and lower die set and are movable, there arises a problem in that a backup mechanism (guide mechanism) is needed. Patent Document 1: Japanese Patent Laid-Open No. H08-290219

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a construction view showing one example of a press forming apparatus in accordance with the present invention; FIG. 2 is an explanatory view showing a pressing operation of the apparatus shown in FIG. 1 ; FIG. 3 is an explanatory view showing the continuation of FIG. 2 ; FIG. 4 is an explanatory view showing the continuation of FIG. 3 ; FIG. 5 is a construction view showing another example of a press forming apparatus in accordance with the present invention; FIG. 6 is an explanatory view showing a pressing operation of the apparatus shown in FIG. 5 ; FIG. 7 is an explanatory view showing the continuation of FIG. 6 ; FIG. 8 is an explanatory view showing the continuation of FIG. 7 ; FIG. 9 is a construction view showing still another example of a press forming apparatus in accordance with the present invention; FIG. 10 is an explanatory view showing a pressing operation of the apparatus shown in FIG. 9 ; FIG. 11 is an explanatory view showing the continuation of FIG. 10 ; FIG. 12 ,is an explanatory view showing the continuation of FIG. 11 ; FIG. 13 is an explanatory view showing the continuation of FIG. 12 ; FIG. 14 is an explanatory view showing the continuation of FIG. 13 ; FIG. 15 is an explanatory view showing the continuation of FIG. 14 ; FIG. 16 is an explanatory view showing a pressing operation of the apparatus shown in FIG. 15 ; FIG. 17 is an explanatory view showing the continuation of FIG. 16 ; FIG. 18 is an explanatory view showing the continuation of FIG. 17 ; and FIG. 19 is an explanatory view showing the continuation of FIG. 18 . detailed-description description="Detailed Description" end="lead"?

20061115

20110531

20070719

62373.0

B29C4302

TOLAN, EDWARD THOMAS

METHOD AND APPARATUS FOR PRESS FORMING SHEET MATERIAL

UNDISCOUNTED

ACCEPTED

B29C

ACCEPTED

Method For Joining Blades to Blade Roots or Rotor Disks When Manufacturing and/or Repairing Gas Turbine Blades or Integrally Bladed Gas Turbine Rotors

A method is provided for joining blades to blade roots or rotor disks when manufacturing and/or repairing gas turbine blades or integrally bladed gas turbine rotors. A blade and a blade root or rotor disk that is to be joined to the blade are supplied, and provided with a thickening in sections that are to be joined together. The sections of the blade and the blade root or rotor disk that are to be joined together are machined so as to form recesses and; c) are then aligned relative to each other, opposite recesses defining at least one groove-shaped seam preparation. The blade and the blade root or rotor disk are joined in the area of the or each seam preparation by means of laser power build-up welding and the joined blade and blade root or rotor disk are machined so as to provide a gas turbine blade or an integrally bladed gas turbine rotor having a predefined geometrical profile.

1-7. (canceled) 8. A method for joining blades to blade roots or rotor disks when manufacturing and/or repairing gas turbine blades or integrally bladed gas turbine rotors, comprising: a) prefabricating a blade and a blade support to be joined to the blade, the blade support being one of a blade root and a rotor disk, the blade having a thickened region at a portion of the blade to be joined to the blade support, the blade support having a thickened region at a portion of the blade support to be joined to the blade; b) machining said portion of the blade and said portion of the blade support to form recesses; c) subsequently mutually aligning the blade and the blade support to be joined to the blade such that said recesses form mutually opposing recesses delimiting at least one groove-shaped weld preparation; d) joining the blade and the blade support in an area of the groove-shaped weld preparation(s) by employing laser powder build-up welding; e) machining the joined blade and blade support to form a gas turbine blade or an integrally bladed gas turbine rotor having a predefined geometric profile. 9. The method as recited in claim 8, wherein the recesses extend between a flow inlet edge and a flow outlet edge of blade the and over an entire axial length of the blade. 10. The method as recited in claim 8, wherein, after the alignment step, the recesses extend both on an intake side of the blade and a thrust side of the blade, and wherein, during the joining step, the laser powder build-up welding is performed simultaneously on the intake side and the thrust side. 11. The method as recited in claim 8, wherein, after the alignment step, the recesses extend on only one side of the blade, said one side being either an intake side of the blade or a thrust side of the blade, and wherein, during the joining step, the laser powder build-up welding is performed on said one side. 12. The method as recited in claim 11, comprising, after the joining step, forming another groove-shaped weld preparation on the other side of the blade such that any nicks and/or imperfections in the area of a root of the weld seam already formed by laser powder build-up welding are removed; and subsequently thereto, and before the machining step, performing a laser powder build-up welding process in an area of said another groove-shaped weld preparation on the other side. 13. The method as recited in claim 8, wherein said machining step is performed via a milling process. 14. A method for repairing gas turbine blades or integrally bladed gas turbine rotors, comprising: a) performing laser powder build-up welding to form a thickened region at least in a separating region of a damaged blade; b) separating the damaged blade from a gas turbine along the separating region to form a blade support, the blade support being one of a blade root and a rotor disk, the blade support having a portion of the thickened region formed in step (a); c) prefabricating a replacement blade, the replacement blade having a thickened region at a portion of the replacement blade to be joined to the blade support; d) machining said portion of the replacement blade and said portion of the blade support to form recesses; c) subsequently mutually aligning the replacement blade and the blade support to be joined to the replacement blade such that said recesses form mutually opposing recesses delimiting at least one groove-shaped weld preparation; d) joining the replacement blade and the blade support in an area of the groove-shaped weld preparation(s) by employing laser powder build-up welding; e) machining the joined blade and blade support to form a gas turbine blade or an integrally bladed gas turbine rotor having a predefined geometric profile. 15. The method as recited in claim 14, wherein the recesses extend between a flow inlet edge and a flow outlet edge of replacement blade the and over an entire axial length of the replacement blade. 16. The method as recited in claim 14, wherein, after the alignment step, the recesses extend both on an intake side of the replacement blade and a thrust side of the replacement blade, and wherein, during the joining step, the laser powder build-up welding is performed simultaneously on the intake side and the thrust side. 17. The method as recited in claim 14, wherein, after the alignment step, the recesses extend on only one side of the replacement blade, said one side being either an intake side of the replacement blade or a thrust side of the replacement blade, and wherein, during the joining step, the laser powder build-up welding is performed on said one side. 18. The method as recited in claim 17, comprising, after the joining step, forming another groove-shaped weld preparation on the other side of the replacement blade such that any nicks and/or imperfections in the area of a root of the weld seam already formed by laser powder build-up welding are removed; and subsequently thereto, and before the machining step, performing a laser powder build-up welding process in an area of said another groove-shaped weld preparation on the other side. 19. The method as recited in claim 14, wherein said machining step is performed via a milling process.

The present invention relates to a method for joining blades to blade roots or rotor disks when manufacturing and/or repairing gas turbine blades or integrally bladed gas turbine rotors. Gas turbines, such as aircraft engines, for example, have at least one compressor, as well as at least one turbine, the or each compressor, as well as the or each turbine having at least one stage, and the or each stage of each compressor, as well as of each turbine being constituted of a stationary guide vane ring, as well as of a rotating rotor blade ring. The rotor blades forming the or each rotating rotor blade ring each have an aerodynamically shaped blade, the blade of each rotor blade either being anchored by a blade root in corresponding recesses of a rotor disk, or being permanently joined to the rotor disk, forming an integrally bladed gas turbine rotor. Integrally bladed gas turbine rotors are also referred to as blisks (bladed disks) or blings (bladed rings). The rotor blades of a gas turbine, in particular, are exposed to heavily oxidizing, corroding or also eroding conditions during operation of the gas turbine, so that they are subjected to substantial wear. Thus, the need may arise, for example, when working with integrally bladed rotors, to replace a damaged blade in order to repair the integrally bladed gas turbine rotor. This then requires joining a new blade to the rotor disk of the gas turbine rotor at the location where a damaged blade had been removed. When rebuilding integrally bladed gas turbine rotors, all of the blades must be joined to the rotor disk. When individual gas turbine blades are rebuilt, it is necessary to join a blade to a corresponding blade root. The related art method provides for using linear friction welding or inductive high-frequency pressure welding to join blades to blade roots or rotor disks when manufacturing and/or repairing gas turbine blades or integrally bladed gas turbine rotors. Both linear friction welding, as well as inductive high-frequency pressure welding are costly, particularly when working with high-temperature resistant materials, and they pose risks in terms of process safety. Against this background, the object of the present invention is to devise a novel method for joining blades to blade roots or rotor disks when manufacturing and/or repairing gas turbine blades or integrally bladed gas turbine rotors. This objective is achieved by a method for joining blades to blade roots or rotor disks when manufacturing and/or repairing gas turbine blades or integrally bladed gas turbine rotors, as set forth in claim 1. The method according to the present invention includes at least the following steps: a) prefabricating a blade and a blade root to be joined to the blade, or a rotor disk to be joined to the blade, the blade and the blade root or the rotor disk having a thickened region at portions of the same to be joined; b) machining the portions of the blade and blade root or of the rotor disk to be joined together, to form recesses; c) subsequently mutually aligning the blade and the blade root to be joined to the blade, or to the rotor disk, mutually opposing recesses delimiting at least one groove-shaped weld preparation; d) joining the blade and blade root or rotor disk in the area of the or each weld preparation by employing laser powder build-up welding; e) machining the mutually joined blade and blade root or rotor disk to prepare a gas turbine blade or an integrally bladed gas turbine rotor having a predefined geometric profile. Preferred embodiments of the present invention are derived from the dependent claims and from the following description. The present invention is described in greater detail in the following on the basis of exemplary embodiments, without being limited to such embodiments. Reference is made to the drawing, whose: FIG. 1a-1g show, in a highly schematized representation, a rotor disk and a blade in a sequence of method steps for illustrating the method according to the present invention when repairing an integrally bladed gas turbine rotor; and FIG. 2a-2d depict, in a highly schematized representation, a blade root and a blade in a sequence of method steps for illustrating the method according to the present invention when manufacturing a gas turbine blade. FIG. 1a through 1g clarify one specific embodiment of the method according to the present invention for joining blades to a rotor disk when repairing an integrally bladed gas turbine rotor. In accordance with the method of the present invention, the following procedure is used when repairing an integrally bladed gas turbine rotor: FIG. 1a shows an integrally bladed gas turbine rotor 10 having a damaged blade 11, the aim being to remove damaged blade 11 from a rotor disk 12 of gas turbine rotor 10 and to replace it with a new blade, in order to repair gas turbine rotor 10 shown in FIG. 1a. Before cutting off damaged blade 11 from rotor disk 12 of integrally bladed gas turbine rotor 10, a thickened region 13 is prepared at least in the area of a later separation site by employing laser powder build-up welding both on the intake side, as well as on the thrust side of blade 11, to ensure a most continuous or uniform possible thickness profile over the entire region of the separation site. Damaged blade 11 is subsequently separated from rotor disk 12 along parting cut 14 shown as a dashed line in FIG. 1a. The separation of damaged blade 11 from rotor disk 12 yields the structure shown in FIG. 1b, thickened region 13 produced beforehand by laser powder build-up welding extending in the area of a portion 15 of rotor disk 12, where a new, prefabricated blade is to be attached in order to repair gas turbine rotor 10. The thus prepared portion 15 of rotor disk 12, to which a new blade 16 (see FIG. 1d through 1g) is to be attached, is machined along the lines of the present invention in such a way that at least one recess 17 is formed in portion 15. In this connection, in the exemplary embodiment of FIG. 1a through 1g, merely one recess 17 is incorporated in portion 15, this recess 17 extending over the entire axial length of portion 15. This may be inferred, in particular, from FIG. 1c. The new, prefabricated blade 16 is likewise provided with a corresponding recess 19 in the area of a portion 18, via which blade 16 is to be attached to portion 15 of rotor disk 12, as may be inferred from FIG. 1d, portion 18 of blade 16 also being provided with a corresponding thickened region 20, in order to prepare a continuous or uniform thickness profile on portion 18 of new blade 16. Likewise introduced into blade 16, merely on one side and in the area of portion 18, is a recess 19, which, in turn, extends over the entire axial length of blade 16. As may be inferred from FIG. 1d, rotor disk 12 and new blade 16 are subsequently mutually aligned in a way that permits a positionally correct joining thereof, recesses 17 and 19 of regions 15 and 18 of rotor disk 12 and blade 16 opposing one another and forming a groove-shaped weld preparation 21. Groove-shaped weld preparation 21 extends, in turn, over the entire axial length of blade 16 and rotor disk 12 in the area of portions 15 and 18 to be joined together, and, to be precise, in the exemplary embodiment of FIG. 1a through 1g, merely on one side of blade 16, this side either being the intake side or the thrust side of blade 16. Blade 16, aligned relative to rotor disk 12 along the lines of FIG. 1d, is subsequently joined to rotor disk 12 by employing a laser powder build-up welding process in the area of weld preparation 21. Thus, in hatched shading, FIG. 1e shows weld preparation 21 filled in by laser powder build-up welding, blade 16 being thereby joined to rotor disk 12 at portions 15 and 18 in the area of weld preparation 21. In the exemplary embodiment of FIG. 1a through 1g, another groove-type weld preparation 22 (see FIG. 1f) is subsequently introduced to the opposite side of blade 16, where blade 16 is not yet joined to rotor disk 12, and thus on the rear side of weld seam introduced into weld preparation 21. If weld preparation 21, where blade 16 is already joined to rotor disk 12, is located on the thrust side of blade 16, then an additional weld preparation 22 is introduced into the intake side accordingly. In the process, additional weld preparation 22 is introduced into portions 15 and 18 of rotor disk 12 and of blade 16 to be joined together, in such a way that nicks and/or imperfections in the area of a root of the weld seam introduced into weld preparation 21 by laser powder build-up welding are eliminated. As shown in FIG. 1g, a laser powder build-up welding process is subsequently carried out in the region of additional weld preparation 22 and, in this region as well, a weld joint is prepared between blade 16 and rotor disk 12. Blade 16 joined on both sides to rotor disk 12, as well as rotor disk 12 are subsequently machined in the area of thickened regions 13 and 20, respectively, in such a way that an integrally bladed gas turbine rotor having a predefined, geometric, aerodynamically favorable profile is finally made ready for use. This is preferably accomplished by milling, in particular by adaptive milling. In this context, thickened regions 13 and 20 in the area of mutually joined portions 15 and 18 of rotor disk 12 and of blade 16 are ablated in a way that yields the contour illustrated by a dashed line in FIG. 1g in the area of rotor disk 12 and of blade 16. Thickened regions 13 and 20 not only extend in the area of the two sides (intake side and thrust side) of blade 16 and of rotor disk 12, but also in the area of a flow inlet edge and flow outlet edge, so that the material provided by thickened regions 13 and 20, in excess of the dashed-line contour, is removed on all sides. It should be pointed out here again that, in the exemplary embodiment of FIG. 1a through 1g, to repair an integrally bladed gas turbine rotor 10, blade 16 and rotor disk 12 are welded in such a way that they are first joined on one side by employing laser powder build-up welding and, on the side that is not yet joined, an additional weld preparation is subsequently formed, where a separate laser powder build-up welding process is then carried out to completely join blade 16 to rotor disk 12. It is also emphasized at this point that, in the context of the present invention, it is understood that the process of joining blade 16 to rotor disk 12 may also be carried out on both sides simultaneously. This then requires introducing corresponding recesses on both sides of portions 15 and 18 of blade 16 and rotor disk 12 to be joined together, so that a positionally correct, mutual alignment of blade 16 and of rotor disk 12 yields groove-type weld preparations on both sides. In this case, blade 16 may be simultaneously welded to rotor disk 12 by laser powder build-up welding. FIG. 2a through 2d illustrate a second exemplary embodiment of the method according to the present invention when joining a blade 23 to a blade root 24 in order to manufacture a gas turbine blade 25. To this end, in accordance with FIG. 2a, a blade root 24 is prefabricated, which, at a portion 26, where blade 23 having a portion 27 is to be attached or joined, has a thickened region 28. In the same way, portion 27 of blade 23 has a corresponding thickened region 29. The purpose of thickened regions 28 and 29 is, in turn, to provide a uniform or continuous thickness distribution at portions 28 and 29 of blade 23 and blade root 24 to be joined to one another. Blade 23, as well as blade root 24 (see, in particular, FIGS. 2b and 2c), are subsequently machined at portions 26 and 27 in such a way that recesses 30 and, respectively, 31 are produced. In the process, in the exemplary embodiment of FIG. 2a through 2d, two recesses 30 are introduced in the area of portion 26 of blade root 24, each of these two recesses extending on one side, namely both on the thrust side, as well as on the intake side, over the entire axial length of portion 26. Likewise introduced into portion 27 of blade 23 are two recesses 31, which also extend on both sides of blade 23 over the entire axial length of the same. Once blade 23 and blade 24 are accurately positionally aligned (see FIG. 2c), groove-type weld preparations 32 and 33 are formed on both sides, thus both on the thrust side, as well as on the intake side, and extend over the entire axial length thereof. Blade 23 is then joined to blade root 24, simultaneously on both sides of blade 23, by employing laser powder build-up welding in the area of these two groove-type weld preparations 32 and 33. In a hatched shading, FIG. 2d shows weld preparations 32 and 33 filled with a weld seam produced by laser powder build-up welding. Once blade 23 is joined to blade root 24 in the manner described above, they are then machined in the area of thickened regions 28 and 29 to prepare a gas turbine blade having a predefined geometric profile, as is shown by dashed lines in FIG. 2d. This machining operation is preferably accomplished, in turn, by milling, in particular by adaptive milling. The method according to the present invention makes it possible to produce high-strength bonds between blades and blade roots and, respectively, between blades and rotor disks when manufacturing and/or repairing gas turbine blades or integrally bladed gas turbine rotors. The method according to the present invention is also especially suited when the components to be joined together are manufactured from high-temperature resistant materials. One skilled in the art whom this technical teaching concerns is already familiar with the details pertaining to laser powder build-up welding, so that no further explanation of this process is needed. It should be merely noted here that, particularly when repairing integrally bladed rotor disks along the lines of the method of the present invention, laser welding heads must be used which permit a beam deflection of up to 90°, since minimal space is available between adjacent blades of an integrally bladed rotor. The laser light, as well as the powdery material required for laser powder build-up welding are externally supplied from the radial direction in this case, and must be deflected in the area of the groove-type weld preparations by up to 90°, to enable the laser light, as well as the powdery material to be introduced into the weld preparations in a manner characterized by positional accuracy.

20060302

20091222

20081009

65055.0

B23P1504

WALTERS, RYAN J

METHOD FOR JOINING BLADES TO BLADE ROOTS OR ROTOR DISKS WHEN MANUFACTURING AND/OR REPAIRING GAS TURBINE BLADES OR INTEGRALLY BLADED GAS TURBINE ROTORS

UNDISCOUNTED

ACCEPTED

B23P

ACCEPTED

Nanofibers, and apparatus and methods for fabricating nanofibers by reactive electrospinning

Apparatus and methods for fabricating nanofibers by reactive electrospinning are described. An electrospinning process is coupled with an in-line reactor where chemical or photochemical reactions take place. This invention expands the application of the electrospinning and allows the production of nanofibers of crosslinked polymers and other new materials, such as gel nanofibers of ceramic precursors.

1. A method for forming nanofibers by reactive electrospinning; said method comprising the steps of: (a) supplying one or more reagents to a reactor; and initiating a chemical reaction or a photochemical reaction of the one or more reagents within the reactor, within the Taylor cone of an electrospinning process, or in an the electrospinning jet of an electrospinning process; (i) wherein the reaction or photochemical reaction produces one or more of: a product with a substantially higher degree of polymerization than the reagents, or a product with a substantially higher degree of crosslinking than the reagents, or a gel product from a sol-gel transition reaction mixture; and (ii) wherein the reaction mixture or photochemical reaction mixture would become too viscous to undergo electrospinning into nanofibers within about 30 minutes or sooner after the reaction is initiated; (b) electrospinning the reaction mixture onto a collector; wherein said electrospinning occurs before the reaction mixture becomes too viscous to undergo electrospinning into nanofibers; and (c) allowing the reaction to continue during electrospinning, or on the collector, or both; to produce nanofibers on the collector, wherein at least some of the nanofibers have a diameter less than about 5 μm. 2. A method as recited in claim 1, wherein said method is conducted as a batch process. 3. A method as recited in claim 1, wherein said method is conducted as a continuous process, without clogging of the capillary, for a time substantially greater than the time during which a batch reaction mixture would become too viscous to undergo electrospinning into nanofibers. 4. A method as recited in claim 1, wherein said electrospinning is enhanced by flowing a sheath of reactive or non-reactive gas around the reaction mixture exiting the capillary, or by flowing reactive or non-reactive gas through the core of the reaction mixture exiting the capillary, or both. 5. A method as recited in claim 1, additionally comprising the step of adding one or more reagents to the reaction mixture exiting a capillary from the reactor, to react chemically with the reaction mixture during electrospinning. 6. A method as recited in claim 1, wherein said electrospinning is enhanced by controlling the temperature of the reaction mixture in a capillary exiting the reactor. 7. A method as recited in claim 1, wherein said electrospinning is enhanced by adding one or more electrolytes to the reaction mixture. 8. A method as recited in claim 1, wherein the reaction is accelerated by applying ultrasound to the reaction mixture. 9. A method as recited in claim 1, wherein the reaction mixture would become too viscous to undergo electrospinning into nanofibers within about 10 minutes or sooner after the reaction is initiated. 10. A method as recited in claim 1, wherein the reaction mixture would become too viscous to undergo electrospinning into nanofibers within about 2 minutes or sooner after the reaction is initiated. 11. A method as recited in claim 1, wherein the reaction mixture would become too viscous to undergo electrospinning into nanofibers within about 30 seconds or sooner after the reaction is initiated. 12. A method as recited in claim 1, wherein the reaction mixture would become too viscous to undergo electrospinning into nanofibers within about 10 seconds or sooner after the reaction is initiated. 13. A method as recited in claim 1, wherein at least some of the nanofibers have a diameter less than about 1 μm. 14. A method as recited in claim 1, wherein at least some of the nanofibers have a diameter less than about 500 nm. 15. (canceled) 16. A nanofiber, wherein: said nanofiber has a diameter less than about 1 μm; said nanofiber is at least about 50 μm long; and said nanofiber comprises at least about 10 mol-% ZrO2. 17. A nanofiber as recited in claim 16, wherein said nanofiber is at least about 100 μm long. 18. A nanofiber as recited in claim 16, wherein said nanofiber additionally comprises at least one component selected from the group consisting of Y2O3, Al2O3, SiO2, CaO, MgO, TiO2, P2O5, CaF2, B2O3, and Na2O. 19. A nanofiber as recited in claim 18, wherein said nanofiber additionally comprises at least one component selected from the group consisting of PO3, OH, F, N, and C. 20. (canceled) 21. Apparatus for electrospinning nanofibers, said apparatus comprising: (a) a mixer adapted to receive reagents, to mix the reagents, and to transfer the resulting reaction mixture to a reactor; (b) a reactor adapted to receive the reaction mixture from said mixer, to allow the reaction mixture to react for a period of time prior to electrospinning, and to transfer the reaction mixture to a capillary; (c) a capillary adapted to receive the reaction mixture from said mixer, and to extrude the reaction mixture for electrospinning; (d) a collector adapted to receive electrospun material from said capillary; and (e) a high voltage source adapted to impose an electrical potential between about 1 kilovolt and about 100 kilovolts between said collector and said capillary, to cause the reaction mixture to electrospin from said capillary to said collector. 22. Apparatus as recited in claim 21, additionally comprising a conduit adapted to flow a sheath of gas around the reaction mixture exiting the capillary, or to flow gas or one or more reagents through the core of the reaction mixture exiting the capillary, or both. 23. Apparatus as recited in claim 21, additionally comprising an ultrasound transducer adapted to supply ultrasound to the reaction mixture. 24. Apparatus as recited in claim 21, additionally comprising one or more light sources adapted to supply actinic radiation to the reaction mixture in said reactor, or during electrospinning between said capillary and said collector, or on said collector. 25. Apparatus as recited in claim 21, wherein said collector is adapted to collect nanofibers continuously. 26. Apparatus as recited in claim 21, wherein said voltage source is adapted to provide a high positive or negative potential to said collector, and to ground said capillary. 27. Apparatus as recited in claim 21, additionally comprising a heater adapted to control the temperature of said capillary.

The benefit of the 05 Sep. 2003 filing date of U.S. provisional patent application Ser. No. 60/500,591 is claimed under 35 U.S.C. § 119(e) in the United States, and is claimed under applicable treaties and conventions in all countries. TECHNICAL FIELD This invention pertains to nanofibers, and to apparatus and methods for producing nanofibers through the in-line coupling of electrospinning with chemical reactions, photochemical reactions, or both. BACKGROUND ART Nanofibers are thin small fibers, with typical diameters ranging from tens to hundreds of nanometers, up to about 1 micrometer. Nanofibers have been formed from polymers, carbon, and ceramic. Nanofibers have attracted great interest because of their extraordinarily high surface area and length-to-width ratio, as well as their unique physical and mechanical properties. Nanofibers are being used in such areas as filtration, fiber-reinforced nanocomposites, wound dressing, drug delivery, artificial organs, micro-electrical systems, and micro-optical systems. However, fabrication of nanofibers is very challenging due to their minute diameters. Traditional methods, such as formation in porous solids or at the step-edges of laminated crystals, are often ineffective and costly. An alternative method is electrostatic fiber formation or electrospinning. Electrospinning is a relatively simple and versatile method. In electrospinning, a high voltage (e.g., ˜3 to ˜50 kV) is applied between a target (or collector) and a conducting capillary into which a polymer solution or melt is injected. The high voltage can also be applied to the solution or melt through a wire if the capillary is a nonconductor such as a glass pipette. The collector may be a metal plate or screen, a rotating drum, or even a liquid bath if the capillary is vertical. Initially the solution at the open tip of the capillary is pulled into a conical shape (the so-called “Taylor cone”) through the interplay of electrical force and surface tension. At a certain voltage range, a fine jet of polymer solution (or melt) forms at the tip of the Taylor cone and shoots toward the target. Forces from the electric field accelerate and stretch the jet. This stretching, together with evaporation of solvent molecules, causes the jet diameter to become smaller. As the jet diameter decreases, the charge density increases until electrostatic forces within the polymer overcome the cohesive forces holding the jet together (e.g., surface tension), causing the jet to split or “splay” into a multifilament of polymer fibers. The fibers continue to splay until they reach the collector, where they are collected as nonwoven fibers, and are optionally dried. The diameter of an electrospun nanofiber is typically between about 50 nm and about 5 μm. High-speed photographic studies have suggested that, at least in some cases, what had appeared to be a multifilament was in fact a single, ultrafine fiber, being whipped very rapidly. A wide variety of polymers have been electrospun from solutions and melts. A large number of papers describing the electrospinning process have been published, particularly in the past decade. Two recent review articles summarizing the state of the art are A. Frenot et al., “Polymer nanofibers assembled by electrospinning,” Current Opinion in Colloid and Interface Science, vol. 8, pp. 64-75 (2003); and Z. Huang et al., “A review on polymer nanofibers by electrospinning and their applications in nanocomposites,” Composites Science and Technology, vol. 63, pp. 2223-2253 (2003). Baker D A, Brown P J. Reactive routes to making modified nanofiber structures via electrospinning. Polymer Preprints (2003), 44(2), 118-119 reported the addition of azides to polymer solutions prior to electrospinning. The azides could react, crosslink, functionalize, and covalently bind polymer chains. Electrospinning mixtures of polymers with the additives could be used for the covalent binding of synthetic polymers with natural polymers in a single manufacturing step. It was said that applying heat or UV light during electrospinning was said to modify nanofiber substrates either during the fiber formation process or by post-spin treatments; however, the only successful experimental results reported were apparently for post-spin reaction and cross-linking. The experimental procedures reported the preparation of solutions containing polymer and azide crosslinking agents. The solutions were then weighed, sealed, and checked for solvent loss during the time taken for dissolution. After an unspecified lapse of time, the solutions were later used in electrospinning procedures. The reaction and crosslinking in these experiments apparently did not take place until a post-spinning thermal analysis step. Cross-linked polymers, hydrogels, hyperbranched polymers, and dendrimers have properties that differ from those of otherwise-comparable linear polymers. For example, they often have higher chemical stability and improved mechanical properties. They often possess unique chemical properties and functionalities. Such polymers have been used in diverse applications including coatings, composite resins, controlled drug release, organic-inorganic hybrid materials, solid supports for catalysts, and supports for chromatography or ion-exchange resins. However, highly cross-linked polymers and hyperbranched polymers are generally difficult to form as fibers through prior techniques, and even more difficult to form into nanofibers, because they typically have low solubility, and they typically will not melt without undergoing heat-induced decomposition, due to the strong intermolecular bonding or entanglement of the polymer molecules and the formation of polymer networks. Ding, B. et al, “Preparation and characterization of a nanoscale poly(vinyl alcohol) fiber aggregate produced by an electrospinning method,” J. Poly. Sci. B: Poly. Phys., (2002), 40, 1261-1268, reported the preparation of crosslinked poly(vinyl alcohol) (PVA) nanofibers (100-500 nm) by first mixing 0˜10% glyoxal (a crosslinking agent) and phosphoric acid (as a catalyst) with a 10% PVA-water solution, then electrospinning the mixed solution at room temperature, followed by post-spinning thermal curing of the electrospun-PVA fiber in an oven at 120° C. for 5 min. It was reported that the crosslinked PVA fiber aggregates were more hydrophobic, and that they exhibited better mechanical properties. U.S. Pat. No. 6,382,526 discloses a process for forming nanofibers by comprising the steps of feeding a fiber-forming material into an annular column, the column having an exit orifice, directing the fiber-forming material into a gas jet space, thereby forming an annular film of fiber-forming material, the annular film having an inner circumference, simultaneously forcing gas through a gas column, which is concentrically positioned within the annular column, and into the gas jet space, thereby causing the gas to contact the inner circumference of the annular film, and ejects the fiber-forming material from the exit orifice of the annular column in the form of a plurality of strands of fiber-forming material that solidify and form nanofibers having a diameter up to about 3,000 nanometers. U.S. Pat. No. 6,520,425 discloses a nozzle for forming nanofibers by using a pressurized gas stream comprising a center tube, a first supply tube that is positioned concentrically around and apart from the center tube, a middle gas tube positioned concentrically around and apart from the first supply tube, and a second supply rube positioned concentrically around and apart from the middle gas tube. The center tube and first supply tube form a first annular column. The middle gas tube and the first supply tube form a second annular column. The middle gas tube and second supply tube form a third annular column. The tubes are positioned so that first and second gas jet spaces are created between the lower ends of the center tube and first supply tube, and the middle gas tube and second supply tube, respectively. U.S. Pat. No. 6,308,509 discloses nanofibers having a diameter ranging from about 4 to 1 nm, and a nano denier of about 10−9. The use of the electro-spinning process permits production of the desired nanofibrils. These fibrils in combination with a carrier or strengthening fibers/filaments can be converted directly into nonwoven fibrous assemblies or converted into linear assemblies (yarns) before weaving, braiding or knitting into 2-dimensional and 3-dimensional fabrics. The electrospun fiber can be fed in an air vortex spinning apparatus developed to form a linear fibrous assembly. The process makes use of an air stream in a properly confined cavity. The vortex of air provides a gentle means to convert a mixture of the fibril fed directly or indirectly from the ESP unit and a fiber mass or filament into an integral assembly with proper level of orientation. Incorporation of thus produced woven products into tissue engineering is part of the present invention. Published international patent application WO 01/27365 discloses a fiber comprising a substantially homogeneous mixture of a hydrophilic polymer and a polymer that is at least weakly hydrophobic. The fiber optionally contains a pH adjusting compound. A method of making the fiber is disclosed, electrospinning fibers of the substantially homogeneous polymer solution. The fibers are disclosed as having application for dressing wounds. Recently, submicron fibers and nanofibers of ceramic oxides, such as silica and alumina-borate have been reported using a sol-gel process and electrospinning. See C. Shao et al., “A novel method for making silica nanofibres by using electrospun fibres of polyvinylalcohol/silica composite as precursor,” Nanotechnology, vol. 13, pp. 635-637 (2002); and H. Dai et al., “A novel method for preparing ultra-fine alumina-borate oxide fibres via an electrospinning technique,” Nanotechnology, vol. 13, pp. 674-677 (2002). A typical process includes (1) acid hydrolysis of organometallic precursors such as tetraethyloxysilane (TEOS) to form a colloid solution (sol), (2) mixing the sol with an aqueous or alcohol solution of a polymer such as polyvinyl alcohol (PVA), and digesting to form a viscous sol; (3) electrospinning the sol to form a silica/PVA composite gel fiber; (4) calcination or sintering the gel fiber to yield a porous silica or alumina fiber. TiO2 and SnO2 nanofibers have been prepared by electrospinning a titanium tetraisopropoxide (Ti(OiPr)4)/poly(vinyl pyrrolidone)(PVP) solution, or a tin (IV) tetraisopropoxide (Sn(OiPr)4) / PVP / ethanol solution, followed by rapid hydrolysis by moisture in air, and calcination. See D. Li et al., “Fabrication of titania nanofibers by electrospinning,” Nano Letters, vol. 3, pp. 555-560 (2003); and D. Li et al., “Electrospinning of polymeric and ceramic nanofibers as uniaxially aligned arrays,” Nano Letters, vol. 3, pp. 1167-1171 (2003). Because the composite gel fibers produced by these processes have contained high levels of organic polymers (typically, about 30% to 66% PVA or PVP), removal of the polymer by calcination has left substantial voids in the final ceramic nanofibers, voids that cannot be healed by calcination or sintering. Such porous ceramic oxide nanofibers have a large-surface area, and may be used in catalysts, filtration, or absorbents. However, they are not well-suited for use as reinforcing elements due to their poor mechanical properties. Bioactive materials, such as bioactive glass, hydroxyapatite, and glass-ceramic A-W can react with biological fluids, and can bond directly to living bone. They have been used in orthopedic and dental implants and cements. However, such materials have had low fracture toughness. Zirconia and titania ceramics have been used to reinforce the bioactive materials. See T. Kasuga et al., “Bioactive glass-ceramic composite toughened by tetragonal zirconia,” pp. 137-142 in Yamamuro et al. (Eds.), CRC Handbook of Bioactive Ceramics, Volume 1 (1990); and Kokubo et al, “Novel bioactive materials with different mechanical properties,” Biomaterials, vol. 24, pp. 2161-2175 (2003). To the inventor's knowledge, however, zirconia-reinforced bioactive glass-ceramic nanofibers or zirconia nanofiber-reinforced bioactive glass-ceramics have not previously been reported. The fabrication of α-alumina nanofibers by sol-gel chemistry and electrospinning was reported by G. Larsen et al., “A method for making inorganic and hybrid (organic/inorganic) fibers and vesicles with diameters in the submicrometer and micrometer range via sol-gel chemistry and electrically forced liquid jets,” J. Am. Chem. Soc., vol. 125, pp. 1154-1155 (2003). Zirconia-based ceramics have superior properties such chemical resistance, thermal stability, high mechanical strength and toughness, high ionic conductivity, and catalytic properties. Zirconia has been widely used in engineering and technological applications. In recent years, zirconia-based ceramics have gained popularity in medical devices and dentistry because of their excellent esthetics, biocompatibility, and high toughness. Zirconia particles and nanoparticles have been used as fillers in dental composites to increase both radiopacity and resistance to hydrolytic degradation. There is an unfilled need for dense ZrO2—SiO2 and ZrO2—Y2O3 nanofibers for use as reinforcement fillers in dental composites. Zirconia-based ceramic nanofibers will significantly increase the mechanical strength and fracture toughness of dental composites, while satisfying the stringent requirements for color and translucency needed for such- purposes. Current commercially available zirconia fibers are too thick for such applications (5˜10 μm), because their resulting composites are highly opaque. To the knowledge of the inventor, continuous, dense zirconia-based nanofibers have not previously been reported. Nor have there been prior reports of any method for the direct fabrication of dense ceramic nanofibers through precursor gel nanofibers by electrospinning, without the incorporation of a significant amount of organic polymer. The production of continuous nanofibers by electrospinning requires polymers (or other macromolecules) in the form of a solution or melt. A solution or suspension of discrete small molecules, including, e.g., monomers, oligomers, colloids, or nanoparticles, cannot ordinarily be electrospun into a continuous nanofiber, but instead through an electrospray will produce droplets or nanoparticles. There is an unfilled need for a method to make continuous, cross-linked or hyperbranched polymer nanofibers, including crosslinked hydrogel nanofibers. There is an unfilled need for a method to modify the chemical or physical properties of polymers in nanofibers to yield cross-linked polymer nanofibers and other nanofiber materials that are difficult or impossible to make by existing techniques. To the inventor's knowledge, no prior work has reported the successful production of nanofibers or crosslinked nanofibers by electrospinning, in which polymerization or cross-linking reactions occur during or immediately prior to the electrospinning itself, as opposed to reactions that have occurred substantially before or substantially after the electrospinning process. DISCLOSURE OF INVENTION I have discovered novel nanofibers, and novel methods and apparatus for producing nanofibers. Cross-linked polymers and other materials, such as gel nanofibers of ceramic precursors, are formed into nanofibers by coupling electrospinning in-line with chemical reactions, photochemical reactions, or both. It is one aspect of this invention to provide a general method for conducting reactive electrospinning in conjunction with chemical reactions, photochemical reactions, or both, and to control the relative timing of electrospinning and chemical or photochemical reaction in order to produce and to control the properties of the resulting nanofibers. It is another aspect of this invention to couple an electrospinning device with an in-line chemical reactor or photochemical reactor, to allow chemical reactions or photochemical reactions to occur during or immediately prior to electrospinning. It is yet another aspect of this invention to optimize the orientation of the electrospinning device relative to the direction of gravitational pull, to optimize the electrospinning procedure and its products. It is yet another aspect of this invention to couple an in-line mixer with an in-line chemical reactor or photochemical reactor to precisely control the reaction time. It is yet another aspect of this invention to control the temperature of the in-line reactor to modify the reaction rate and viscosity during electrospinning. It is yet another aspect of this invention to use a pressurized sheath flow gas, or a pressurized central flow gas to aid in the electrospinning of highly viscous materials. It is yet another aspect of this invention to add salts to the reaction mixture to aid in the electrospinning of highly viscous materials. It is yet another aspect of this invention to use an acoustic source (e.g., an ultrasonic transducer) to aid the mixing of reactants and the electrospinning of highly viscous materials. It is yet another aspect of this invention to configure the apparatus to avoid high voltage hazard from devices attached to the reactive nozzle. It is yet another aspect of this invention to provide an apparatus for continuously forming nanofibers and post-spinning processing. The combination of some or all of these aspects of the invention offers significant advantages over prior processes and nanofibers. This invention will significantly expand the applications of electrospinning. It allows the production of nanofibers of cross-linked polymers, as well as non-polymeric materials such as gel nanofibers of ceramic precursors. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 depicts a chart showing the change in viscosity of the spinable materials as a function of reaction time. Curve (a) depicts a fast reaction. Curve (b) depicts a slow reaction. FIG. 2 depicts schematically an apparatus for performing chemical reactive electrospinning in accordance with this invention. FIG. 3 depicts schematically an embodiment of apparatus in accordance with this invention, including an ultrasonic transducer. FIG. 4 depicts schematically an embodiment of apparatus in accordance with this invention, including a reactive nozzle for chemical reactive electrospinning, and an in-line mixer with an ultrasonic transducer. FIG. 5 depicts schematically an embodiment of apparatus in accordance with this invention, including a central tube that may be used to introduce a composition such as a flowing gas, an additional reagent, an immiscible polymer solution, or a suspension of nanoparticles. FIG. 6 depicts schematically an apparatus for performing photochemical reactive electrospinning in accordance with this invention. FIG. 7 depicts schematically an apparatus for performing photochemical reactive electrospinning, including an ultrasonic transducer and a mixer connected to the in-line reactor through flexible tubing. FIG. 8 depicts schematically an apparatus for performing photochemical reactive electrospinning, including an ultrasonic transducer and central gas tubing. FIG. 9 depicts schematically an apparatus for performing photochemical reactive electrospinning in accordance with this invention, including a laser source aimed at the outlet (Taylor cone) of the electrospinning capillary. FIG. 10 depicts schematically an apparatus for continuous production of nanofibers in accordance with this invention, where the nozzles and attached devices are placed at ground potential while the high voltage is connected to the collector, which in this embodiment comprises a conducting moving belt around a pair of rotating metal drums supported by insulating materials. FIG. 11 depicts a scanning electron micrograph of a calcinated ceramic fiber prepared in accordance with this invention, comprising about 80% ZrO2 and about 20% SiO2. MODES FOR CARRYING OUT THE INVENTION Cross-linking or hyperbranching causes the viscosity of the solution or melt to increase rapidly. At the so-called “gel point” or “gel time,” the viscosity has increased so much that the solution becomes a gel or even a solid, leading to phase separation or precipitation. FIG. 1 depicts two such reactions. Curve (a) depicts a fast reaction, where the viscosity increases rapidly from the beginning. Examples of such reactions include the photopolymerization of cross-linkable monomers, cross-linking reactions induced by UV or gamma radiation, some metal-initiated polymerizations, and some chemical crosslinking reactions. Curve (b) depicts a slow-starting reaction, where the viscosity initially changes slowly and later accelerates. Many chemically induced polymerization and cross-linking reactions are characterized by this type of curve. Electrospinning is coupled in-line with solution chemistry, photochemistry, or both. The spinning reagents, such as soluble linear polymers, prepolymers or macromonomers, are mixed with cross-linkers, initiators, catalysts, or other reagents immediately before or even directly inside an in-line reactor, so that chemical reactions, photochemical reactions, or both occur immediately before electrospinning, during electrospinning, or both. In special cases, such as a reaction that will not proceed (or that will proceed only slowly) without photochemical or heat activation, the various reaction components may be mixed in advance, but will delay reaction until photochemical activation. The relative fraction of cross-linkers and catalysts is normally small, e.g., 1˜10% of the reaction mixture by mass. Their effects on surface tension are generally insignificant. The limiting factor in reactive electrospinning will normally be the viscosity of the mixture, particularly the gel point, i.e., the point at which the viscosity increases dramatically. Timing thus becomes very important. It is highly desirable, and in most cases is essential, for the reaction mixture to exit the electrospinning capillary before it reaches the gel point. Otherwise, the viscosity of the material can become so high that stable electrospinning cannot be maintained, or the backpressure can exceed the limits of the delivering pump'or precipitates may clog the capillary. In FIG. 1, η0 represents the initial viscosity (immediately after mixing), and ηm represents the maximum viscosity that still allows stable electrospinning. The value of ηm may be determined, for example, by varying the concentration of a soluble linear polymer (preferably, the main component of the desired product) under otherwise identical electrospinning operating conditions (e.g., high voltage, flow rate, capillary-collector distance). In FIG. 1, tm represents the maximum reaction time, i.e., the reaction time corresponding to the maximum viscosity ηm. For fast reactions, tm ≈tin, where tin is the in-line reaction time, including any time delay between the mixer and the in-line reactor, and also including the time the reaction mixture remains inside the electrospinning capillary. For slow reactions, tm ≈tin +toff, where toff is the off-line reaction time, the period during which the reactants are be mixed and react in an off-line reactor. Typically, a slower reaction is initiated by heating or light radiation in the off-line reactor for a period of time (toff), then inhibited by lowering the temperature or turning off the light source, and the partially reacted material is then injected into the in-line reactor under heating or light radiation to continue further reaction. The overall controlling condition is: tin+toff≦tm=ktg (1) where tg is the gel time, and k is a constant. The gel time tg may, for example, be determined by the intersection of the extrapolation of the slowly-increasing portion and the rapidly-increasing portion of the plot of viscosity versus time. The gel time tg may also be determined by other methods such as measuring the loss tangent (tan δ) or the critical strain using either a dynamic stress rheometer or a Fourier transform mechanical spectrometer. The constant k is typically between about 0.8 and about 1.1, and depends on the shape of the viscosity-versus-time curve and the method used for measuring tg. For many applications, k equals 1; tm equals tg and therefore the maximum viscosity ηm is the value at the gel point. The spinning material leaves the electrospinning capillary before or near the gel point, before the reaction has proceeded to completion. Therefore, post-spinning processing may include, for example: merely allowing the reaction to proceed post-spinning under ambient conditions, adding further reactants, adding further solvent or nonsolvent liquids, heat, and radiation from UV, visible, or infrared light, gamma rays, or electron beam. There are several advantages to producing cross-linked nanofibers and the like by reactive electrospinning in accordance with the present invention, as opposed to a process that relies entirely on post-spinning processing, for example: (1) the reactants are more thoroughly mixed in a homogeneous medium, rather than depending on the swelling of solid fibers or the diffusion of components (e.g., the cross-linker); (2) even nanofibers that are only partially crosslinked may exhibit substantially better chemical stability and better mechanical properties than their linear counterparts, which may be too fragile or too soluble for post-spinning processing (e.g., many hydrogels); (3) some multifunctional cross-linkable monomers (e.g., di-, or tri-acrylates, methacrylates, vinylbenzene, vinyl alkenes) must be mixed with other co-monomers and then undergo co-polymerization so that each polymerizable group on the cross-linking monomer is inserted in to the linear polymer backbone, which is not feasible with post-spinning processing alone. There are several techniques that may be used to simultaneously control the reaction rate, to lower the viscosity, and to allow a more viscous solution to be spun. Such techniques include the following: (1) Heating the electrospinning capillary to increase reaction rates. Many polymerization or cross-link reactions require higher temperatures, e.g., in the range from about 60° C. to about 250° C. Higher temperature also typically increases solubility and decreases viscosity of the polymer solution or melt because viscosity in a polymer system significantly depends on temperature. The viscosity of a polymer melt or solution often may be approximated as η(T)=A0exp(Ea/RT) (2) where η(T) is the zero-shear viscosity at temperature T (in degrees Kelvin); Ea. is the flow activation energy (J), R is the ideal gas constant (8.314 J/K), and A0 is a constant. Heating the capillary of an electrospinning apparatus has generally been avoided, because the capillary has been at high voltage. But by grounding the capillary and placing the collector at high voltage instead, heaters, ultrasound transducers, or other devices may be placed on the capillary with less concern about high voltage hazards. (2) Attaching an acoustic device (e.g., an ultrasonic transducer) to the electrospinning device. Alternatively, a focused, non-contacting ultrasonic source may be used. The application of ultrasound typically increases chemical reaction rates, decreases apparent viscosity, and increases solubility, because it induces acoustic cavitation and promotes convection. Because ultrasound helps mix reactants more thoroughly, it may produce more uniform fibers for some reaction mixtures. As a side benefit, ultrasound may also help to clean out the capillary without dismantling the device for mechanical cleaning. To minimize potential adverse effects from sonication, such as decreasing the stability of the electrospinning jet or disrupting the electrospinning process by turning it into an electrospray, it is preferred to use low frequency acoustic energy (e.g., ˜22 kHz), and the power of the acoustic energy should be controlled. To the knowledge of the inventor, the use of ultrasound in conjunction with electrospinning has never previously been proposed. (3) Adding a pressurized gas (e.g., nitrogen gas) in a coaxial sheath flow, a coaxial central flow, or both. The pressurized gas flow helps to promote solvent evaporation and to produce finer and drier fibers. A pressurized gas flow may be particularly helpful when a high boiling point solvent is used (e.g., DMF, isopropanol, or H2O). Nitrogen is preferred for the pressurized gas because it is inert, inexpensive, and nonflammable. Nitrogen gas can help prevent fire or explosion of an organic solvent/air mixture, which might be ignited by sparks generated by a high electric field. An inert gas such as nitrogen can also help to suppress corona discharge (dielectric breakdown of the air), thus allowing the use of higher voltages in electrospinning. Other gases may also be used, such as carbon dioxide, air, argon, helium, vapor of solvent or non-solvent liquids, sulfur hexafluoride, fluorocarbons, and mixtures. (4) Adding electrolytes (salts) to the reaction mixture will increase conductivity and charge density, and can help to produce finer fibers from the viscous solution due to coulombic repulsion. For example, salts such as NaCI, LiCI, CaCl2, and (Bu)4NCl can be used. Preferred is a tetraalkylammonium triflate salt such as (Bu)4N (CF3SO3) (Tetrabutylammonium trifluoromethanesulphonate (triflate) or TBATFL) due to its high solubility in organic solvents and to the low nucleophilicity of its anion (triflate F3CSO3). TBATFL thus has relatively low potential for interference with polymerization or cross-linking reactions. Some general guidelines, or preferred approaches, in electrospinning nanofibers are the following: (1) Parameters that affect the diameter and morphology of electrospun nanofibers include the electric field strength, solution concentration, viscosity, surface tension, and conductivity—particularly viscosity. A viscosity in the range from tens to hundreds poise helps promote a stable electrospinning process. Within a certain range (e.g., ˜30 to ˜150 μL/min), the flow rate of the solution does not strongly affect the diameter or morphology of the fiber. (2) Adding a small amount of a salt increases conductivity and thus the electrospinning current. But the conductivity should not be too high, or electrospinning turns into electrospray, producing droplets and particles instead of fibers. (3) When a less volatile solvent such as DMF or water is used as the solvent, the fibers generated by electrospinning are often “wet” (containing 30˜80% solvent). Wet fibers tend to attach to one another. As a result, a fused mat is produced instead of long continuous fibers. Also, wet polymer or gel fibers may bond to the electrospinning collector, making it difficult to separate fibers from the collector without damaging the fibers. Therefore, dry fibers are usually preferred. A longer distance between nozzle and collector helps produce drier fibers. EXAMPLE 1 FIG. 2 depicts an embodiment of a reactive nozzle for chemical reactive electrospinning. It comprises an in-line mixer 6, an in-line chemical reactor 10, one or more coil heaters 11, an electrospinning capillary 12, and a sheath gas tube 13. The reactants are separately introduced though ports 16 and 17, and are mixed in mixer 6. The mixture 7 undergoes chemical reaction in the heated in-line reactor 10 and commences electrospinning at outlet 8 of capillary 12 with the assistance of sheath gas 19, which is introduced through port 18. The total in-line reaction time is tin=(V1+V2+V3)/F (3) or tin=π(L1d12+L2d22+L3d32)/(4F) (4) where tin is the total in-line reaction time (min.); V1, V2, and V3 are the volumes (ml) of the mixer, the reactor, and the capillary, respectively; L1, L2 and L3 are length (mm) of the mixer, the reactor, and the capillary, respectively; d1, d2, and d3 are the inner diameters (mm) of the mixer, the reactor, and the capillary, respectively; and F is the total flow rate (ml/min). Referring to FIG. 2, electrospinning capillary 12 should have an outer diameter from about 0.1 to about 15 mm, preferably from about 0.5 to about 3 mm. Sheath gas tube 13 in FIG. 2 is positioned concentrically outside and apart from capillary 12. The space between the inner wall of the sheath gas tube and the outer wall of the capillary is preferably from about 0.05 to about 10 mm. The sheath gas tube 13 is preferably also heated by the coil heater(s) 11. EXAMPLE 2 In another embodiment of the reactive nozzle, shown in FIG. 3, an ultrasonic transducer 20 is attached to mixer 6. EXAMPLE 3 In another embodiment of a reactive nozzle (FIG. 4), a separate in-line mixer 6 with an ultrasonic transducer 20 attached is connected to the inlet port 15 of the reactor through a flexible tubing. This configuration allows the use of a high efficiency commercial mixer such as is commonly used in chromatography. Connecting the mixer 6 to the reactor 10 through flexible tubing can help reduce potential adverse effects of sonication on the electrospinning process, while maximizing its benefits. The flexible tubing makes it easier to control both processes. In such a case, the “L1” parameter should include the length of connecting tubing. EXAMPLE 4 In another embodiment of a reactive nozzle, depicted in FIG. 5, the nozzle includes central tubing 21, positioned concentrically inside and apart from capillary 12. The annular distance 9, between the outer wall of the central tubing and the inner wall of the capillary, is between about 0.05 and about 7 mm. The relative positions of the outlet of central tubing 21 and that of the capillary 12 may optionally be adjusted, for example through ferrule-and-nut combination 22. A pressurized gas 23 is introduced through the central tubing 21 to assist electrospinning; the gas flow may also result in a plurality of finer output jets. The total in-line reaction time tin is: tin=(V1+V2+V3−V4)/F (5) or tin=π(L1d12+L2d22+L3d32−L D42)/(4F) (6) where V4, L4, and D4 are the volume, length, and outer diameter, respectively, of the central gas tubing 21. Other symbols have the same meanings as given above. Central tubing 21 may also be used to introduce other reagents or substances to the electrospinning reaction mixture, e.g., a catalyst, another polymer solution, a therapeutic drug, or a suspension of solid nanoparticles or nanotubes. Such a configuration can help to reduce back-pressure and to reduce potential problems with clogging of the mixer or reactor by a highly viscous solution. If one reactant (e.g., a linear polymer solution) is introduced through inlet 16 (with another inlet 17 blocked), and a second reactant (e.g., cross-linker or catalyst) is introduced through the central tubing 21, the two reactants do not mix until the second reactant leaves the tip of the central tubing 21. Then the in-line reaction time tin is: tin=π(L2′d22+L3′d32)/(4F) (7) where L2′ is the distance from the end of central tubing 21 to the end of the reactor 8; L3′is the distance from the end of central tubing 21 to the end of capillary 12; d2 and d3 are the inner diameters of the reactor and the capillary, respectively; and F is the total flow rate. A device coupling electrospinning and photochemical reaction may be made by inserting a metal wire into a disposable glass Pasteur pipette hung vertically, and placing a light source beside the pipette. However, it is difficult to control the flow rate with such a device. EXAMPLE 5 FIG. 6 is a schematic representation of an apparatus for performing photochemical reactive electrospinning. Spinable material 16 is introduced through inlet 14 into the heated chamber or tubing 25, and then into the photochemical reactor 26, whose walls are formed of a transparent, inert material that can withstand the required temperature. A preferred material for this purpose is glass or quartz. Other materials such as fused silica, sapphire, ZnSe, or diamond may also be used. Even a transparent, rigid polymer such as polystyrene or poly(methyl methacrylate) might be used in a suitable temperature range (e.g., less than about 100° C.). Typically, the mixture of reactants and photoinitiator require relatively intense light radiation of appropriate wavelength before photochemical reactions commence at a substantial rate. An in-line mixer may therefore not be required when the reactants can be safely mixed off-line under relatively dim ambient lighting conditions. In such a case, there will also be minimal reaction in chamber 25. The total in-line reaction time in this apparatus is: tin=(V3+V5)/F (8) where V3 and V5 are the volume (ml) of capillary 12 and photochemical reactor 26, respectively; F is the total flow rate (ml/min). In the apparatus of FIGS. 6, 8, and 9, a mixer 6 is optional, and is therefore not depicted. (Compare the apparatus of FIGS. 3, 4, and 5). EXAMPLE 6 FIG. 7 depicts another embodiment of a reactive nozzle for photochemical reactive electrospinning. The apparatus includes an ultrasonic transducer 20 and a separate mixer 6 that is connected to the in-line reactor through flexible tubing. This configuration combines an in-line chemical reactor with a photochemical reactor (a “dual-cure” system), and thus offers more versatility for certain applications. For example, a soluble linear polymer or prepolymer solution and a cross-linker solution (with catalysts or photoinitiators) may be introduced separately through ports 16 and 17 and then mixed in mixer 6 with the aid of another ultrasonic transducer 51. The mixture undergoes a chemical reaction in the in-line reactor 25, then a photochemical -reaction in the photochemical reactor 26, then followed by electrospinning. The total in-line reaction time is tin=(V1+V2+V3+V5)/F (9) where V1, V2, V3 and V5 are the volume (ml) of the mixer 6 (including the connecting tubing), chamber 25, capillary 12, and photochemical reactor 26, respectively. EXAMPLE 7 FIG. 8 depicts another embodiment of a reactive nozzle for photochemical reactive electrospinning. The nozzle includes central tubing 28, whose position may be adjusted, for example through ferrule-and-nut combination 22. A pressurized gas 23 is introduced to further assist electrospinning, and optionally to produce a plurality of finer jets. The total in-line reaction time is: tin=(V3+V5−V4)/F (10) where V3 and V5 are the volume (ml) of capillary 12 and photochemical reactor 26, respectively; V4 is the volume occupied by central tubing 28; and F is the total flow rate (ml/min). In the apparatus of each of FIGS. 6, 7, and 8, the light source comprises an actinic radiation source, for example one with a wavelength between about 170 nanometer and about 2000 nanometer, preferably between about 220 nm and about 760 nm (ultraviolet-visible light); and having an irradiance between about 100 mW/cm2 and about 100,000 milliwaft per square centimeter, preferably between about 500 mW/cm2 and about 10,000 mW/cm2. The light source is preferably a focused light beam, for example a focused light beam having a diameter or length between about 0.1 and about 500 millimeter, focused with hyperbolic mirrors, lenses, or a fiber optic bundle, or the optics found in a typical laser source. The light source may, for example, be emitted by a tungsten source, tungsten-halogen, tungsten-quartz-halogen, mercury, xenon, plasma, light-emitting-diode (LED), electric sparks, or laser. EXAMPLE 8 FIG. 9 depicts another embodiment of a reactive nozzle for photochemical reactive electrospinning. In this embodiment, the photochemical reactor is the Taylor cone 30 itself, formed at the outlet of the electrospinning capillary. A laser beam irradiates the Taylor cone. The diameter of the laser beam is preferably about the same as the inner diameter of capillary 12. This design reduces clogging resulting from high viscosity solutions, melts, or precipitates. A potential disadvantage to this design is that the photochemical reaction time is very short (typically, a few milliseconds). To help prolong the reaction time somewhat, the diameter of the capillary may be increased, and the flow rate may be slowed, provided that a stable electrospinning process is maintained. Also, a high power laser source may be used, so long as the power is not so high as to cause decomposition or burning of the spinning material. A short-wavelength (˜200 nm to ˜500 nm, ultraviolet to blue light) is generally preferred over a red or infrared laser. In an alternative embodiment for photochemical electrospinning (not shown), multiple light sources may be used to simultaneously illuminate some or all of the photochemical reactor, the electrospinning jet, and the collector. In cases where the electrospinning solution is highly photosensitive, for example, one might expose only the electrospinning jet and the collector, but not the reactor. Multiple light sources may, for example, be an array of fiber optic bundles, an array or lamps, or equivalently, a single lamp that is large enough or long enough to illuminate the entire region of interest. It is preferred that the outlets of the capillary and of the sheath gas tube be beveled, to minimize interferences in the electric field. The high voltage power supply depicted in the apparatus of FIGS. 2 through 10 should provide a voltage between about 1 and about 100 kilovolt. A preferred range is from about 3 to about 50 kV. In most prior electrospinning apparatus, the capillary has been placed at a high positive potential, and the collector has been grounded, to make it relatively easy and safe to collect spun fibers for post-spinning processing. However, in the present invention that configuration might pose a high voltage hazard to the devices attached to the capillary (e.g., heater, ultrasonic transducer, temperature sensor, pumps). It is therefore preferred that the capillary and all attached components should be grounded; and that the collector, electrically insulated from the ground and the capillary, should be set at high (negative or positive) potential. The fibers may be collected after the high voltage has been switched off and the collector discharged. An additional advantage to such a configuration is that optical devices, such as a light guide, may be placed closer to the capillary without serious interference to the electric field because they are at the same ground potential. Another advantage of this configuration is that the charges on the spun fiber may be preserved or manipulated, and used for such applications as high efficiency air filters. When accessories such as a temperature control or acoustic source are not used, the “ordinary” electrospinning configuration, with the capillary at high voltage and the collector at ground, may be used instead. EXAMPLE 9 In one embodiment, depicted in FIG. 10, an apparatus for the continuous production of nanofibers comprises a plurality of grounded nozzles and attached devices as previously described, with high voltage connected through a brush 43 to the collector, which is a conducting moving substrate 42 (e.g., a moving belt covered with a metal film or foil), which travels around a pair of a rotating metal drums 41 supported by insulating materials 40. Rotating metal drums 41 are driven by an insulating belt, which in turn is driven by a slow-rotating motor. Alternatively, metal drums 41 are driven by a low-voltage (e.g., 12-96 V) DC motor or a gear-motor assembly that is powered by batteries. The motor, gear-motor assembly, and batteries are all insulated from the ground and floated at the same high voltage as the drums. Post-spinning processor 44 may, for example, be an actinic radiation source (or combination of sources) such as UV light, visible light, infrared light, a gamma ray source, or a heater. Once the high voltage is switched off and the substrate 42 discharged, the spun fiber may optionally be processed with further chemical reactions, with solvent or nonsolvent liquids, or with an electron beam. EXAMPLE 10 A prototype electrospinning apparatus as shown in FIG. 2 was constructed. Stainless steel tubes were purchased from Small Parts Inc. (Miami Lakes, Fl.). Fittings (Tees, unions, and ferrules) were purchased from VICI-Valco Instruments Co. Inc. (Houston, Tex.). Mixer 6 was an HPLC tee ( 1/16 inch nuts and ferrules, 0.75 mm l.D. holes). In-line chemical reactor 10 was a stainless steel tube (0.065 inch O.D., 0.053 inch l.D., 4 inch long). Capillary 12 was a stainless steel tube (0.0355 inch O.D., 0.026 inch l.D., 6 inch long), connected to in-line chemical reactor 10 through a reducing union. Sheath gas tube 13 was a stainless steel tube (0.065 inch O.D., 0.047 inch l.D., 4 inch long). Nitrogen gas was introduced through a second HPLC tee, which fixed both capillary 12 and sheath gas tube 13 using ferrules of different sizes. A flexible coil heater with an insulated surface (157.5 Ω, 27 inch long) was wrapped around the tubing. An adjustable transformer was used to supply power to the coil heater. Temperature was measured with a Cole-Parmer digital thermister thermometer (Model 810-20,Cole-Parmer Instrument Co., Vernon Hills, Ill.). The flexible thermister probe was wrapped under the coil heater. The distance between the tip of the capillary and the collector was 18 cm. EXAMPLE 11 A prototype photochemical electrospinning device as shown in FIG. 6 (except as otherwise described below) was constructed by fusing a section of a disposable Pasteur pipette onto a stainless steel tube (0.065 inch O.D., 0.026 inch l.D., 4 inch long). The volume of the “bulb” was approximately 150 μl. The capillary following the bulb was 45 mm long and 1.4 mm O.D. Because the glass capillary was fragile, no coil heater or stainless steel tube for nitrogen gas was employed in the prototype. The distance between the tip of the capillary and the collector was 18 cm. The device was placed inside a box (15 cm W×12 cm H×45 cm L) made of 10 mm thick transparent Plexiglas to reduce any high voltage hazard (which was small anyway, because the current was minute), and also to reduce the influence of stray airflow on the electrospinning process. The box may be placed horizontally, vertically, or at any other tilt angle. A reversible high voltage supply (Model ES30R0.1R/DAM) from Gamma High Voltage Research, Inc., Ormond Beach, Fla.) was used. This voltage supply could provide from 0 to about 30 kV potential, 100 μA current with reversible polarity. A syringe pump (Cole-Parmer model 74900-00, Cole-Parmer Instrument Co.) and a 5 ml glass syringe (Gastight #1005, Hamilton Co., Reno, Nev.) were used to deliver electrospinning solutions. (An ultrasonic generator was not available at the time the prototype experiments with this device were conducted.) EXAMPLE 12 A poly (styrene-co-methyl methacrylate) or poly(styrene- methyl methacrylate) solution was synthesized as follows: All chemicals were ACS reagent grade and were purchased from Aldrich (Milwaukee, Wiss.). Isopropanol, xylene, styrene, methyl methacrylate, and methacrylic acid were freshly distilled. In a 20 ml scintillation vial, 7 ml isopropanol, 3 ml xylene, 5 ml styrene, 5 ml methyl methacrylate, 0.005 ml methacrylic acid, and 0.05 g 2,2′-azobisisobutyronitrile (a free radical initiator) were added and mixed under sonication. Nitrogen gas was passed through the solution (to remove oxygen) for 5 min, and the solution was sealed and degassed by sonication for 1 min. The solution was stirred magnetically, and was kept at 60°C. for 18 hours on a hotplate. The resulting solution was a clear, highly viscous solution, which presumptively contained 50% poly(styrene-MMA), 35% isopropanol, and 15% xylene. It was so viscous that it took about two minutes to draw 5 ml of the resulting solution into a syringe at room temperature. The solution was stored at 4° C. until used. EXAMPLE 13 To begin optimizing the operating parameters, a series of electrospinning experiments was conducted using the synthesized poly(styrene-MMA) solution prepared as described above, using the electrospinning device as otherwise shown in FIG. 2, but with side port 17 blocked. A 40% poly(styrene-MMA) solution (synthesized polymer solution plus 20% isopropanol) was infused at 30 μl/min at room temperature. The viscous solution simply dropped from the tip of the capillary. Some large droplets reached the collector, and audible spikes were generated when the voltage approached the power supply's upper limit of 30 kV. Stable electrospinning conditions were not established. Then the temperature was raised to ˜80° C. (The temperature fluctuated somewhat, depending on the flow rate, but could be stabilized using a means known in the art, such as a water jacket.). At ˜80° C. the droplets became smaller and a sporadic electrospinning state appeared. Then a nitrogen sheath gas was introduced, while holding the temperature at ˜80° C. The nitrogen flow rate was adjusted to establish stable electrospinning (or electrospray, if desired), as indicated by a Taylor cone at the tip of the capillary, a fine jet stream of solution, and a fine mist appearing on the collector (Al foil). The voltage was ˜20 to ˜25 kV, and the current ˜5 to ˜8 μA. The spun sample collected on the Al foil was dried at 80° C. in an oven for 15 min, gently rinsed with methanol, and dried again for 15 min. The dried sample was observed under a polarizing light microscope (Nikon Microphot-SA). Some fibers were observed, but most of the polymer was in the form of “beads”—droplets connected by fibers. Next, 2 mM tetrabutylammonium triflate (TBATFL) salt was added by mixing 1 ml of a 0.01M TBATFL-isopropanol solution with 4 ml synthesized polymer solution prior to electrospinning with nitrogen sheath flow at ˜80° C. A SEM micrograph (not shown) of the spun sample showed that submicron polymer fibers (0.3˜1.5 μm) were successfully produced. EXAMPLE 14 Another electrospinning experiment as otherwise described in Example 13, but using a 20% poly(styrene-MMA)/2 mM TBATFL solution. A SEM micrograph of the resulting nanofibers (not shown) revealed that nanofibers of ˜30 to ˜300 nm diameter had been produced, though a small amount of elongated “beads” (˜0.5 to ˜1 μm wide, ˜2 to ˜3 μm long) were present. EXAMPLE 15 Additional tests, otherwise similar to those in Examples 13 and 14, indicated that the gravitational orientation of the electrospinning device influenced the stability of the electrospinning process, and the morphology of the product. When the device was horizontal, a growing droplet at the capillary tip gradually forced the jet stream downwards, and eventually caused electrospinning to stop. On the other hand, positioning the device vertically would cause a significant amount of droplets and solution to collect with the fibers. A preferred orientation was to tilt the device between about 45 degrees and about 60 degrees from horizontal, which effectively separated the fibers from the droplets. EXAMPLE 16 Reactive electrospinning in accordance with this invention may be used to fabricate cross-linked polymer nanofibers and submicron fibers. Cross-linked polymers may be fabricated by either of two general types of reactions. The first type is the reaction of a soluble liner polymer with pendent functional groups (e.g., alcohols, acids, aldehydes, acid chlorides, amides, and azides) with a cross-linker that contains two or more functional groups (e.g., alcohols, aldehydes, acid chlorides, and amines) that can react with the pendent functional groups in the linear polymer to form covalent bonds. Most hydrogels are formed by this type of reaction. Multivalent metal ions (Ca+2, AI+3, etc) may also be used as cross-linkers to form a so-called physical gel in which the cross-linking bonds are ionic or coordination bonds. Traditional electrospinning techniques may be used to form nanofibers with soluble linear polymers. Cross-linked nanofibers based this first type of reaction can may be formed either by reactive electrospinning for fast reactions, or by post-spinning treatment for slow reactions. The second type of reaction to form cross-linked polymers is the copolymerization of monomers to form a linear polymer backbone with cross-linking monomers that have two or more polymerizable groups. Because monomers or oligomers will not form nanofibers by electrospinning, and because fully cross-linked polymers are generally insoluble, it has not previously been possible to prepare cross-linked polymer nanofibers. However, cross-linked polymer nanofibers may readily be fabricated by reactive electrospinning in accordance with the present invention. For example, nanofibers or submicron fibers of cross-linked vinyl-acrylic copolymers can be synthesized by the copolymerization of acrylic monomers, substituted vinyl monomers, and diacrylic or divinyl cross-linking monomers. A general reaction can be expressed as follows: where R1 is H, CH3, Cl, or F; R2 is H, OH, Cl, NH2, OCH3, or an ether group containing 2 to 12 carbons; R3 is OH, Cl, F, CN, OC(O)CH3, OC(O)C3H7, NC(O)CH2CH2CH2 (pyrrolidone); Ar is an aromatic group with one of the following structures: X an aliphatic or aromatic group with one of the following structures: where i is an integer from 1 to 6; l, m, and n are integers from 0 to 500 but at least one of them is 1. In the reaction above, R1 influences the reactivity of the monomer; R2, R3, and Ar determine the functionalities of the polymer; X affects the distance between the polymer chains, and thus physical properties such as swelling ability, rigidity, glass transition temperature, etc. Although some such cross-linked co-polymers have previously been prepared in bulk, in films, or as coatings, to the inventor's knowledge none has ever been prepared as sub-micron fibers or nanofibers. Such cross-linked nanofibers have advantages such as high relative surface area, high chemical and thermal stability, the ability to encompass a wide variety of functional groups, and the ability to selectively bond to certain metal ions, compounds, and biomolecules. They find wide applications in a wide variety of fields, including high efficiency filters, and absorbents, ion-exchangers, sensors, and protective clothing. In a prototype demonstration of the fabrication of cross-linked polymer nanofibers, 8 g of poly(vinyl alcohol)(PVA) (Polysciences, Inc, 98 mol% hydrolyzed, Mw 78,000) was first dissolved in deionized water (92 ml) at 85° C. HCI (207.5 μl, 37% aq.) was then added to this 8 wt-% PVA solution at room temperature. Glutaric dialdehyde or glutaraldehyde (GLA) (Aldrich, 50 wt-% aq.) was diluted to 5 wt-% with deionized water. Upon mixing four parts of the 8 wt-% PVA solution with one part of the 5 wt-% GLA solution, the gel time, as determined from the viscosity-time curve, was found to be 18 minutes 45 seconds at room temperature, and 30 seconds at 50° C. Reactive electrospinning was then carried out at 50° C. using the device described in Example 4 and FIG. 5. The 8% PVA solution was injected at a flow rate of 1.2 ml/h through inlet 16, and the 5% GLA solution was injected at a flow rate of 0.395 ml/h through central tubing 21. The distance from the end of the central tubing to the end of the capillary L3′was 40 mm. According to Equation (7) in Example 4, the in-line reaction time was calculated as 31 seconds. Nitrogen gas (25 psi) was used as a sheath gas. The electrospun, cross-linked PVA hydrogel nanofibers were dried at 80° C. for two hours. A scanning electron micrograph (not shown) revealed that nanofibers with a diameter 195±72 nm (20 measurements) had been formed. The dried hydrogel nanofibers were then exposed to steam (95° C.) for 30 minutes, dried at 80° C. for two hours, and again observed by SEM (not shown). The morphology and size of the nanofibers were not significantly different from the original electrospun nanofibers, indicating the successful fabrication of cross-linked hydrogel nanofibers. EXAMPLE 17 Cross-linked poly(methyl methacrylate-co-styrene-co-divinylbenzene) nanofibers were fabricated using a combination of chemical and photochemical reactive electrospinning as follows. Reagents were prepared as otherwise described in Example 12. A mixture was formed of 2.5 g (0.025 mol) methyl methacrylate (MAA), 2.6 g (0.025 mol) styrene, 0.163 g (0.001 mol) of divinylbenzene, and 0.053 g of 2,2′-aizobisisobutyronitrile (AIBN, 1 wt-% total monomers), in 6.8 ml (5.4g) mixed isopropanol and xylene (1:1, v/v) solvent containing 2 mM tetrabutylammonium triflate (TBATFL). The resulting solution contained 50 wt-% of mixed monomers, and 0.5 wt-% initiator. Nitrogen gas was passed through the solution for 10 min. to remove dissolved oxygen. The mixture was sealed and stirred at 70°C. for 1 hour 15 minutes to conduct free-radical polymerization off-line. Then 0.0185 g 1-phenyl-1,2-propane-dione (PPD, a photoinitiator) and 0.024g ethyl 4-dimethylaminobenzoate (EDAB, an accelerator) were added to the mixture. After the mixture had been stirred 10 min at room temperature, the viscosity was measured as about 4 cp. About 2 ml solution was withdrawn to make fibers by reactive electrospinning. To the remaining liquid (10.31 g) was added 18 ml (15.48 g) of the mixed solvent to make the monomer concentration in the mixture 20 wt-%. This new mixture was stirred at 70° C. to continue the polymerization reaction for another 4 hours and 4 minutes, after which the viscosity increased to 72 cp. Then the mixture was removed from heat and used for electrospinning. The reactive electrospinning device was similar to that used in Example 16, except that the central tubing was removed and its fitting inlet was blocked. Additionally, a 275 W GE RSM UV Sunlamp was used to induce photochemical reactions. The UV lamp had an irradiating face diameter of 12 cm and a reflective back coating. The UV lamp was placed perpendicular to the capillary-collector axis. The edge of the lamp was 6.5 cm above the tip of the electrospinning capillary. The UV light simultaneously illuminated the capillary tip, the electrospinning jet stream, and the fibers on the collector. Reactive electrospinning was conducted at 80° C. at a flow rate of 1.2 ml/h and a nitrogen sheath gas (25 psi). The resulting fibers were cured with the UV light for additional 15 minutes, dried at 80°C. for one hour. An SEM micrograph (not shown) of the product from the 50 wt-% solution after two hours heating (off-line polymerization reaction) showed mostly droplets with a small number of nanofibers. An SEM micrograph (not shown) of the product from the 20 wt-% solution after 6 hours of off-line polymerization reaction showed mostly nanofibers, with diameters ranging from 35 nm to 529 nm, average diameter 193±144 nm (20 measurements). A small number of beads was still present. The size and morphology of the nanofibers did not change substantially upon immersion in an organic solvent such as methanol, acetone, or chloroform, and then drying. However a mixed xylene-isopropanol (1:1, v/v) solution did dissolve the nanofibers. Nevertheless, some nanofiber survived the xylene-isopropanol solvent, as seen by SEM. These results demonstrated that the nanofibers produced by reactive electrospinning were at least partially cross-linked. The cross-linking is optimized by steps such as more precise measurements of the gel point, matching absorption spectrum of photoinitiator to spectrum of UV light, and optimizing radiation power. EXAMPLE 18 The novel electrospinning method and apparatus may also be used to form ceramic nanofibers by sol-gel electrospinning. In a prototype demonstration of this aspect of the invention, zirconia-based nanofibers were prepared by electrospinning. Dense ZrO2—Y2O3 and ZrO2—SiO2 nanofibers were prepared using a sol-gel procedure followed by electrospinning with minimum organic additive on a specially designed heated pneumatic electrospinning device. The resulting ceramic nanofibers were characterized by SEM, TEM, and XRD. The direct fabrication of ceramic precursor gel nanofibers by prior electrospinning techniques, without incorporating an organic polymer, has not previously been reported. In this embodiment of the present invention, the hydrolysis of an alkoxide and the polymerization of an inorganic precursor sol occur close to the gel point, as indicated by a sudden increase in viscosity. The so-gel transition takes place due to a dramatic increase in the sol-air interface and rapid solvent evaporation during the “time-of-flight” of an electrospun jet between the capillary and the collector. The sol-gel transition may be thought of as a form of crosslink polymerization reaction, one that produces a three-dimensional inorganic polymer network that is insoluble in most solvents. If the viscosity of the sol is too low, droplets and beads instead of straight fibers form due to the low degree of polymerization; while if the viscosity is too high (approaching the gel point), a steady electrospinning process is difficult to maintain without clogging the capillary. There is thus a relatively narrow window of opportunity to successfully produce nanofibers by electrospinning. The heated pneumatic electrospinning device and method of the present invention have been successfully used to fabricate dense yttria-zirconia and silica-zirconia nanofibers with minimum additives of organic polymer through reactive electrospinning process. Zirconia-yttria sol was prepared by a modification of the procedure of Pullar, R. C.; Taylor, M. D; Bhaffacharya, A. K.; J. of the Eur. Ceramic Soc. 2001, 21, 19-27. Zirconia so t: To zirconium (IV) propoxide solution in 1-propanol (Aldrich, 70 wt%, 0.1 mol, 46.80 g) in anhydrous 2-propanol (200 ml) was added dropwise a solution containing water (18 g, 1 mol), concentrated nitric acid (70.2 wt %, 0.1 mol), and anhydrous 2-propanol (50 ml). A gelatinous precipitate resulted. The mixture was concentrated to about 100 ml, and rediluted with 400 ml water. The concentration/redilution procedure was repeated twice, and the resulting mixture was filtered to give a yellow zirconia solution (about 100 ml). Yttria sol: Yttrium nitrate (Aldrich, 25 mmol, 9.58 g) was dissolved in 100 ml water, and titrated to pH 9.5 with a 4% ammonia solution. The gelatinous precipitate was filtered, washed with deionized water (3×30 ml), and peptized with 0.5 M nitric acid (25 ml) for 12 hrs to form a milky yttria solution. Silica sol: Phosphoric acid (85 wt%, 50 μl) was slowly dropped into a mixture of tetraethyl orthosilicate (7.5 g, Aldrich) and water (7.5 g). The resulting solution was vigorously stirred for 40 minutes at room temperature to obtain a colorless silica sol, which was immediately mixed with the zirconia solution described above, to prepare nanofibers as described below. Ceramic nanofibers. A small amount (1 wt%) of polyethylene oxide (PEO, Aldrich, Mw≅4×105) was added to both a mixed zirconia-yttria sol (molar ratio 92:8) and also to a mixed zirconia-silica sol (molar ratio 4:1), and both were then heated at 70° C. to concentrate the sols to the desired viscosity (˜170 to ˜3000 cP). The viscous solution was delivered to an electrospinning device as depicted in FIG. 5 with a syringe pump at a flow rate between about 2 and about 10 ml/hr. The device and capillary were heated to 80° C., and a coaxial nitrogen sheath gas (20 psi) was applied. A potential of 25 kV was applied between the capillary and the collector. Nanofibers were collected on a flat piece of aluminum foil positioned about 165 mm below the tip of the needle. The fibers were dried overnight at 110° C., and were then calcinated at 500° C. for 1 hour, 1000° C. for 2 hrs and 1200° C. for 1 hr. Both the as-spun nanofibers and the calcinated nanofibers were observed and photographed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The calcinated ceramic nanofibers were also analyzed by X-ray diffraction (XRD). The viscosity of zirconia-silica sol containing 1 wt % PEO at 70° C. changed slowly initially, but after about 4.5 hours increased sharply, indicating the approach of the gel point and the formation of a three-dimensional gel network. Viscosity is an important factor in the generation of gel fibers by electrospinning. Nanofibers could be electrospun from the sol at a viscosity between about 170 and about 3000 cP (i.e., after about 3.5 to 4.5 hours heating). Below 200cP, the principal product was droplets; and above 3000 cP the electrospinning process became less stable, and the capillary tended to clog. When the electrospinning capillary was not heated, fibers could only be generated in a narrow viscosity range (˜1000 to ˜2000cP), and electrospinning near the gel point was difficult to control. However, when the electrospinning capillary was heated to 80° C., sols with a wider range of viscosities could be used. A core gas flow of nitrogen was used to enhance the electrospinning process, to split the solution jet into finer fibers. Without the sheath gas, neat gel fibers were generated only at lower flow rates (less than about 2 ml/hr). With coaxial nitrogen gas flow, the solution flow rate could be increased to about 10 ml/hr without significant formation of droplets. SEM micrographs of electrospun gel fibers dried at 110° C. showed fibers having diameters in the range from about 200 nm to about 500 nm. For example, FIG. 11 depicts a scanning electron micrograph of a calcinated ceramic fiber prepared in accordance with this invention, comprising about 80% ZrO2 and about 20% SiO2. The diameters shrank to about 100 nm to about 300 nm following calcination. The fibers produced from a 80% ZrO2+20% SiO2 sol were thinner and denser than those from a 92% ZrO2+8% Y2O3 sol. Adding SiO2 to the ZrO2 system appeared to enhance formation of three-dimensional gel network. Silica has the additional advantage that it assists in surface treatment using a silane coupling agent, to bond ceramic fibers to a polymer matrix to form a fiber-reinforced composite. The calcinated ceramic nanofibers were also characterized using TEM. The TEM micrographs of 92% ZrO2+8% Y2O3 ceramic fibers calcinated at 1000° C. (not shown) showed a slightly porous layer (˜20 to ˜40 nm) on top of a denser core (˜120 to ˜150 nm). After further calcination at 1200° C. for one hour, the fiber become denser and thinner (˜100 to ˜150 nm). However, some larger grains (˜50 nm) had formed, and the surface of the fiber had become rougher. The particular conditions employed will depend on the tradeoff between smaller-diameter fibers and larger grain size and roughness, and may be optimized to fit the needs of a particular situation. Electron diffraction patterns (not shown) for the 92% ZrO2+8% Y2O3 ceramic fiber calcinated at 1000° C. indicated that the fibers were crystalline. A variety of zirconia-reinforced ceramic nanofibers or glass-ceramic nanofibers may be produced in a similar way changing the composition of the sol, or by adding other components to the sols. For example, adding alumina sol to a zirconia-yttria sol can produce zirconia-reinforced alumina nanofibers. Glass-forming or apatite-forming elements such as Na, B, Ca, P, Ti, and F can also be added in the form of sols, salts, or acids to a sol such as a zirconia-yttria sol or a zirconia-silica sol, or they may be added and mixed in the in-line reactor. Reactive electrospinning and calcination of such mixtures produces nanofibers of zirconia-reinforced bioactive glass-ceramics. Alternatively, the zirconia or other sol may be introduced through a central tubing, such as shown in FIG. 5 (with the end positioned at or near the level of the capillary tip); and the solution or sol containing glass-forming or apatite-forming compounds, organic polymers (PVA, PEO, etc.), or other materials may be introduced through the space between the central tubing and the electrospinning capillary. The coaxial reactive electrospinning of the two solutions can produce composite nanofibers, such as nanofibers with a zirconia core and a bioactive glass surface layer. Zirconia-reinforced bioactive glass-ceramics nanofibers will have significant higher strength and toughness than previously reported bioactive glass fibers or zirconia- or titania-particle-reinforced bioactive. The reactions employed in reactive electrospinning may be any of a wide range of chemical reactions including the formation of new covalent bonds or coordination bonds, or the breaking of existing covalent bonds or coordination bonds. Although the chemical reactions and photochemical reactions and apparatus discussed above have primarily been those involved in polymerization or cross-linking reactions, the apparatus and methods described here may also be used in other types of reactions including, by way of example, hydrolysis, coordination, chelating, addition, replacement, condensation, rearrangement, oxidation, reduction, ionization, and decomposition. These reactions may be directed at modifying chemical structures and properties of polymers, attaching or removing functional groups, and the like. The novel process offers the advantage (over post-spinning processing) that the reactions occur in a homogeneous media, at least in their early stages. Although the chemical reactions and photochemical reactions and apparatus discussed above have been primarily directed toward the production of nanofibers and submicron fibers by electrospinning, they may also be used for the production of nanodroplets and nanoparticles by electrospray. While the apparatus and methods would not require substantial modification, operating conditions might vary somewhat. For example, in an otherwise similar method, using lower polymer concentration, or higher electrolyte concentration, or higher gas flow rate and pressure, or higher acoustic energy might be used to produce nanoparticles instead of fibers. A preferred collector for such an application would then be a bath of a nonsolvent liquid or a dispersant. The complete disclosures of all references cited in the specification are hereby incorporated by reference. Also incorporated by reference is the complete disclosure of X. Xu et al., “Preparation of zirconia-based ceramics nanofibers by sol-gel electrospinning,” Polymeric Materials Science & Engineering, vol. 91, pp. 517-518 (2004). In the event of an otherwise irreconcilable conflict, however, the present specification shall control.

<SOH> BACKGROUND ART <EOH>Nanofibers are thin small fibers, with typical diameters ranging from tens to hundreds of nanometers, up to about 1 micrometer. Nanofibers have been formed from polymers, carbon, and ceramic. Nanofibers have attracted great interest because of their extraordinarily high surface area and length-to-width ratio, as well as their unique physical and mechanical properties. Nanofibers are being used in such areas as filtration, fiber-reinforced nanocomposites, wound dressing, drug delivery, artificial organs, micro-electrical systems, and micro-optical systems. However, fabrication of nanofibers is very challenging due to their minute diameters. Traditional methods, such as formation in porous solids or at the step-edges of laminated crystals, are often ineffective and costly. An alternative method is electrostatic fiber formation or electrospinning. Electrospinning is a relatively simple and versatile method. In electrospinning, a high voltage (e.g., ˜3 to ˜50 kV) is applied between a target (or collector) and a conducting capillary into which a polymer solution or melt is injected. The high voltage can also be applied to the solution or melt through a wire if the capillary is a nonconductor such as a glass pipette. The collector may be a metal plate or screen, a rotating drum, or even a liquid bath if the capillary is vertical. Initially the solution at the open tip of the capillary is pulled into a conical shape (the so-called “Taylor cone”) through the interplay of electrical force and surface tension. At a certain voltage range, a fine jet of polymer solution (or melt) forms at the tip of the Taylor cone and shoots toward the target. Forces from the electric field accelerate and stretch the jet. This stretching, together with evaporation of solvent molecules, causes the jet diameter to become smaller. As the jet diameter decreases, the charge density increases until electrostatic forces within the polymer overcome the cohesive forces holding the jet together (e.g., surface tension), causing the jet to split or “splay” into a multifilament of polymer fibers. The fibers continue to splay until they reach the collector, where they are collected as nonwoven fibers, and are optionally dried. The diameter of an electrospun nanofiber is typically between about 50 nm and about 5 μm. High-speed photographic studies have suggested that, at least in some cases, what had appeared to be a multifilament was in fact a single, ultrafine fiber, being whipped very rapidly. A wide variety of polymers have been electrospun from solutions and melts. A large number of papers describing the electrospinning process have been published, particularly in the past decade. Two recent review articles summarizing the state of the art are A. Frenot et al., “Polymer nanofibers assembled by electrospinning,” Current Opinion in Colloid and Interface Science , vol. 8, pp. 64-75 (2003); and Z. Huang et al., “A review on polymer nanofibers by electrospinning and their applications in nanocomposites,” Composites Science and Technology, vol. 63, pp. 2223-2253 (2003). Baker D A, Brown P J. Reactive routes to making modified nanofiber structures via electrospinning. Polymer Preprints (2003), 44(2), 118-119 reported the addition of azides to polymer solutions prior to electrospinning. The azides could react, crosslink, functionalize, and covalently bind polymer chains. Electrospinning mixtures of polymers with the additives could be used for the covalent binding of synthetic polymers with natural polymers in a single manufacturing step. It was said that applying heat or UV light during electrospinning was said to modify nanofiber substrates either during the fiber formation process or by post-spin treatments; however, the only successful experimental results reported were apparently for post-spin reaction and cross-linking. The experimental procedures reported the preparation of solutions containing polymer and azide crosslinking agents. The solutions were then weighed, sealed, and checked for solvent loss during the time taken for dissolution. After an unspecified lapse of time, the solutions were later used in electrospinning procedures. The reaction and crosslinking in these experiments apparently did not take place until a post-spinning thermal analysis step. Cross-linked polymers, hydrogels, hyperbranched polymers, and dendrimers have properties that differ from those of otherwise-comparable linear polymers. For example, they often have higher chemical stability and improved mechanical properties. They often possess unique chemical properties and functionalities. Such polymers have been used in diverse applications including coatings, composite resins, controlled drug release, organic-inorganic hybrid materials, solid supports for catalysts, and supports for chromatography or ion-exchange resins. However, highly cross-linked polymers and hyperbranched polymers are generally difficult to form as fibers through prior techniques, and even more difficult to form into nanofibers, because they typically have low solubility, and they typically will not melt without undergoing heat-induced decomposition, due to the strong intermolecular bonding or entanglement of the polymer molecules and the formation of polymer networks. Ding, B. et al, “Preparation and characterization of a nanoscale poly(vinyl alcohol) fiber aggregate produced by an electrospinning method,” J. Poly. Sci. B: Poly. Phys., (2002), 40, 1261-1268, reported the preparation of crosslinked poly(vinyl alcohol) (PVA) nanofibers (100-500 nm) by first mixing 0˜10% glyoxal (a crosslinking agent) and phosphoric acid (as a catalyst) with a 10% PVA-water solution, then electrospinning the mixed solution at room temperature, followed by post-spinning thermal curing of the electrospun-PVA fiber in an oven at 120° C. for 5 min. It was reported that the crosslinked PVA fiber aggregates were more hydrophobic, and that they exhibited better mechanical properties. U.S. Pat. No. 6,382,526 discloses a process for forming nanofibers by comprising the steps of feeding a fiber-forming material into an annular column, the column having an exit orifice, directing the fiber-forming material into a gas jet space, thereby forming an annular film of fiber-forming material, the annular film having an inner circumference, simultaneously forcing gas through a gas column, which is concentrically positioned within the annular column, and into the gas jet space, thereby causing the gas to contact the inner circumference of the annular film, and ejects the fiber-forming material from the exit orifice of the annular column in the form of a plurality of strands of fiber-forming material that solidify and form nanofibers having a diameter up to about 3,000 nanometers. U.S. Pat. No. 6,520,425 discloses a nozzle for forming nanofibers by using a pressurized gas stream comprising a center tube, a first supply tube that is positioned concentrically around and apart from the center tube, a middle gas tube positioned concentrically around and apart from the first supply tube, and a second supply rube positioned concentrically around and apart from the middle gas tube. The center tube and first supply tube form a first annular column. The middle gas tube and the first supply tube form a second annular column. The middle gas tube and second supply tube form a third annular column. The tubes are positioned so that first and second gas jet spaces are created between the lower ends of the center tube and first supply tube, and the middle gas tube and second supply tube, respectively. U.S. Pat. No. 6,308,509 discloses nanofibers having a diameter ranging from about 4 to 1 nm, and a nano denier of about 10 −9 . The use of the electro-spinning process permits production of the desired nanofibrils. These fibrils in combination with a carrier or strengthening fibers/filaments can be converted directly into nonwoven fibrous assemblies or converted into linear assemblies (yarns) before weaving, braiding or knitting into 2-dimensional and 3-dimensional fabrics. The electrospun fiber can be fed in an air vortex spinning apparatus developed to form a linear fibrous assembly. The process makes use of an air stream in a properly confined cavity. The vortex of air provides a gentle means to convert a mixture of the fibril fed directly or indirectly from the ESP unit and a fiber mass or filament into an integral assembly with proper level of orientation. Incorporation of thus produced woven products into tissue engineering is part of the present invention. Published international patent application WO 01/27365 discloses a fiber comprising a substantially homogeneous mixture of a hydrophilic polymer and a polymer that is at least weakly hydrophobic. The fiber optionally contains a pH adjusting compound. A method of making the fiber is disclosed, electrospinning fibers of the substantially homogeneous polymer solution. The fibers are disclosed as having application for dressing wounds. Recently, submicron fibers and nanofibers of ceramic oxides, such as silica and alumina-borate have been reported using a sol-gel process and electrospinning. See C. Shao et al., “A novel method for making silica nanofibres by using electrospun fibres of polyvinylalcohol/silica composite as precursor,” Nanotechnology , vol. 13, pp. 635-637 (2002); and H. Dai et al., “A novel method for preparing ultra-fine alumina-borate oxide fibres via an electrospinning technique,” Nanotechnology, vol. 13, pp. 674-677 (2002). A typical process includes (1) acid hydrolysis of organometallic precursors such as tetraethyloxysilane (TEOS) to form a colloid solution (sol), (2) mixing the sol with an aqueous or alcohol solution of a polymer such as polyvinyl alcohol (PVA), and digesting to form a viscous sol; (3) electrospinning the sol to form a silica/PVA composite gel fiber; (4) calcination or sintering the gel fiber to yield a porous silica or alumina fiber. TiO 2 and SnO 2 nanofibers have been prepared by electrospinning a titanium tetraisopropoxide (Ti(OiPr) 4 )/poly(vinyl pyrrolidone)(PVP) solution, or a tin (IV) tetraisopropoxide (Sn(OiPr) 4 ) / PVP / ethanol solution, followed by rapid hydrolysis by moisture in air, and calcination. See D. Li et al., “Fabrication of titania nanofibers by electrospinning,” Nano Letters , vol. 3, pp. 555-560 (2003); and D. Li et al., “Electrospinning of polymeric and ceramic nanofibers as uniaxially aligned arrays,” Nano Letters , vol. 3, pp. 1167-1171 (2003). Because the composite gel fibers produced by these processes have contained high levels of organic polymers (typically, about 30% to 66% PVA or PVP), removal of the polymer by calcination has left substantial voids in the final ceramic nanofibers, voids that cannot be healed by calcination or sintering. Such porous ceramic oxide nanofibers have a large-surface area, and may be used in catalysts, filtration, or absorbents. However, they are not well-suited for use as reinforcing elements due to their poor mechanical properties. Bioactive materials, such as bioactive glass, hydroxyapatite, and glass-ceramic A-W can react with biological fluids, and can bond directly to living bone. They have been used in orthopedic and dental implants and cements. However, such materials have had low fracture toughness. Zirconia and titania ceramics have been used to reinforce the bioactive materials. See T. Kasuga et al., “Bioactive glass-ceramic composite toughened by tetragonal zirconia,” pp. 137-142 in Yamamuro et al. (Eds.), CRC Handbook of Bioactive Ceramics , Volume 1 (1990); and Kokubo et al, “Novel bioactive materials with different mechanical properties,” Biomaterials , vol. 24, pp. 2161-2175 (2003). To the inventor's knowledge, however, zirconia-reinforced bioactive glass-ceramic nanofibers or zirconia nanofiber-reinforced bioactive glass-ceramics have not previously been reported. The fabrication of α-alumina nanofibers by sol-gel chemistry and electrospinning was reported by G. Larsen et al., “A method for making inorganic and hybrid (organic/inorganic) fibers and vesicles with diameters in the submicrometer and micrometer range via sol-gel chemistry and electrically forced liquid jets,” J. Am. Chem. Soc ., vol. 125, pp. 1154-1155 (2003). Zirconia-based ceramics have superior properties such chemical resistance, thermal stability, high mechanical strength and toughness, high ionic conductivity, and catalytic properties. Zirconia has been widely used in engineering and technological applications. In recent years, zirconia-based ceramics have gained popularity in medical devices and dentistry because of their excellent esthetics, biocompatibility, and high toughness. Zirconia particles and nanoparticles have been used as fillers in dental composites to increase both radiopacity and resistance to hydrolytic degradation. There is an unfilled need for dense ZrO 2— SiO 2 and ZrO 2— Y 2 O 3 nanofibers for use as reinforcement fillers in dental composites. Zirconia-based ceramic nanofibers will significantly increase the mechanical strength and fracture toughness of dental composites, while satisfying the stringent requirements for color and translucency needed for such- purposes. Current commercially available zirconia fibers are too thick for such applications (5˜10 μm), because their resulting composites are highly opaque. To the knowledge of the inventor, continuous, dense zirconia-based nanofibers have not previously been reported. Nor have there been prior reports of any method for the direct fabrication of dense ceramic nanofibers through precursor gel nanofibers by electrospinning, without the incorporation of a significant amount of organic polymer. The production of continuous nanofibers by electrospinning requires polymers (or other macromolecules) in the form of a solution or melt. A solution or suspension of discrete small molecules, including, e.g., monomers, oligomers, colloids, or nanoparticles, cannot ordinarily be electrospun into a continuous nanofiber, but instead through an electrospray will produce droplets or nanoparticles. There is an unfilled need for a method to make continuous, cross-linked or hyperbranched polymer nanofibers, including crosslinked hydrogel nanofibers. There is an unfilled need for a method to modify the chemical or physical properties of polymers in nanofibers to yield cross-linked polymer nanofibers and other nanofiber materials that are difficult or impossible to make by existing techniques. To the inventor's knowledge, no prior work has reported the successful production of nanofibers or crosslinked nanofibers by electrospinning, in which polymerization or cross-linking reactions occur during or immediately prior to the electrospinning itself, as opposed to reactions that have occurred substantially before or substantially after the electrospinning process.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 depicts a chart showing the change in viscosity of the spinable materials as a function of reaction time. Curve (a) depicts a fast reaction. Curve (b) depicts a slow reaction. FIG. 2 depicts schematically an apparatus for performing chemical reactive electrospinning in accordance with this invention. FIG. 3 depicts schematically an embodiment of apparatus in accordance with this invention, including an ultrasonic transducer. FIG. 4 depicts schematically an embodiment of apparatus in accordance with this invention, including a reactive nozzle for chemical reactive electrospinning, and an in-line mixer with an ultrasonic transducer. FIG. 5 depicts schematically an embodiment of apparatus in accordance with this invention, including a central tube that may be used to introduce a composition such as a flowing gas, an additional reagent, an immiscible polymer solution, or a suspension of nanoparticles. FIG. 6 depicts schematically an apparatus for performing photochemical reactive electrospinning in accordance with this invention. FIG. 7 depicts schematically an apparatus for performing photochemical reactive electrospinning, including an ultrasonic transducer and a mixer connected to the in-line reactor through flexible tubing. FIG. 8 depicts schematically an apparatus for performing photochemical reactive electrospinning, including an ultrasonic transducer and central gas tubing. FIG. 9 depicts schematically an apparatus for performing photochemical reactive electrospinning in accordance with this invention, including a laser source aimed at the outlet (Taylor cone) of the electrospinning capillary. FIG. 10 depicts schematically an apparatus for continuous production of nanofibers in accordance with this invention, where the nozzles and attached devices are placed at ground potential while the high voltage is connected to the collector, which in this embodiment comprises a conducting moving belt around a pair of rotating metal drums supported by insulating materials. FIG. 11 depicts a scanning electron micrograph of a calcinated ceramic fiber prepared in accordance with this invention, comprising about 80% ZrO 2 and about 20% SiO 2 . detailed-description description="Detailed Description" end="lead"?

20060302

20111129

20070125

84390.0

B29C4700

TENTONI, LEO B

PROCESS OF FABRICATING NANOFIBERS BY REACTIVE ELECTROSPINNING

MICRO

ACCEPTED

B29C

ACCEPTED

Dispensing closure

A dispensing closure (15) for a container (20), such as a beverage container, is provided so as to selectively dispense a product (30) carried by the closure (15) into the container (20). The container has a neck portion with which the closure is engaged to close or seal the container (20). The closure (15) has a body (21) having an outer wall portion (22) to engage an outer surface of the container neck to releasably secure the closure to the container. The closure (15) is provided with a compartment (16) to contain the product (30) to be dispensed. The compartment (16) is formed by a cylindrical side wall (17), a top wall (18) and a frangible bottom wall (19). A cutting blade (31) is moveable relative to the side wall (17) and the bottom wall (19) to break open the frangible bottom wall (19) to selectively dispense the contents (30) into the container (20). The closure (15) has means restricting inadvertent relative movement of the cutting blade (31).

1-28. (canceled) 29. A dispensing closure for dispensing at least one product into a container having a neck portion with which said closure is to engage, said dispensing closure comprising: a body having an outer wall portion adapted to engage an outer surface of the container neck to releasably secure said closure to the container; a compartment to contain at least one product to be dispensed, said compartment being adapted to fit at least partly within the container neck and being defined by a substantially cylindrical side wall, a top wall and a frangible bottom wall; a cutting means moveable relative to said side wall and said frangible bottom wall to break open said frangible bottom wall of said compartment to selectively dispense contents of said compartment into the container; and a means restricting inadvertent relative movement of said cutting means, said closure and product to be dispensed being assembled together prior to application of the closure to the container neck. 30. The dispensing closure according to claim 29, wherein said outer wall portion of said body is substantially cylindrical, and said body further includes a coaxial inner wall adapted to engage within the container neck. 31. The dispensing closure according to claim 30, wherein said outer wall portion of said body is provided with internal threads adapted to threadingly engage a threaded neck of a container to which said closure is to be fitted. 32. The dispensing closure according to claim 30, wherein said inner wall closely engages within the container neck, and said compartment fits within said inner wall. 33. The dispensing closure according to claim 32, wherein said compartment is separate from said body and is interconnected thereto to facilitate relative rotation therebetween about the axes thereof. 34. The dispensing closure according to claim 33, wherein an upper end of said compartment is formed with a rim having engaging means to engage corresponding engaging means on said closure body whereby said compartment is assembled to said body and is rotatable relatively thereto. 35. The dispensing closure according to claim 34, wherein said compartment and said body are able to be snap-fitted together so that said compartment is able to rotate about its axis relative to said body. 36. The dispensing closure according to claim 35, wherein said bottom wall of said compartment extends at an angle to a plane perpendicular to the axis. 37. The dispensing closure according to claim 36, wherein said cutting means includes a cutting knife carried on a flange extending generally radially inwardly from a lower edge portion of an inner wall of said body, said flange being axially spaced from said frangible bottom wall of said compartment, said knife extending in a generally axial direction from said flange towards said frangible bottom wall. 38. The dispensing closure according to claim 36, wherein said cutting means includes a cutting knife extending axially from said top wall of said compartment inwardly of said compartment side wall and movable about the axis, and wherein on relative movement of said knife, said frangible bottom wall is brought into contact with said knife which cuts and breaks open said bottom wall from said compartment permitting contents thereof to be dispensed into the container to which said closure is fitted. 39. The dispensing closure according to claim 31, wherein said compartment and body are integral such that said cylindrical side wall of said compartment constitutes an inner wall of said body, and a substantially cylindrical band engages with an outer surface of said side wall adjacent its free edge, said band having a generally radially inwardly extending flange carrying said cutting means. 40. The dispensing closure according to claim 39, wherein said cutting means is a cutting knife which extends from said flange in a generally axial direction towards said top wall. 41. The dispensing closure according to claim 40, wherein said cutting knife is housed in a pocket formed in said side wall of said compartment, said cutting knife being movable about the axis of said compartment to be released from said pocket so as to then cut said bottom wall at least partly from the container to allow the product in said compartment to pass into the container. 42. The dispensing closure according to claim 35, wherein said cutting means includes a cutting knife carried on a flange extending generally radially inwardly from a lower edge portion of an inner wall of said body, said flange being axially spaced from said frangible bottom wall of said compartment, said knife extending in a generally axial direction from said flange towards said top wall, said cutting knife being housed in a pocket formed in said side wall of said compartment, said cutting knife being movable about the axis of said compartment to be released from said pocket so as to then cut said bottom wall at least partly from said container to allow the product in said compartment to pass into the container. 43. The dispensing closure according to claim 36, wherein said compartment is axially moveable relative to said cutting means to cause said cutting means to cut said frangible bottom wall. 44. The dispensing closure according to claim 43, wherein said cutting means comprises a cutting knife integrally moulded with a wall of said closure, said knife having at least two cutting edges extending at an acute angle to each other. 45. The dispensing closure according to claim 36, wherein said cutting means comprises a knife edge formed on a lower edge portion of an internal wall extending from said compartment top wall, said top wall being axially movable relative to said bottom wall to cause said knife edge to cut away at least a portion of said bottom wall to allow the product in said compartment to pass into the container. 46. The dispensing closure according to claim 45, wherein a centre portion of said top wall is resiliently axially movable relative to said closure body, and said internal wall is connected to said centre portion to be movable therewith whereby said frangible bottom wall is cut by a resilient axial movement of said centre portion. 47. The dispensing closure according to claim 29, wherein said body includes, on a lower edge of said outer wall, a tamper proof evidence release band to provide an indication of tampering with said closure prior to its use. 48. The dispensing closure according to claim 29, wherein said body includes, on an upper edge of said outer wall portion, a tab adapted to engage within an opening formed in a rim of said compartment, said tab ensuring proper alignment of said compartment and said body when assembled as well as acting to resist inadvertent relative movement of said cutting means. 49. The dispensing closure according to claim 29 further comprising a contents dispensing valve integrally formed with said top wall of said compartment to facilitate dispensing contents of the container after said frangible bottom wall of said compartment has been cut to allow the product in said compartment to pass into the container. 50. The dispensing closure according to claim 29, wherein said compartment is separated into a plurality of parts by one or more internal partitions to separately house a plurality of different products to be selectively dispensed into the container. 51. A dispensing closure for a container having a neck portion, said dispensing closure comprising: a body having engaging means and an outer wall portion adapted to engage an outer surface of the container neck to releasably secure said closure to the container, said outer wall portion includes an upper edge having a tamper proof evidence release band to provide an indication of tampering with said closure prior to its use, wherein said outer wall portion of said body is substantially cylindrical, and said body further includes a coaxial inner wall adapted to engage within the container neck; a compartment to contain at least one product to be dispensed, said compartment being adapted to fit at least partly within the container neck and being defined by a substantially cylindrical side wall, a top wall and a frangible bottom wall, wherein an upper end of said compartment is formed with a rim having engaging means to engage corresponding engaging means on said closure body whereby said compartment is assembled to said body and is rotatable relatively thereto, said bottom wall of said compartment extends at an angle to a plane perpendicular to the axis; a cutting knife attached to said body and moveable relative to said side wall and said frangible bottom wall to break open said frangible bottom wall of said compartment to selectively dispense contents of said compartment into the container; a means restricting inadvertent relative movement of said cutting knife; a contents dispensing valve integrally formed with said top wall of said compartment to facilitate dispensing contents of the container after said frangible bottom wall of said compartment has been cut to allow the product in said compartment to pass into the container; and wherein said upper edge of said outer wall portion further includes a tab adapted to engage within an opening formed in a rim of said compartment, said tab ensuring proper alignment of said compartment and said body when assembled as well as acting to resist inadvertent relative movement of said cutting means. 52. The dispensing closure according to claim 51, wherein said cutting means includes a cutting knife carried on a flange extending generally radially inwardly from a lower edge portion of an inner wall of said body, said flange being axially spaced from said frangible bottom wall of said compartment, said knife extending in a generally axial direction from said flange towards said frangible bottom wall. 53. The dispensing closure according to claim 51, wherein said cutting means includes a cutting knife extending axially from said top wall of said compartment inwardly of said compartment side wall and movable about the axis, and wherein on relative movement of said knife, said frangible bottom wall is brought into contact with said knife which cuts and breaks open said bottom wall from said compartment permitting contents thereof to be dispensed into the container to which said closure is fitted. 54. A method of dispensing at least one product into a container having a neck, the method including the steps of: providing a dispensing closure comprising a body having an outer wall portion adapted to engage an outer surface of the container neck to releasably secure said closure to the container; a compartment to contain at least one product to be dispensed, said compartment being adapted to fit at least partly within the container neck and being defined by a substantially cylindrical side wall, a top wall and a frangible bottom wall, wherein an upper end of said compartment is formed with a rim having engaging means to engage corresponding engaging means on said closure body whereby said compartment is assembled to said body and is rotatable relatively thereto, said bottom wall of said compartment extends at an angle to a plane perpendicular to the axis; a cutting knife attached to said body and moveable relative to said side wall and said frangible bottom wall to break open said frangible bottom wall of said compartment to selectively dispense contents of said compartment into the container; and a means restricting inadvertent relative movement of said cutting knife; placing a product to be dispensed into said compartment between said top wall and said frangible bottom wall; sealing said frangible bottom wall to said side wall of said compartment; assembling said compartment containing the product with said closure body; engaging said assembled closure with a neck portion of a container into which the product is to be dispensed; and axially moving said knife relative to the bottom wall to cause said knife to cut into said bottom wall to thereby release the contents of said compartment into the container.

FIELD OF THE INVENTION This invention relates to a dispensing closure for containers and relates particularly to a dispensing closure which is adapted to engage a container and facilitate dispensing of a material, such as a liquid, solid, powder or granular material, into the container. BACKGROUND OF THE INVENTION The invention will be described with particular reference to a cap for a liquid container, such as a beverage container. However, it will be appreciated that the principals of the invention can be applied to containers and closures of many different types to enable two or more materials to be kept separated up to the moment of use, and to then dispense, discharge or mix at least one of the materials into another. Thus, the invention is applicable to, for example, dispensing pharmaceuticals in liquid, powder, tablet or granule form into an appropriate medium for ingestion of the pharmaceutical; dispensing colour pigments, in liquid or powder form or in capsules, into base paint carriers; mixing cosmetic colouring material into a carrier; mixing chemicals, including catalysts and hardeners, and particularly those that may be toxic or dangerous to touch, into an active ingredient; discharging food flavouring, colouring, sweeteners or other food product into an appropriate beverage medium or the like. The invention is therefore useful for combining materials of many types where it is necessary or desirable to selectively dispense or mix one material or substance into another. DISCUSSION OF PRIOR ART A number of proposals have previously been made for containers to be constructed in a way that two products are maintained separated until the moment of use at which time one product is admixed with the other in the container. Containers of this type have been proposed with closures which are used to effect the product separation and facilitate the introduction of one product into the other. However, the containers and closures previously proposed are relatively complicated. For example, in one proposal a closure is formed of three parts, a first part including a compartment to hold one product, the compartment being adapted to engage in the neck of a container, a second part which moves relative to the first part and has a means for opening a bottom wall of the compartment to release the first product into the container, and a sealing cap which engages over the compartment and second part to seal the closure on the container. Such a structure is relatively complicated and expensive to manufacture, requires the assembly of three separate parts as well as introduction of a product into the compartment during assembly, and necessarily involves a number of separate actions in order to release the product in the compartment into the container. In another proposal as outlined in Patent GB2012714, a container is disclosed having an inner wall which divides the container into two compartments. An upper compartment contains a piercing device that is moveable by pressure applied to a top wall to cause a tip of the piercing device to pierce a hole in the dividing wall. However, this structure requires a moveable top wall and is, therefore, susceptible to accidental actuation. It is therefore desirable to provide an improved dispensing closure for containers which obviates at least some of the disadvantages of previously proposed dispensing closures. It is also desirable to provide a dispensing closure for containers whereby a material or substance in liquid, powder, solid, granular or other form is able to be quickly and easily dispensed into the product in the container on which the closure is attached. It is also desirable to provide a dispensing closure for containers which is relatively easy to produce, assemble and use. It is also desirable to provide a dispensing closure for a variety of container types, including beverage containers, paint containers, cosmetic containers and others. It is also desirable to provide a dispensing closure which may be adapted for a variety of different products to be dispensed into the container on which the closure is mounted. SUMMARY OF THE INVENTION According to one aspect of the invention there is provided a dispensing closure to dispense at least one product into a container, the closure including a container closure body adapted to sealingly engage with a neck of the container, the body having securing means to secure the closure to the container neck, a compartment to contain the at least one product to be dispensed, the compartment being adapted to fit within the container neck and being defined by a side wall, a top wall and a frangible bottom wall, and cutting means moveable relative to the side wall and the bottom wall to break open the frangible bottom wall of the compartment to selectively dispense contents of the compartment into the container. In one form of the invention, the closure body includes an outer, cylindrical wall and a coaxial inner wall. The outer wall is provided with internal threads adapted to threadingly engage the threaded neck of a container to which the closure is to be fitted The inner wall engages within the container neck, and the compartment fits within the inner wall. The upper end of the compartment is formed with a radially outwardly extending flange having reversely formed shoulders to engage corresponding shoulders on the closure body. In this way, the two parts of the closure are able to be snap-fitted together so that the compartment is able to rotate about its axis relative to the body. In this embodiment, the inner wall of the body carries a cutting knife edge which is inwardly and upwardly turned towards the frangible bottom wall of the compartment. The bottom wall of the compartment extends at an angle to a plane perpendicular to the axis such that, in first assembled position, the bottom wall does not contact the knife. On relative rotation of the compartment, however, the frangible bottom wall is brought into contact with the knife which cuts and breaks the wall from the compartment permitting contents thereof to be dispensed into the container to which the closure is fitted. In another embodiment of the invention, the compartment and closure body are integral and are engaged with a cylindrical band which fits over the wall of the compartment. The band carries the cutting knife which operates in the manner described above. Preferably, the container closure body includes, on the lower end of the outer wall, a tamper proof evidence release band to provide any indication of tampering with the closure prior to its use. According to another aspect of the invention there is provided a dispensing device for dispensing product into a container, the device having a sealed compartment containing the product, the compartment having a substantially cylindrical side wall, a frangible bottom wall and a top wall, the compartment being adapted to fit within a neck of the container, the device further having an outer wall to engage an outer surface of the container neck and including securing means to secure the device to the container, and cutting means adapted to be rotated relative to the frangible bottom wall, the cutting means and/or the frangible bottom wall being arranged such that the relative movement causes the cutting means to break open the frangible bottom wall of the compartment to selectively dispense contents of the compartment into the container. The cutting means may extend from a separate cylindrical band coaxial with the side wall of the compartment but rotatable relative thereto. Alternatively, the compartment and outer wall may be separate integers with the cutting means extending from an intermediate wall located between the compartment and the inner surface of the neck of the container. According to a further aspect of the invention there is provided a method of dispensing at least one product into a container, the method including the steps of assembling a compartment containing a product to be dispensed with a closure body, engaging the assembled closure with a neck portion of a container into which the contents are to be dispensed, providing a cutting knife adjacent to a bottom wall of the assembled closure, and rotating the knife relative to the bottom wall to cause the knife to cut into the bottom wall to thereby release the contents of the compartment into the container. According to a further aspect of the present invention there is provided a cutting knife for use with a dispensing closure, the knife being integrally moulded with a wall of the closure, the knife having at least two cutting edges extending at an acute angle to each other. In order that the invention is more readily understood, embodiments thereof will now be described with reference to the accompanying drawings wherein: FIG. 1 is a cross sectional, elevational view of a first embodiment of the invention; FIG. 2 is a cross sectional, elevational view of the first embodiment of the invention taken at 900 to that of FIG. 1; FIG. 3 is a cross sectional, elevational view of a second embodiment of the invention; FIG. 4 is a cross sectional, elevational view of the second embodiment of the invention taken at 900 to that of FIG. 3; FIG. 5 is a cross sectional, elevational view of a third embodiment of the invention; FIG. 6 is a cross sectional, elevational view of the third embodiment of the invention taken at 900 to that of FIG. 5; FIG. 7 is a cross sectional, elevational view of a fourth embodiment of the invention; FIG. 8 is a cross sectional, elevational view of the fourth embodiment of the invention taken at 900 to that of FIG. 7; FIG. 9 is a cross sectional, elevational view of a fifth embodiment of the invention; FIG. 10 is a cross sectional, elevational view of the fifth embodiment of the invention taken at 900 to that of FIG. 9; FIG. 11 is a cross sectional, elevational view of a sixth embodiment of the invention; FIG. 12 is a cross sectional, elevational view of the sixth embodiment of the invention taken at 900 to that of FIG. 11; FIG. 13 is a cross sectional, elevational view of a seventh embodiment of the invention; FIG. 14 is a cross sectional, elevational view of the seventh embodiment of the invention taken at 900 to that of FIG. 13; FIG. 15 is a cross sectional, elevational view of the seventh embodiment of the invention similar to FIG. 14 showing the closure after an initial actuation; FIG. 16 is a cross sectional, elevational view of an eighth embodiment of the invention; FIG. 17 is a cross sectional, elevational view of the eighth embodiment of the invention taken at 900 to that of FIG. 16; FIG. 18 is a cross sectional elevational view of a ninth embodiment of the invention; FIG. 19 is a cross sectional, elevational view of the ninth embodiment of the invention taken at 900 to that of FIG. 18; FIG. 20 is a cross sectional, elevational view of a tenth embodiment of the invention; FIG. 21 is a cross sectional elevational view of the tenth embodiment of the invention taken at 900 to that of FIG., and showing an initial actuation of the closure; FIG. 22 is a cross sectional, elevational view of an eleventh embodiment of the invention; FIG. 23 is a cross sectional, elevational view of the eleventh embodiment of the invention taken at 900 to that of FIG. 1, and showing an initial actuation of the closure; FIG. 24 is a cross sectional, elevational view of a twelfth embodiment of the invention; FIG. 25 is a cross sectional, elevational view of the twelfth embodiment of the invention taken at 900 to that of FIG. 24, and showing an initial actuation of the closure FIG. 26 is a perspective view of a form of closure in accordance with embodiments of the invention; FIG. 27 is a perspective view of a compartment for a closure, shown upside down, in accordance with embodiments of the invention; FIG. 28 is a perspective view of another compartment for a closure, shown upside down, in accordance with embodiments of the invention; FIG. 29 is a perspective view of a further form of compartment for a closure, shown upside down, in accordance with other embodiments of the invention; FIG. 30 is an enlarged elevational view of one embodiment of cutting knife in accordance with the invention; and FIG. 31 is a perspective view of a further form of cutting knife in accordance with some embodiments of the present invention. Referring to the drawings, FIGS. 1 and 2 illustrates a first embodiment of the invention in which a dispensing closure 15 has a compartment 16 defined by a cylindrical side wall 17, a top wall 18 and a frangible bottom wall 19. The height of the side wall 17 varies around the perimeter of the compartment 16 so that the bottom wall 19 extends at an angle to a plane perpendicular to the axis of the cylindrical side wall 17. The closure of this embodiment includes a closure body 21 which comprises an outer side wall 22 and an intermediate wall 23. The outer side wall 22 is provided with internal threads 24 that engage with corresponding threads on the neck of a container 20 to which the closure is fitted. When fitted to the neck of a container 20 as shown, the intermediate wall 23 closely engages the internal surface of the container 20 neck. The top wall 18 of the compartment 16 has an outwardly and downwardly extending rim 26 with an inwardly directed shoulder 27 to engage a corresponding shoulder 27a on an upper extension of the intermediate wall 23. Thus, the compartment 16 and closure body 21 are snapped into engagement by the inter-engagement of the respective shoulders 27 and 27a. The engagement, however, is sufficiently free that the compartment 16 is able to rotate relative to the closure body 21 about the axis of the closure 15. A lower edge of the intermediate wall 23 carries an inwardly extending flange 28. At one point around the flange 28, a cutting blade 31 extends upwardly from the inner edge of the flange 28 towards the top wall 18 of the compartment 16. The blade 31 is spaced from the intermediate wall 23 by a distance that is slightly greater than the thickness of the side wall 17. When the compartment 16 is assembled with the closure body 21, the blade 31 is located at that portion of the side wall 17 having the least extent so that the blade 31 does not penetrate the frangible bottom wall 19. When the closure 15 is engaged with the neck of a container 20, the compartment 16 is located width the container 20 neck. A tamper-proof evident release band 32 extends from the lower edge of the outer side wall 22 to provide evidence of tampering with the closure 15 after engagement with a container 20. A further tamper evident tab 32a is formed integral with the upper edge of the outer side wall 22, the tab 32a being adapted to engage within a cooperating gap in the rim 26, as described and shown with reference to FIGS. 26 and 27. In use of the closure 15, when it is desired to dispense a product sealed within the compartment 16, after removal of the tab 32a, the rim 26, which is preferably provided with a knurl ribs or the like, is rotated relative to the closure body 21 thereby causing the angled bottom wall 19 to engage with the upper edge of the blade 31. The blade 31 cuts into the bottom wall 19 with continued rotation thereof thereby releasing the bottom wall 19 to enable contents 30 of the compartment 16 to fill into the container 20. Shoulders or the like may be provided to prevent relative rotation to less than 3600 so that the bottom wall remains connected by a small portion to the side wall 17. The contents 30 of the compartment 16 may be any of those referred to above or any product that is to be mixed with another within the container 20. The frangible bottom wall 19 may be formed of an aluminium foil which is adhered to the lower edges of the side wall 17. Alternatively, the frangible bottom wall 19 may be formed of the same material as the side wall 17, or it may be of any other suitable material for sealing contents 30 within the compartment 16, such as a synthetic plastics material adhered or welded to the lower edge of the side wall 17. The top wall 18 is formed with an undercut lip 10 for receipt and retention of a label, marker, price disk or other material. Referring to FIGS. 3 and 4, this embodiment is similar to that shown in FIGS. 1 and 2 except that the compartment 16 is formed integral with the outer side wall 22. In this embodiment, a cylindrical band 34 is a snap-fit over the outer surface of the compartment side wall 17, which is formed with an appropriate groove 35. The cylindrical band 34 carries the inwardly extending flange 28 and the cutting blade 31. In use of the closure of this embodiment, the cylindrical band frictionally engages the inner surface of the container 20 neck thereby holding the band against rotation during rotational movement of the compartment 16. The outer side wall 22 may be formed with threads, as described previously, or is provided with ribs, ridges or the like which enable the closure to be snap-fitted to the neck of a container 20. In the event that threads are used, an internal groove and stop shoulder may be used so that the compartment 16 is able to be rotated relative to the cylindrical band 34 in one direction only, the shoulder preventing rotation in the opposite direction. This, then, enables the cap to be screwed onto a container 20 neck without relative rotation occurring, but reverse relative rotation will cause the compartment 16 to rotate relative to the blade 31 thereby causing the blade to cut into the frangible bottom wall 19 to release the contents 30 of the compartment which pass into the container 20. Referring to FIGS. 5 and 6, this embodiment is similar to that of FIGS. 1 and 2 in which a separate compartment 16 and separate closure body 21 are utilised, the parts being fitted together through inter-engaging shoulders 27. In this embodiment, the bottom wall 19 extends in a plane perpendicular to the axis of the closure 15. The cutting blade 31 is contained in a protective pocket 36 formed at one side of the side wall 17. Relative rotation between the compartment 16 and the closure body 21 causes the cutting blade 31 to jump out of the protective pocket 36 thereby causing the blade to pierce and cut through the frangible bottom wall 19 releasing the contents 30 of the compartment 16 into the container 20. The cutting knife 31, which is shown in both side and front views in FIGS. 5 and 6 has two cutting edges 37 angled away from each other which ensures that the knife is able to cut irrespective of the direction of relative rotation of the compartment 16 and the closure body 21. Referring to FIGS. 7 and 8, this embodiment is similar to that of FIGS. 3 and 4 but incorporating the bottom wall and knife construction of FIGS. 5 and 6. The cutting blade 31 of this and the previous embodiment has a third cutting edge 38 which is substantially parallel to the first cutting edge. It has been found, in use, that when the compartment 16 is rotated relative to the cylindrical band 34 in a direction that moves the cutting blade 31 as illustrated in FIG. 8 towards the right, the action of cutting also causes the cut bottom wall 19 to peel downwardly thereby facilitating release of contents 30 of the compartment 16 into the container 20 to which the closure 15 is fitted. Referring to FIGS. 9 and 10, a modified construction of closure is illustrated in which the compartment 16 is defined by the side walls 17, which fit closely within the container 20 neck, and a separate top wall 18 that is attached to the side wall 17 by the inter-engaging shoulders 27. In this embodiment, the cutting blade 31 is disposed on the end of a downwardly extending carrier 39. The compartment 16 is thus formed of separate parts snap-fitted together, and is particularly suitable for a product which is unaffected by the atmosphere. A shoulder 41 is provided at the upper edge of the side wall 17 at that part of the side wall of least extent to restrict relative rotation of the blade carrier 39 so that the bottom wall 19 is not completely severed from its engagement with the side wall 17. As with all other embodiments, the outer side wall 22 may be provided with internal screw threads or snap-fitting ribs or ridges or the like for engagement with a correspondingly shaped neck of the container 20 to which the closure is to be fitted. Referring to FIGS. 11 and 12, this embodiment is similar to that of FIGS. 9 and 10 except that the outer side wall 22 is formed integral with the top wall 18 and is snap-fitted to the side wall 17 of the compartment 16 using the inter-engaging shoulders 27. The side wall 17 is formed with an annular enlargement 40 on its outer surface that tightly engages against the inside surface of the container 20 neck The enlargement 40 holds the side wall 17, and the bottom wall 19, against rotation relative to the container 20 neck when the outer wall 22, and the integral blade carrier 39, is rotated thereby enabling the blade 31 to cut through the bottom wall 19. Referring to FIGS. 13 to 15, this embodiment is similar to that of FIGS. 5 and 6. However, in this embodiment, the rim 26 of the top wall 18 is provided with a tamper proof evident band 42 which extends from the outer edge of the top wall to engage with the upper edge of the outer side wall 22. The inter-engaging shoulders 27 and 27a are separated, and the cutting blade 31, carried by the flange 28, is spaced from the frangible bottom wall 19. In this embodiment, there is no protective pocket for the cutting blade 31. The contents 30 of the compartment 16 are released, in this embodiment, by removal of the tamper proof evident band 42 thereby permitting the compartment 16 to be snap-engaged with the closure body 21 by a relative axial, downward movement of the compartment 16. Such movement causes the cutting blade 31 to cut into the frangible bottom wall 19 whereupon relative rotation of the respective compartment 16 and closure body 21 causes the cutting blade to cut around the edge of the bottom wall 19 and break open the bottom wall 19 to release the contents 30 of the compartment 16. The shoulder 41 acts to stop the rotational movement of the cutting blade 31 cutting through a full 3600, thereby retaining a connection between the bottom wall 19 and side wall 17 which stops the severed bottom wall falling into the container 20. Referring to FIGS. 16 and 17, the dispensing closure of this embodiment is designed particularly for use on containers having a threaded neck, such as a beverage bottle or the like. The closure comprises a compartment 16 engaged with a closure body 21. The compartment has a top wall 18 and a side wall 17 while the body has an outer wall 22, an intermediate wall 23 and a bottom wall 19 formed of a frangible membrane which extends from the lower edges of the intermediate wall 23. The peripheral edge of the top wall 18 is formed with a groove 43 to receive a rib 44 extending from the closure body 21 when the compartment 16 and body 21 are moved to a dispensing position. A cutting blade 31 extends downwardly from the side wall 17 so that, on relative axial downward and rotational movement of the compartment 16 and body 21, the cutting blade 31 pierces and cuts the membrane forming the bottom wall 19 thereby permitting contents 30 of the compartment to be dispensed into the container 20. If desired, means for relatively rotating the compartment and the closure body, such as grooved outer surfaces, may be provided on periphery of the top wall 18 and on the outer side wall 22 to facilitate cutting and removal of the bottom wall or membrane 19. Referring to FIGS. 18 and 19, this embodiment is similar to that of FIGS. 16 and 17 except that the side wall 17 is formed at its lower edge as a serrated cutter 45 that engages and cuts through the bottom wall or membrane 19 on relative axial movement in a downward motion between the compartment 16 and the closure body 21. A portion 50 of the side wall 17 is relieved adjacent a hinge 50a whereby a section of the bottom wall 19 is not cut by the cutter 45 allowing the cut wall part to fold down about the hinge 50a to allow the contents 30 to fall into the container 20. Referring to FIGS. 20 and 21, this embodiment is similar to that of FIGS. 1 and 2 except that the top wall is formed with a release valve 46 which allows contents of the container 20, when mixed with the contents 30 of the compartment 16, to be withdrawn from the container 20 through the valve 46. The release valve 46, which is known per se and will not be described in great detail, is maintained in a sealed condition by a cap 48 or shrink wrap or other sealing means to minimise the possibility of actuating the valve before the relative rotation of the compartment 16 and closure body 21 to release the contents 30 of the compartment into the container 20. However, once the contents 30 have been mixed, and the cap, shrink wrap or other sealing means is removed, the release valve 46 is able to be used to remove beverage or other contents from the container 20. The release valve 46 has channels 46a by which, when the outer portion of the release valve is moved inwardly, relative to the top wall 18 to cut open the valve wall 46b, the compartment is open to the atmosphere to permit extraction of the container 20 contents. Referring to FIGS. 22 and 23, the embodiment illustrated is similar in some respects to that of FIGS. 18 and 19. In this embodiment, however, the compartment 16 is formed by the intermediate wall 23, which is integral with the outer wall side wall 22, the top wall 18 and the bottom wall or membrane 19. This forms a sealed compartment 16 in which is located the wall cutting structure comprising the side wall 17 having its lower edge formed as a cutting knife, and an inner top wall 18a by which the side wall 17 may be axially moved. As shown in FIG. 23, the top wall 18 of the closure 15 is flexible or deformable, such as by forming the periphery thereof as a hinge, so that the centre thereof is able to be axially moved downwardly thereby causing the cutting knife to cut through the bottom wall 19. Preferably, the centre section of the inner top wall 18a is connected, such as by a cooperating rib and groove forming a snap fit, or by adhesive or other means, to the outer top wall 18. As with the embodiment shown in FIGS. 18 and 19, a portion 50 of the side wall 17 is relieved adjacent a hinge 50a whereby a section of the bottom wall 19 is not cut by the cutter, thereby allowing the cut wall part to fold down about the hinge 50a to allow the contents 30 to fall into the container 20. The cutting edge can also be similar to the serrated cutter of FIGS. 18 and 19. FIGS. 24 and 25 illustrate a modified form of the embodiment of FIGS. 22 and 23 in which the inner top wall 18a is omitted and the top wall 18 is formed with a release valve 46 that operates in a similar fashion to that described with reference to FIGS. 20 and 21. In this embodiment, a cap 48 prevents inadvertent operation of the valve and the cutting structure. On removal of the cap 48, movement of the valve 46 towards the container 20 firstly causes the top wall 18, that is integral with the valve housing, to move downwardly relative to the side wall 23 thereby causing the inner top wall 18a and associated side wall 17 to move relative to the bottom wall 19. The cutting knife edge on the lower edge of the side wall 17 cuts through the bottom wall 19 thus allowing the contents 30 of the compartment 16 to drop into the container 20 for mixing with the contents thereof. Further downward movement of the valve 46 stem cuts or breaks the frangible membrane 19a closing the bottom of the valve housing so that the mixed container contents are able to be dispensed through the channels 46a and the outlet of the valve 46. The cutting edge could also be similar to the serrated cutter. FIG. 26 illustrates a closure 15 that may be a closure of any one of the embodiments of FIGS. 1 and 2, 5 and 6, or 9 and 10. The rim 26 extending radially outwardly and downwardly of the top wall 18 has an opening 33 (FIG. 27) to receive the tamper evident tab 32a which is integral with the upper edge of the outer wall 22 to thereby prevent inadvertent relative rotation between the rim 26 and the closure body 21. It will be appreciated that it is important, when assembling the compartment 16 with the closure body 21 that the parts are properly aligned so that the cutting blade 31 is appropriately located in a position which does not cause it to cut into the bottom wall 19 prior to intended use. The tamper evident tab 32a thereby also serves that purpose of ensuring proper alignment as a registration point when the parts are assembled. The lower edge of the outer side wall 22 is integrally formed with a tamper evident band 32 that snaps behind a shoulder 32b formed on the container neck when the closure 15 is engaged on the neck of a beverage container 20 or the like, to prevent removal of the closure from the container 20 without removing the tamper evident band 32. FIG. 27 illustrates one form of compartment 16 such as is used in the closure of FIG. 26. The compartments 16 described and illustrated with reference to FIGS. 1 to 25, may contain a single product 30 to be dispensed into a container 20 which, in one example, may hold a beverage or the like. However, the compartment 16 may be divided into two or more parts by a dividing walls 47 thereby enabling two or more products to be dispensed from the dispensing closure 15. Thus, the contents 30 of a twin compartment 16, as shown in FIG. 28, may be dispensed as alternate products or sequentially to dispense both products. Referring to FIG. 29, a compartment may be divided into three or more chambers by walls or partitions 47. This allows three substances to be dispensed by causing relative rotation of the compartment 16 and the closure body 21 so that the cutting knife cuts through the frangible bottom wall 19 until it reaches a petition or dividing wall 47 at which it then jumps across the petition wall into the next compartment as rotation is continued. The top wall 18 of the compartments 16 may be appropriately marked to indicate the contents 30 thereof so that selections may be made in dispensing those contents 30. Thus, one compartment may contain a beverage mix, such as coffee, while another compartment contains sugar granules and a third compartment contains a creamer. The user is thus able to choose a desired mix. Referring to FIG. 30, there is illustrated one embodiment of a cutting blade 31 for use in the performance of the invention. The cutting blade 31 is preferably formed by moulding of the same material as is used in the construction of the compartment 16 and/or the closure body 21. The blade 31 is moulded integrally with the respective wall parts of the closure 15. The blade 31 is specifically designed to first cut through the frangible bottom wall 19, which may be a membrane formed of synthetic plastics material, aluminium foil or any other suitable material used as the frangible bottom wall 19. The blade includes, on each side, a first cutting edge 51 and a second cutting edge 52. In use, with the wall 19 moving in the direction of arrow “A” relative to the blade 31, the first cutting edge 51 cuts into the wall 19. As the relative position of the wall changes, due to the angle between the wall 19 and the plane perpendicular to the rotational axis, the wall 19 moves axially relative to the cutting edge 51 until it reaches the second cutting edge 52. Continued relative movement results in the membrane material being peeled back from the opening formed by the cutting blade 31 so that the bottom wall 19 is peeled away from its engagement with the respective compartment wall thereby permitting compartment contents 30 to fall into the container 20 without hindrance by the bottom wall 19. Embodiments of the invention will be designed so that the bottom wall 19 is not completely removed from its attachment to the respective compartment wall so as not to full into the container 20. Thus, a stop or other means may be provided to reduce the likelihood of the bottom wall 19 being completely removed and falling into the container 20. By having a cutting blade 31 formed with opposing edges as illustrated in FIG. 30, the direction of relative rotation is irrelevant as either side of the blade is able to be used according to the direction of relative rotation. FIG. 31 illustrates another embodiment of cutting blade 31 having two legs each with three cutting edges 51, 52 and 53. This blade works in a similar manner to that of FIG. 30 except that, if the direction of relative rotation is reversed, the blade edges 53 can also cut the material of the bottom wall 19.

<SOH> BACKGROUND OF THE INVENTION <EOH>The invention will be described with particular reference to a cap for a liquid container, such as a beverage container. However, it will be appreciated that the principals of the invention can be applied to containers and closures of many different types to enable two or more materials to be kept separated up to the moment of use, and to then dispense, discharge or mix at least one of the materials into another. Thus, the invention is applicable to, for example, dispensing pharmaceuticals in liquid, powder, tablet or granule form into an appropriate medium for ingestion of the pharmaceutical; dispensing colour pigments, in liquid or powder form or in capsules, into base paint carriers; mixing cosmetic colouring material into a carrier; mixing chemicals, including catalysts and hardeners, and particularly those that may be toxic or dangerous to touch, into an active ingredient; discharging food flavouring, colouring, sweeteners or other food product into an appropriate beverage medium or the like. The invention is therefore useful for combining materials of many types where it is necessary or desirable to selectively dispense or mix one material or substance into another.

<SOH> SUMMARY OF THE INVENTION <EOH>According to one aspect of the invention there is provided a dispensing closure to dispense at least one product into a container, the closure including a container closure body adapted to sealingly engage with a neck of the container, the body having securing means to secure the closure to the container neck, a compartment to contain the at least one product to be dispensed, the compartment being adapted to fit within the container neck and being defined by a side wall, a top wall and a frangible bottom wall, and cutting means moveable relative to the side wall and the bottom wall to break open the frangible bottom wall of the compartment to selectively dispense contents of the compartment into the container. In one form of the invention, the closure body includes an outer, cylindrical wall and a coaxial inner wall. The outer wall is provided with internal threads adapted to threadingly engage the threaded neck of a container to which the closure is to be fitted The inner wall engages within the container neck, and the compartment fits within the inner wall. The upper end of the compartment is formed with a radially outwardly extending flange having reversely formed shoulders to engage corresponding shoulders on the closure body. In this way, the two parts of the closure are able to be snap-fitted together so that the compartment is able to rotate about its axis relative to the body. In this embodiment, the inner wall of the body carries a cutting knife edge which is inwardly and upwardly turned towards the frangible bottom wall of the compartment. The bottom wall of the compartment extends at an angle to a plane perpendicular to the axis such that, in first assembled position, the bottom wall does not contact the knife. On relative rotation of the compartment, however, the frangible bottom wall is brought into contact with the knife which cuts and breaks the wall from the compartment permitting contents thereof to be dispensed into the container to which the closure is fitted. In another embodiment of the invention, the compartment and closure body are integral and are engaged with a cylindrical band which fits over the wall of the compartment. The band carries the cutting knife which operates in the manner described above. Preferably, the container closure body includes, on the lower end of the outer wall, a tamper proof evidence release band to provide any indication of tampering with the closure prior to its use. According to another aspect of the invention there is provided a dispensing device for dispensing product into a container, the device having a sealed compartment containing the product, the compartment having a substantially cylindrical side wall, a frangible bottom wall and a top wall, the compartment being adapted to fit within a neck of the container, the device further having an outer wall to engage an outer surface of the container neck and including securing means to secure the device to the container, and cutting means adapted to be rotated relative to the frangible bottom wall, the cutting means and/or the frangible bottom wall being arranged such that the relative movement causes the cutting means to break open the frangible bottom wall of the compartment to selectively dispense contents of the compartment into the container. The cutting means may extend from a separate cylindrical band coaxial with the side wall of the compartment but rotatable relative thereto. Alternatively, the compartment and outer wall may be separate integers with the cutting means extending from an intermediate wall located between the compartment and the inner surface of the neck of the container. According to a further aspect of the invention there is provided a method of dispensing at least one product into a container, the method including the steps of assembling a compartment containing a product to be dispensed with a closure body, engaging the assembled closure with a neck portion of a container into which the contents are to be dispensed, providing a cutting knife adjacent to a bottom wall of the assembled closure, and rotating the knife relative to the bottom wall to cause the knife to cut into the bottom wall to thereby release the contents of the compartment into the container. According to a further aspect of the present invention there is provided a cutting knife for use with a dispensing closure, the knife being integrally moulded with a wall of the closure, the knife having at least two cutting edges extending at an acute angle to each other. In order that the invention is more readily understood, embodiments thereof will now be described with reference to the accompanying drawings wherein: FIG. 1 is a cross sectional, elevational view of a first embodiment of the invention; FIG. 2 is a cross sectional, elevational view of the first embodiment of the invention taken at 900 to that of FIG. 1 ; FIG. 3 is a cross sectional, elevational view of a second embodiment of the invention; FIG. 4 is a cross sectional, elevational view of the second embodiment of the invention taken at 900 to that of FIG. 3 ; FIG. 5 is a cross sectional, elevational view of a third embodiment of the invention; FIG. 6 is a cross sectional, elevational view of the third embodiment of the invention taken at 900 to that of FIG. 5 ; FIG. 7 is a cross sectional, elevational view of a fourth embodiment of the invention; FIG. 8 is a cross sectional, elevational view of the fourth embodiment of the invention taken at 900 to that of FIG. 7 ; FIG. 9 is a cross sectional, elevational view of a fifth embodiment of the invention; FIG. 10 is a cross sectional, elevational view of the fifth embodiment of the invention taken at 900 to that of FIG. 9 ; FIG. 11 is a cross sectional, elevational view of a sixth embodiment of the invention; FIG. 12 is a cross sectional, elevational view of the sixth embodiment of the invention taken at 900 to that of FIG. 11 ; FIG. 13 is a cross sectional, elevational view of a seventh embodiment of the invention; FIG. 14 is a cross sectional, elevational view of the seventh embodiment of the invention taken at 900 to that of FIG. 13 ; FIG. 15 is a cross sectional, elevational view of the seventh embodiment of the invention similar to FIG. 14 showing the closure after an initial actuation; FIG. 16 is a cross sectional, elevational view of an eighth embodiment of the invention; FIG. 17 is a cross sectional, elevational view of the eighth embodiment of the invention taken at 900 to that of FIG. 16 ; FIG. 18 is a cross sectional elevational view of a ninth embodiment of the invention; FIG. 19 is a cross sectional, elevational view of the ninth embodiment of the invention taken at 900 to that of FIG. 18 ; FIG. 20 is a cross sectional, elevational view of a tenth embodiment of the invention; FIG. 21 is a cross sectional elevational view of the tenth embodiment of the invention taken at 900 to that of FIG., and showing an initial actuation of the closure; FIG. 22 is a cross sectional, elevational view of an eleventh embodiment of the invention; FIG. 23 is a cross sectional, elevational view of the eleventh embodiment of the invention taken at 900 to that of FIG. 1 , and showing an initial actuation of the closure; FIG. 24 is a cross sectional, elevational view of a twelfth embodiment of the invention; FIG. 25 is a cross sectional, elevational view of the twelfth embodiment of the invention taken at 900 to that of FIG. 24 , and showing an initial actuation of the closure FIG. 26 is a perspective view of a form of closure in accordance with embodiments of the invention; FIG. 27 is a perspective view of a compartment for a closure, shown upside down, in accordance with embodiments of the invention; FIG. 28 is a perspective view of another compartment for a closure, shown upside down, in accordance with embodiments of the invention; FIG. 29 is a perspective view of a further form of compartment for a closure, shown upside down, in accordance with other embodiments of the invention; FIG. 30 is an enlarged elevational view of one embodiment of cutting knife in accordance with the invention; and FIG. 31 is a perspective view of a further form of cutting knife in accordance with some embodiments of the present invention. detailed-description description="Detailed Description" end="lead"? Referring to the drawings, FIGS. 1 and 2 illustrates a first embodiment of the invention in which a dispensing closure 15 has a compartment 16 defined by a cylindrical side wall 17 , a top wall 18 and a frangible bottom wall 19 . The height of the side wall 17 varies around the perimeter of the compartment 16 so that the bottom wall 19 extends at an angle to a plane perpendicular to the axis of the cylindrical side wall 17 . The closure of this embodiment includes a closure body 21 which comprises an outer side wall 22 and an intermediate wall 23 . The outer side wall 22 is provided with internal threads 24 that engage with corresponding threads on the neck of a container 20 to which the closure is fitted. When fitted to the neck of a container 20 as shown, the intermediate wall 23 closely engages the internal surface of the container 20 neck. The top wall 18 of the compartment 16 has an outwardly and downwardly extending rim 26 with an inwardly directed shoulder 27 to engage a corresponding shoulder 27 a on an upper extension of the intermediate wall 23 . Thus, the compartment 16 and closure body 21 are snapped into engagement by the inter-engagement of the respective shoulders 27 and 27 a. The engagement, however, is sufficiently free that the compartment 16 is able to rotate relative to the closure body 21 about the axis of the closure 15 . A lower edge of the intermediate wall 23 carries an inwardly extending flange 28 . At one point around the flange 28 , a cutting blade 31 extends upwardly from the inner edge of the flange 28 towards the top wall 18 of the compartment 16 . The blade 31 is spaced from the intermediate wall 23 by a distance that is slightly greater than the thickness of the side wall 17 . When the compartment 16 is assembled with the closure body 21 , the blade 31 is located at that portion of the side wall 17 having the least extent so that the blade 31 does not penetrate the frangible bottom wall 19 . When the closure 15 is engaged with the neck of a container 20 , the compartment 16 is located width the container 20 neck. A tamper-proof evident release band 32 extends from the lower edge of the outer side wall 22 to provide evidence of tampering with the closure 15 after engagement with a container 20 . A further tamper evident tab 32 a is formed integral with the upper edge of the outer side wall 22 , the tab 32 a being adapted to engage within a cooperating gap in the rim 26 , as described and shown with reference to FIGS. 26 and 27 . In use of the closure 15 , when it is desired to dispense a product sealed within the compartment 16 , after removal of the tab 32 a, the rim 26 , which is preferably provided with a knurl ribs or the like, is rotated relative to the closure body 21 thereby causing the angled bottom wall 19 to engage with the upper edge of the blade 31 . The blade 31 cuts into the bottom wall 19 with continued rotation thereof thereby releasing the bottom wall 19 to enable contents 30 of the compartment 16 to fill into the container 20 . Shoulders or the like may be provided to prevent relative rotation to less than 3600 so that the bottom wall remains connected by a small portion to the side wall 17 . The contents 30 of the compartment 16 may be any of those referred to above or any product that is to be mixed with another within the container 20 . The frangible bottom wall 19 may be formed of an aluminium foil which is adhered to the lower edges of the side wall 17 . Alternatively, the frangible bottom wall 19 may be formed of the same material as the side wall 17 , or it may be of any other suitable material for sealing contents 30 within the compartment 16 , such as a synthetic plastics material adhered or welded to the lower edge of the side wall 17 . The top wall 18 is formed with an undercut lip 10 for receipt and retention of a label, marker, price disk or other material. Referring to FIGS. 3 and 4 , this embodiment is similar to that shown in FIGS. 1 and 2 except that the compartment 16 is formed integral with the outer side wall 22 . In this embodiment, a cylindrical band 34 is a snap-fit over the outer surface of the compartment side wall 17 , which is formed with an appropriate groove 35 . The cylindrical band 34 carries the inwardly extending flange 28 and the cutting blade 31 . In use of the closure of this embodiment, the cylindrical band frictionally engages the inner surface of the container 20 neck thereby holding the band against rotation during rotational movement of the compartment 16 . The outer side wall 22 may be formed with threads, as described previously, or is provided with ribs, ridges or the like which enable the closure to be snap-fitted to the neck of a container 20 . In the event that threads are used, an internal groove and stop shoulder may be used so that the compartment 16 is able to be rotated relative to the cylindrical band 34 in one direction only, the shoulder preventing rotation in the opposite direction. This, then, enables the cap to be screwed onto a container 20 neck without relative rotation occurring, but reverse relative rotation will cause the compartment 16 to rotate relative to the blade 31 thereby causing the blade to cut into the frangible bottom wall 19 to release the contents 30 of the compartment which pass into the container 20 . Referring to FIGS. 5 and 6 , this embodiment is similar to that of FIGS. 1 and 2 in which a separate compartment 16 and separate closure body 21 are utilised, the parts being fitted together through inter-engaging shoulders 27 . In this embodiment, the bottom wall 19 extends in a plane perpendicular to the axis of the closure 15 . The cutting blade 31 is contained in a protective pocket 36 formed at one side of the side wall 17 . Relative rotation between the compartment 16 and the closure body 21 causes the cutting blade 31 to jump out of the protective pocket 36 thereby causing the blade to pierce and cut through the frangible bottom wall 19 releasing the contents 30 of the compartment 16 into the container 20 . The cutting knife 31 , which is shown in both side and front views in FIGS. 5 and 6 has two cutting edges 37 angled away from each other which ensures that the knife is able to cut irrespective of the direction of relative rotation of the compartment 16 and the closure body 21 . Referring to FIGS. 7 and 8 , this embodiment is similar to that of FIGS. 3 and 4 but incorporating the bottom wall and knife construction of FIGS. 5 and 6 . The cutting blade 31 of this and the previous embodiment has a third cutting edge 38 which is substantially parallel to the first cutting edge. It has been found, in use, that when the compartment 16 is rotated relative to the cylindrical band 34 in a direction that moves the cutting blade 31 as illustrated in FIG. 8 towards the right, the action of cutting also causes the cut bottom wall 19 to peel downwardly thereby facilitating release of contents 30 of the compartment 16 into the container 20 to which the closure 15 is fitted. Referring to FIGS. 9 and 10 , a modified construction of closure is illustrated in which the compartment 16 is defined by the side walls 17 , which fit closely within the container 20 neck, and a separate top wall 18 that is attached to the side wall 17 by the inter-engaging shoulders 27 . In this embodiment, the cutting blade 31 is disposed on the end of a downwardly extending carrier 39 . The compartment 16 is thus formed of separate parts snap-fitted together, and is particularly suitable for a product which is unaffected by the atmosphere. A shoulder 41 is provided at the upper edge of the side wall 17 at that part of the side wall of least extent to restrict relative rotation of the blade carrier 39 so that the bottom wall 19 is not completely severed from its engagement with the side wall 17 . As with all other embodiments, the outer side wall 22 may be provided with internal screw threads or snap-fitting ribs or ridges or the like for engagement with a correspondingly shaped neck of the container 20 to which the closure is to be fitted. Referring to FIGS. 11 and 12 , this embodiment is similar to that of FIGS. 9 and 10 except that the outer side wall 22 is formed integral with the top wall 18 and is snap-fitted to the side wall 17 of the compartment 16 using the inter-engaging shoulders 27 . The side wall 17 is formed with an annular enlargement 40 on its outer surface that tightly engages against the inside surface of the container 20 neck The enlargement 40 holds the side wall 17 , and the bottom wall 19 , against rotation relative to the container 20 neck when the outer wall 22 , and the integral blade carrier 39 , is rotated thereby enabling the blade 31 to cut through the bottom wall 19 . Referring to FIGS. 13 to 15 , this embodiment is similar to that of FIGS. 5 and 6 . However, in this embodiment, the rim 26 of the top wall 18 is provided with a tamper proof evident band 42 which extends from the outer edge of the top wall to engage with the upper edge of the outer side wall 22 . The inter-engaging shoulders 27 and 27 a are separated, and the cutting blade 31 , carried by the flange 28 , is spaced from the frangible bottom wall 19 . In this embodiment, there is no protective pocket for the cutting blade 31 . The contents 30 of the compartment 16 are released, in this embodiment, by removal of the tamper proof evident band 42 thereby permitting the compartment 16 to be snap-engaged with the closure body 21 by a relative axial, downward movement of the compartment 16 . Such movement causes the cutting blade 31 to cut into the frangible bottom wall 19 whereupon relative rotation of the respective compartment 16 and closure body 21 causes the cutting blade to cut around the edge of the bottom wall 19 and break open the bottom wall 19 to release the contents 30 of the compartment 16 . The shoulder 41 acts to stop the rotational movement of the cutting blade 31 cutting through a full 3600, thereby retaining a connection between the bottom wall 19 and side wall 17 which stops the severed bottom wall falling into the container 20 . Referring to FIGS. 16 and 17 , the dispensing closure of this embodiment is designed particularly for use on containers having a threaded neck, such as a beverage bottle or the like. The closure comprises a compartment 16 engaged with a closure body 21 . The compartment has a top wall 18 and a side wall 17 while the body has an outer wall 22 , an intermediate wall 23 and a bottom wall 19 formed of a frangible membrane which extends from the lower edges of the intermediate wall 23 . The peripheral edge of the top wall 18 is formed with a groove 43 to receive a rib 44 extending from the closure body 21 when the compartment 16 and body 21 are moved to a dispensing position. A cutting blade 31 extends downwardly from the side wall 17 so that, on relative axial downward and rotational movement of the compartment 16 and body 21 , the cutting blade 31 pierces and cuts the membrane forming the bottom wall 19 thereby permitting contents 30 of the compartment to be dispensed into the container 20 . If desired, means for relatively rotating the compartment and the closure body, such as grooved outer surfaces, may be provided on periphery of the top wall 18 and on the outer side wall 22 to facilitate cutting and removal of the bottom wall or membrane 19 . Referring to FIGS. 18 and 19 , this embodiment is similar to that of FIGS. 16 and 17 except that the side wall 17 is formed at its lower edge as a serrated cutter 45 that engages and cuts through the bottom wall or membrane 19 on relative axial movement in a downward motion between the compartment 16 and the closure body 21 . A portion 50 of the side wall 17 is relieved adjacent a hinge 50 a whereby a section of the bottom wall 19 is not cut by the cutter 45 allowing the cut wall part to fold down about the hinge 50 a to allow the contents 30 to fall into the container 20 . Referring to FIGS. 20 and 21 , this embodiment is similar to that of FIGS. 1 and 2 except that the top wall is formed with a release valve 46 which allows contents of the container 20 , when mixed with the contents 30 of the compartment 16 , to be withdrawn from the container 20 through the valve 46 . The release valve 46 , which is known per se and will not be described in great detail, is maintained in a sealed condition by a cap 48 or shrink wrap or other sealing means to minimise the possibility of actuating the valve before the relative rotation of the compartment 16 and closure body 21 to release the contents 30 of the compartment into the container 20 . However, once the contents 30 have been mixed, and the cap, shrink wrap or other sealing means is removed, the release valve 46 is able to be used to remove beverage or other contents from the container 20 . The release valve 46 has channels 46 a by which, when the outer portion of the release valve is moved inwardly, relative to the top wall 18 to cut open the valve wall 46 b, the compartment is open to the atmosphere to permit extraction of the container 20 contents. Referring to FIGS. 22 and 23 , the embodiment illustrated is similar in some respects to that of FIGS. 18 and 19 . In this embodiment, however, the compartment 16 is formed by the intermediate wall 23 , which is integral with the outer wall side wall 22 , the top wall 18 and the bottom wall or membrane 19 . This forms a sealed compartment 16 in which is located the wall cutting structure comprising the side wall 17 having its lower edge formed as a cutting knife, and an inner top wall 18 a by which the side wall 17 may be axially moved. As shown in FIG. 23 , the top wall 18 of the closure 15 is flexible or deformable, such as by forming the periphery thereof as a hinge, so that the centre thereof is able to be axially moved downwardly thereby causing the cutting knife to cut through the bottom wall 19 . Preferably, the centre section of the inner top wall 18 a is connected, such as by a cooperating rib and groove forming a snap fit, or by adhesive or other means, to the outer top wall 18 . As with the embodiment shown in FIGS. 18 and 19 , a portion 50 of the side wall 17 is relieved adjacent a hinge 50 a whereby a section of the bottom wall 19 is not cut by the cutter, thereby allowing the cut wall part to fold down about the hinge 50 a to allow the contents 30 to fall into the container 20 . The cutting edge can also be similar to the serrated cutter of FIGS. 18 and 19 . FIGS. 24 and 25 illustrate a modified form of the embodiment of FIGS. 22 and 23 in which the inner top wall 18 a is omitted and the top wall 18 is formed with a release valve 46 that operates in a similar fashion to that described with reference to FIGS. 20 and 21 . In this embodiment, a cap 48 prevents inadvertent operation of the valve and the cutting structure. On removal of the cap 48 , movement of the valve 46 towards the container 20 firstly causes the top wall 18 , that is integral with the valve housing, to move downwardly relative to the side wall 23 thereby causing the inner top wall 18 a and associated side wall 17 to move relative to the bottom wall 19 . The cutting knife edge on the lower edge of the side wall 17 cuts through the bottom wall 19 thus allowing the contents 30 of the compartment 16 to drop into the container 20 for mixing with the contents thereof. Further downward movement of the valve 46 stem cuts or breaks the frangible membrane 19 a closing the bottom of the valve housing so that the mixed container contents are able to be dispensed through the channels 46 a and the outlet of the valve 46 . The cutting edge could also be similar to the serrated cutter. FIG. 26 illustrates a closure 15 that may be a closure of any one of the embodiments of FIGS. 1 and 2 , 5 and 6 , or 9 and 10 . The rim 26 extending radially outwardly and downwardly of the top wall 18 has an opening 33 ( FIG. 27 ) to receive the tamper evident tab 32 a which is integral with the upper edge of the outer wall 22 to thereby prevent inadvertent relative rotation between the rim 26 and the closure body 21 . It will be appreciated that it is important, when assembling the compartment 16 with the closure body 21 that the parts are properly aligned so that the cutting blade 31 is appropriately located in a position which does not cause it to cut into the bottom wall 19 prior to intended use. The tamper evident tab 32 a thereby also serves that purpose of ensuring proper alignment as a registration point when the parts are assembled. The lower edge of the outer side wall 22 is integrally formed with a tamper evident band 32 that snaps behind a shoulder 32 b formed on the container neck when the closure 15 is engaged on the neck of a beverage container 20 or the like, to prevent removal of the closure from the container 20 without removing the tamper evident band 32 . FIG. 27 illustrates one form of compartment 16 such as is used in the closure of FIG. 26 . The compartments 16 described and illustrated with reference to FIGS. 1 to 25 , may contain a single product 30 to be dispensed into a container 20 which, in one example, may hold a beverage or the like. However, the compartment 16 may be divided into two or more parts by a dividing walls 47 thereby enabling two or more products to be dispensed from the dispensing closure 15 . Thus, the contents 30 of a twin compartment 16 , as shown in FIG. 28 , may be dispensed as alternate products or sequentially to dispense both products. Referring to FIG. 29 , a compartment may be divided into three or more chambers by walls or partitions 47 . This allows three substances to be dispensed by causing relative rotation of the compartment 16 and the closure body 21 so that the cutting knife cuts through the frangible bottom wall 19 until it reaches a petition or dividing wall 47 at which it then jumps across the petition wall into the next compartment as rotation is continued. The top wall 18 of the compartments 16 may be appropriately marked to indicate the contents 30 thereof so that selections may be made in dispensing those contents 30 . Thus, one compartment may contain a beverage mix, such as coffee, while another compartment contains sugar granules and a third compartment contains a creamer. The user is thus able to choose a desired mix. Referring to FIG. 30 , there is illustrated one embodiment of a cutting blade 31 for use in the performance of the invention. The cutting blade 31 is preferably formed by moulding of the same material as is used in the construction of the compartment 16 and/or the closure body 21 . The blade 31 is moulded integrally with the respective wall parts of the closure 15 . The blade 31 is specifically designed to first cut through the frangible bottom wall 19 , which may be a membrane formed of synthetic plastics material, aluminium foil or any other suitable material used as the frangible bottom wall 19 . The blade includes, on each side, a first cutting edge 51 and a second cutting edge 52 . In use, with the wall 19 moving in the direction of arrow “A” relative to the blade 31 , the first cutting edge 51 cuts into the wall 19 . As the relative position of the wall changes, due to the angle between the wall 19 and the plane perpendicular to the rotational axis, the wall 19 moves axially relative to the cutting edge 51 until it reaches the second cutting edge 52 . Continued relative movement results in the membrane material being peeled back from the opening formed by the cutting blade 31 so that the bottom wall 19 is peeled away from its engagement with the respective compartment wall thereby permitting compartment contents 30 to fall into the container 20 without hindrance by the bottom wall 19 . Embodiments of the invention will be designed so that the bottom wall 19 is not completely removed from its attachment to the respective compartment wall so as not to full into the container 20 . Thus, a stop or other means may be provided to reduce the likelihood of the bottom wall 19 being completely removed and falling into the container 20 . By having a cutting blade 31 formed with opposing edges as illustrated in FIG. 30 , the direction of relative rotation is irrelevant as either side of the blade is able to be used according to the direction of relative rotation. FIG. 31 illustrates another embodiment of cutting blade 31 having two legs each with three cutting edges 51 , 52 and 53 . This blade works in a similar manner to that of FIG. 30 except that, if the direction of relative rotation is reversed, the blade edges 53 can also cut the material of the bottom wall 19 . detailed-description description="Detailed Description" end="tail"?

20060306

20090113

20070201

71729.0

B65D2508

ACKUN, JACOB K

DISPENSING CLOSURE

MICRO

ACCEPTED

B65D

ACCEPTED

Antisense inhibition of laminin-8 expression to inhibit human gliomas

Using gene array technology, we observed that an increase of the α4 chain-containing Laminin-8 correlated with poor prognosis for patients with brain gliomas. We established that inhibition of Laminin-8 expression by a new generation of highly specific and stable antisense oligonucleotides (Morpholino™) against chains of Laminin-8 could slow or stop the spread of glioma. This was demonstrated in an in vitro model using human glioblastoma multiforme cell lines M059K and U-87MG co-cultured with normal human brain microvascular endothelial cells (HBMVEC). Using Western blot analysis and immunohistochemistry, we con-firmed that antisense treatment effectively blocked laminin-8 protein synthesis. Antisense oligonucleotides against both α4 and β1 chains of laminin-8 blocked significantly the invasion of co-cultures through Matrigel. The results show that Linin-8 may not only contribute to glioma progression and recurrence as part of the neovascularization process but also by directly increasing the invasive potential of tumor cells.

1. A method for reducing invasiveness of a human glioma comprising the step of contacting said glioma with a composition that inhibits expression of Laminin-8 by said glioma. 2. The method according to claim 1, wherein Laminin-8 expression is inhibited by inhibiting the expression of Laminin α4 chain. 3. The method according to claim 1, wherein Laminin-8 expression is inhibited by inhibiting the expression of Laminin β1 chain. 4. The method according to claim 1, wherein Laminin-8 expression is inhibited by inhibiting the expression of both Laminin α4 chain and Laminin β1 chain. 5. The method according to claim 1, wherein the composition includes a composition selected from the group consisting of an antisense polynucleotide, a monoclonal antibody and a small interfering RNA. 6. The method according to claim 5, wherein said polynucleotide is a morpholino polynucleotide. 7. The method according to claim 5, wherein the antisense polynucleotide includes an antisense of Laminin α4 chain. 8. The method according to claim 7, wherein the antisense of Laminin α4 chain comprises the 5′ to 3′ polynucleotide sequence characterized by SEQ ID NO: 1. 9. The method according to claim 5, wherein the antisense polynucleotide includes an antisense of Laminin β1 chain. 10. The method according to claim 9, wherein the antisense of Laminin β1 chain comprises the 5′ to 3′ polynucleotide sequence characterized by SEQ ID NO:3. 11. The method according to claim 5, wherein the antisense polynucleotide includes both an antisense of Laminin α4 chain and an antisense of Laminin β1 chain. 12. The method according to claim 11, wherein the antisense polynucleotide includes polynucleotides comprising 5′ to 3′ sequences characterized by SEQ ID NO: 3 and SEQ ID NO: 1.

The current application is based on and claims priority from U.S. Provisional Patent Application 60/502,729, filed on Sept. 12, 2003. INTRODUCTION Glial tumors are the leading cause of cancer death in children [1]. Overall, they account for 1.4% of all cancers and 2.4% of all cancer deaths. Average survival time for low-grade astrocytoma or oligodendroglioma patients is 6 to 8 years. It decreases to 3 years for patients with anaplastic astrocytoma and drops to 12-18 months for glioblastoma multiforme (GBM). Currently, these tumors are treated by surgical removal, radiation therapy, chemotherapy or combinations of these treatments. The majority of GBMs is highly invasive and rapidly develops recurrences at the primary site. Tumor prognoses and responses to therapy can vary greatly even with the same histological diagnosis [2]. It is generally recognized that the improvement of prognosis, prediction of response to treatment, and development of novel effective therapeutic approaches for glial tumors may largely depend upon the introduction into clinical practice of novel specific markers involved in the development of different gliomas and their subsequent recurrences. Attempts have been made to establish and characterize a number of glioma markers, such as glial fibrillary acidic protein, vimentin, synaptophysin, and nestin. Determination of differential expression of these markers (immunophenotyping) in gliomas, however, has thus far not altered existing therapeutic approaches, treatment success rates, or disease outcome prediction [2, 3]. Researchers next sought to identify novel glioma markers using powerful gene array technology [4-7]. Recently, our group described a new molecular marker of glial tumors, laminin-8, that was differentially expressed in malignant tumors compared to benign tumors and normal brain tissues [5]. All laminins consist of three covalenfly linked chains, α, β and γ. To date, 15 members (isoforms) of this family that are present in different basement membranes (BMs) have been described [8-10]. Laminins interact with cells through various receptors. Most of these receptors belong to the family of integrin heterodimers, although other molecules including dystroglycan complex and Lutheran blood group glycoprotein have also been shown to bind to laminins. In different cell types, integrins α1β1, α2β1, α3β1, α6β1, α6β4 and α7β1 have been reported to have the capability to bind to laminins. Specific laminin isoforms bind some but not all of these different integrins, and each integrin can bind to more than one laminin isoform [10, 11]. Along with type IV collagens, nidogens and perlecan, glycoproteins of the laminin family are the major constituents of brain microvessel BMs [8, 12, 13]. These BMs have a complex structure and are produced by both endothelial and glial cells [13]. Endothelial cells contribute laminins containing α4 and α5 chains to these BMs, whereas glial cells synthesize laminins containing α1 and α2 chains [13]. In human brain capillary BMs we have recently observed a weak expression of the α4 chain-containing laminin-9. Interestingly, during progression of human gliomas, the expression of capillary BM laminins containing α4 chain switches from the predominant laminin-9 (α4β2γ1) to laminin-8 (α4β1γ1) [5]. Laminin-8 and its receptors, integrins α3β1 and α6β1, appear to be important to the functioning of endothelial cell BMs, which play a role in the maintenance of the blood-brain barrier [14, 15]. Recently, the association of the laminin α4 chain with angiogenesis has been demonstrated in vivo and in vitro [16]. Some cultured glioma cell lines can also produce α4-containing laminins. Laminin-8 is thought to play a role in cell migration during development, wound healing, and angiogenesis [8, 10, 14]. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows uptake of Ac-LDL by various cultures and co-cultures; endothelial cells (HBMVEC) are positive (green fluorescence) but glioma cells (M59K) and normal astrocytes (HAST 040) are negative; in co-cultures HBMVEC+M059K and HBMVEC+HAST040, endothelial cells are positive, whereas other cells are negative (DAPI was used to counterstain cell nuclei (blue fluorescence)). FIG. 2 shows Laminin α4, β1, and β2 chain expression in cells and conditioned media of pure cultures: FIG. 2A. Immunolocalization of laminin chains in cells where normal brain endothelium (HBMVEC) expresses α4 and β2 chains (consistent with laminin-9, α4β2γ1), whereas astrocytes (HAST 040) do not express these laminin chains; M059K glioma cells, however, express α4 and β1 chains consistent with laminin-8 (α4β1γ1). Indirect immunofluorescence. FIG. 2B. Western blot analysis of conditioned media shows that endothelial cells (HBMVEC) secrete chains of laminin-9 (α4 and β2), astrocytes (HAST 040) show little to no secretion of any studied chains, and M059K glioma cells secrete chains of laminin-8 (α4 and β1) (T98G, lysate of T98G glioma cells expressing laminin-8 chains only (α4 and β1) were used as positive control; equal amounts of conditioned media protein were applied to each lane. Note complete agreement between the results of immunostaining (FIG. 2A) and Western blotting (FIG. 2B)). FIG. 3 shows the Laminin α4, β1, and β2 chain staining of co-cultures; live co-cultures were exposed to Ac-LDL (green color, to reveal endothelial cells) and then fixed and simultaneously stained for select laminin chains (red color) and nuclei (DAPI, blue color); in endothelial-astrocyte co-cultures (HBMVEC+HAST040) α4 and β2 chains are expressed in Ac-LDL-positive endothelial cells only but not in Ac-LDL-negative astrocytes (arrows); β1 chain is largely absent; in endothelial-glioma co-cultures (HBMVEC+M059K), α4 chain is expressed by both cell types and β2 chain, only by endothelial cells; significantly, β1 chain is expressed not only by Ac-LDL-negative glioma cells (arrowheads) but also by Ac-LDL-positive endothelial cells. FIG. 4 shows the Cell viability assay; viability of glioma cell lines M059K and U-87MG as well as of normal endothelial cell line HBMVEC after treatment with Morpholinos sense or antisense oligos and delivery factor is higher than 90%; no significant difference from parallel untreated control cultures was detected with any treatment (cell viability without treatment was taken as 100% and cell numbers were determined using MTS assay). FIG. 5 shows indirect immunofluorescence Laminin α4 and β1 staining of antisense-treated co-cultures; co-cultures of M059K or U-87MG with HBMVEC treated with sense oligos to laminin α4 and β1 chains for 5 days, and the patterns of laminin chain expression are similar to untreated cultures (upper row, cf. FIG. 3), whereas treatment with antisense oligos to either laminin α4 (antisense α4) or laminin β1 (antisense β1) chain partially inhibits both α4 and β1 chain expression (middle rows); finally, treatment with antisense oligos for both chains (antisense α4+β1) abolishes staining (lower row). FIG. 6 shows Western blot analysis of laminin-8 α4 and β1 chains in conditioned media of co-cultured M059K and HBMVEC cells where incubation with Morpholino sense and antisense oligos was for 3 or 6 days. FIG. 6A, a 200-kDa band corresponding to laminin α4 chain in co-culture on days 3 and 6, and the amount of immunoreactive α4 laminin was diminished by antisense oligos to either α4 or β1 or, especially, α4+β1. FIG. 6B, a 230-kDa band corresponding to laminin β1 chain in co-cultures on days 3 and 6, and the combination of antisense oligos (α4+β1) was efficient in decreasing the amount of immunoreactive β1 chain band at both time points. FIGS. 6C and 6D, Western blots of fibronectin (240 kDa band) on day 6 after stripping the respective membranes from α4 and β1 chain detection and reprobing them for fibronectin (these lanes are shown for loading control purpose), and only human (but not serum) fibronectin was detected by this antibody: Lane 1, sense oligos for α4+β1 chains; Lane 2, antisense oligo for α4 chain; Lane 3, antisense oligo for β1 chain; Lane 4, antisense oligos for α4+β1 chains. FIG. 7 shows measurement of invasion in co-cultures after antisense treatment using the Matrigel invasion assay which demonstrates a significant decrease in the fraction of cells that invaded through Matrigel in antisense-treated cultures (an even more pronounced effect is seen with a combination of antisense oligos; similar results were obtained with M059K and U-87MG glioma cell lines; *, p<0.04; **, p<0.001 by ANOVA with invasion in sense-treated cultures was taken as 100%). DETAILED DESCRIPTION OF THE INVENTION Since laminin-8 appears to be associated with GBM recurrence in vivo, we hypothesized that it might play a role in tumor invasion. Because of the complexity of in vivo experiments, we first explored this possibility in vitro using single cultures and co-cultures of brain microvascular endothelial cells, normal fetal brain astrocytes and several GBMs. We sought to analyze whether the patterns of laminin chain expression in cell culture would be similar to those seen in normal brain and in gliomas, and whether inhibition of laminin-8 expression by an antisense approach would alter glioma invasiveness through a reconstituted BM (Matrigel). Antisense oligonucleotides (oligos) that bind and inactivate specific RNA sequences may be the best tools for studying gene function, regulation of gene expression, and interactions between gene products. Highly specific anfisense oligos that mimic the DNA template for RNA production are used to bind to the complementary RNA and to prevent protein translation [17,18]. Antisense oligos are the fastest, simplest and most cost effective tools for testing new therapeutic targets for drug development. The antisense approach was used in our present study to inhibit the expression of laminin-8 in cell culture. Our results show that normal cultured astrocytes and endothelial cells mostly express laminin-9 as seen in normal brain tissue. Glioma cells predominantly express laminin-8, again similar to the in vivo situation. Most importantly, antisense blocking of laminin-8 chain expression resulted in the inhibition of glioma invasion through Matrigel. These data show that laminin-8 is an important for glioma invasion and an effective target for antitumor therapy. That is, the differences in laminin-8 chain expression are not merely indicators of the malignant cells but are actually linked to invasiveness of the malignancy. Co-Culture of Gliomas, Astrocytes and Brain Endothelial Cell Lines. Two types of human GBM cell lines (M059K and U-87MG; from ATCC, Rockville, MD), a normal human brain microvascular endothelial cell line (HBMVEC, obtained from Dr. Ken Samoto, Japan), and normal human fetal brain astrocytes HAST 040 (from Clonexpress, Inc., Gaithersburg, Md.) were used. U-87MG cells were cultured in Eagle's MEM with 10% fetal calf serum (FCS), L-glutamine, sodium bicarbonate, non-essential amino acids, antibiotics, and sodium pyruvate. M059K cell line was maintained in DMEM/F12 medium, FCS, supplements and antibiotics as above. The HAST 040 cell line was cultured in 50:50 DMEM/F12 supplemented with 5% FCS and antibiotics (25 μg/ml of gentamycin and 2.5 μg/ml of fungizone) during regular maintenance of astrocytes. The medium was replaced with fresh medium every third day to maintain optimal growth. HBMVEC were cultured in RPMI 1640 medium with 10% FCS, 10% NU-serum, sodium pyruvate, L-glutamine, non-essential amino acids, and antibiotics. Cell lines were maintained at 37° C. in a humidified 5% CO2 incubator and subcultured with trypsin-EDTA every 3-4 days. Cell lines were co-cultured at a ratio glioma:endothelium of 5:1 in 4-well chambers and examined at different time points (24 h, 3 days, 5 days). Co-cultures of normal human astrocytes HAST 040 and HBMVEC cells were cultured at the same ratio of 5:1 in 4-well chambers and examined at different time points (24 h, 3 days, 5 days). Antisense Treatment of Glioma-Endothelial Co-Cultures. Morpholinom™ (phosphorodiamidate morpholino oligomer) oligos custom made by Gene Tools, Inc. (St. Louis, Mo.) for laminin α□ and β1 chains were as follows: α4 antisense 5′AGCTCAAAGCCATTTCTCCGCTGAC3′, α4 sense 5′GTCAGCGGAGAAATGGCTTTGAGCT3′; β1 antisense 5′CTAGCAACTGGAGAAGCCCCATGCC3′; β1 sense 5′GGCATGGGGCTTCTCCAGTTGCTAG3′. Gene Tools protocol was used according to company recommendations. The new Special Delivery Formulation consisted of a pre-paired duplex of Morpholino oligo and partially complementary DNA oligo, together with a weakly basic delivery reagent, ethoxylated polyethylenimine (EPEI). Morpholino oligos are stable and totally nuclease-resistant so there is no need for re-delivery. Co-cultures of glioma cells with normal brain endothelium were treated with anti-sense oligos to laminin-8 chains, α4 and β1, for select time intervals (3 and 6 days), alone or in combination. To make the delivery mixture, 0.5 mM antisense α4 or β1 laminin chain or 0.5 mM sense oligos (negative control) Morpholino/DNA stock solution (Gene Tools) were added to H2O and mixed. Two hundred μM EPEI Special Delivery solution was added, vortexed and incubated at room temperature for 20 min. to generate the complete delivery solution. Medium was removed from a 24-hr co-culture and the solution with a specific oligo in fresh medium was added to cells, and placed into a CO2 incubator. After 3 hrs, delivery solution was aspirated and replaced with fresh serum-containing medium. Medium was changed every 2 days. Each oligo was assessed at 4 incubation time points: 2, 4, 6 and 8 days (co-culture time being 3, 5, 7, and 9 days, respectively). Another set of controls included endothelial or glioma cells alone. Immunohistochemistry. Cells were incubated in culture with or without Morpholino and at select time periods were fixed with 4% paraformaldehyde, permeabilized with 0.2% Triton X-100, and immunostained for laminin chains and endothelial cell markers. These markers included von Willebrand factor (Sigma Chemical Co., St. Louis, Mo.), CD31 (clone HC1/6, Cymbus Biotechnology/Chemicon International, Temecula, Calif., and clone JC70A, Dako, Carpinteria, Calif.), CD34 (clone QBEnd 10, Dako), and CD105 (clone P3D1, Chemicon). Uptake of Alexa Fluor 488-labeled acetylated low-density lipoprotein (Ac-LDL, Molecular Probes, Eugene, Oreg.) was also used to identify endothelial cells. Briefly, cells were incubated for 24 hr in medium with 5 μg/ml labeled Ac-LDL, then washed, fixed and permeabilized. Cells were then counterstained with 10 ng/ml 4′,6-diamidino-2-phenylindole (DAPI, Sigma) to visualize nuclei and additionally immunostained for select laminin chains. Primary monoclonal (mAb) and polyclonal (pAb) antibodies were used to the α4 laminin chain (mAb FC10 [19], and pAb 377 [5]), β1 laminin chain (mAb LT3; Upstate Biotechnology, Lake Placid, N.Y.), and β2 laminin chain (mAb C4 obtained from the Developmental Studies Hybridoma Bank, Department of Biology, University of Iowa, Iowa City, Iowa). Western Blot Analysis. Serum-free conditioned medium was obtained from the same number of cells in the same volume of medium from the co-cultures that were cultured for the same period of time. Conditioned media from co-cultures were concentrated 10-fold by filtering through Centriplus filtration devices (Millipore, Bedford, Mass.) and proteins were separated using 3-8% gradient Tris-acetate SDS-PAGE (Invitrogen, Carlsbad, Calif.) under reducing conditions. Lysates of human glioma T98G, known to express laminin-8 [15], were used as a positive control. The gels were blotted onto nitrocellulose membrane (Invitrogen, Carlsbad, Calif.). The membranes were probed with mAbs followed by chemiluminescent detection using the Immune-Star kit with alkaline phosphatase-conjugated secondary antibodies (Bio-Rad, Hercules, Calif.). Antibodies were used to the laminin α4 chain (mAb 8B12 [15]) and β1 chain (mAb LT3). Antibody to fibronectin 8th type III repeat (mAb 568 [20]) was used to control for equal loading of gel lanes. Cell Viability Assay. Cell numbers were measured with the CellTiter 96® AQueous One Solution Cell Proliferation Assay kit (Promega, Madison, Wis.). It was designed for the determination of the number of viable cells using MTS dye [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt]. According to the manufacturer's instructions, a small amount of the CellTiter 96® AQueous One Solution Reagent was added directly to culture wells, and after 3 hours of incubation the absorbance at 490 nm was recorded using an ELISA reader, Spectra Max Plus 384 (Molecular Devices, Sunnyvale, Calif.). The quantity of formazan product as measured by the amount of 490 nm absorbance is directly proportional to the number of living cells in culture. All cell lines were treated exactly as described above in the section “Antisense Treatment of Glioma-Endothelial Co-Cultures”. For viability assay, cells were incubated after treatment with Morpholino sense and antisense oligos and/or delivery factor for three days, the average time point that was used in our experiments. Each experiment was performed in triplicate and was repeated twice. In Vitro Invasion Assay. Invasion studies were conducted using the Matrigel™ BM matrix assay developed for quantitative measurement of tumor cell invasiveness. Most tested cells characterized as invasive and metastatic in vivo are able to invade Matrigel in vitro [21,22,23]. We used BioCoat™ Matrigel™ invasion chambers (12-well cell culture inserts containing an 8.0 μm PET membrane with a uniform layer of Matrigel, from Becton Dickinson, Bedford, Mass.). The coated filters were rehydrated with warm serum-free DMEM (2 ml per chamber). The upper chamber was filled with 2.5×104 cells in serum-free medium. The lower chamber was filled with DMEM containing 5% FCS as a chemoattractant towards which the cells migrate. The chambers were incubated for 22 h at 37° C. in a 5% CO2 atmosphere. Cells from the upper surface of the filters were removed by scrubbing with a cotton swab and those migrating to the lower surface of the filters were fixed and stained with hematoxylin and eosin. The number of cells that penetrated the filter was counted in 10 microscopic fields of each filter under ×200 magnification in both experimental and special control membranes using a Zeiss Axiophot microscope connected to an image processing and measuring system (Hamamatsu, Japan). Percent invasion is expressed as mean cell number from invasion chamber to mean cell number from control chamber according to the manufacturer's recommendation. Assays were carried out in triplicates. Four independent experiments were performed for each type of co-culture with each treatment. Statistical analysis. The data from the cell viability assay and invasion experiments were statistically evaluated by ANOVA test using GraphPad Prism 3 software program (GraphPad Software, San Diego, Calif.). P<0.05 was considered significant. Immunohistochemistry of Endothelial Markers and Laminin Chain Expression in Untreated Cultures. Several endothelial markers were tested in order to select the best one, which might be used to reliably differentiate endothelial cells from normal and malignant astrocytes in co-cultures. In preliminary experiments, fluorescent Ac-LDL consistently labeled endothelial cells [24] much more uniformly than did antibodies against von Willebrand factor, CD31, CD34 or CD105. Uptake of fluorescent Ac-LDL was, therefore, used to identify endothelial cells in subsequent experiments with co-cultures. In pure endothelial cultures, most if not all cells displayed predominantly punctate fluorescence with a perinuclear distribution (FIG. 1). Cultures of normal astrocytes and glioma cell lines were largely negative (FIG. 1), although some cells showed low background fluorescence. Ac-LDL uptake allowed identifying positive endothelial cells in co-cultures as well (FIG. 1). Cultures were then immunostained for chains of laminin-8 and laminin-9. In accordance with the in vivo situation, cultured normal endothelial cells stained positive for α4 and β2 chains, compatible with the presence of laminin-9 (FIG. 2A). At the same time, staining for laminin-8 β1 chain was mostly negative (FIG. 2A). Normal fetal astrocytes did not appreciably stain for any tested laminin chain (FIG. 2A). In contrast, glioma U-87MG (not shown) and M059K cells were positive for laminin-8 α4 and β1 chains but largely negative for laminin-9 β2 chain (FIG. 2A). These results were fully confirmed by Western blot analysis of conditioned media from cultures with equal protein loading (FIG. 2B). In co-cultures of normal astrocytes and HBMVEC, mostly α4 and β2 chains could be seen, with very little β1 chain expression (FIG. 3). However, in co-cultures of glioma cells with HBMVEC, α4 and β1 chains were predominantly expressed (FIG. 3). An important finding was that HBMVEC, when co-cultured with malignant astrocytes, started expressing laminin β1 chain, in contrast with its absence in endothelial cells alone or in co-culture with normal astrocytes (FIG. 3). These data show that co-cultures of normal astrocytes and endothelial cells mostly expressed laminin-9 in accordance with our previous in vivo results [5]. Furthermore, similar to the in vivo situation, glioma cells alone and in co-cultures with endothelial cells mostly expressed laminin-8. Therefore, the established co-culture system resembled the situation in vivo in both a normal and a tumor brain environment. The laminin expression data thus strongly support the hypothesis that glioma-endothelial co-cultures is a valid model to study further the inhibition of expression of laminin-8 as a new glioma marker associated with tumor progression and recurrence development. Cell Viability Assay. In order to test the potential toxicity of sense and antisense Morpholino oligos and the delivery factor EPEI, cell viability was measured using MTS-based CellTiter 96 assay. The relative numbers of viable cells of three cell lines U-87MG, M059K and HBMVEC, which had been treated with oligos and/or delivery factor, were compared with cell numbers of replicate cultures of corresponding cell lines without any treatment (taken as 100%). Cell viability for each cell line after oligo treatment in two separate experiments was higher than 90% (FIG. 4). This did not differ significantly from untreated controls (p>0.05). Based on these data we conclude that Morpholinos oligos and/or delivery factor did not exert any significant toxic effect on any of the cell lines. Immunohistochemistry of Laminin Chain Expression in Antisense-Treated Cultures. Since glioma-endothelial co-cultures mostly expressed α4 and β1 chains of laminin-8 (but not laminin-9 β2 chain), antisense oligos were used only to block laminin-8 expression. Treatment with α4 antisense resulted in markedly decreased staining for this chain and a reduction of staining for the β1 chain (FIG. 5). A similar result was seen with β1 antisense treatment, compatible with the role of this chain in laminin trimer assembly. As shown in the lower row in FIG. 5, a combination of the two oligos dramatically reduced staining for α4 and β1 chains at all time points. Western Blot Analysis of Pure Cultures and Co-Cultures. In lysates of cultures and co-cultured cells, the signals for laminin α4 and β1 chains were very weak and detectable only on days 5-7 of culture or co-culture (data not shown). Therefore, the amounts of these chains were further analyzed in conditioned media after their substantial and equal fold concentration and normalization by total protein and fibronectin content. As shown in FIG. 6, both α4 and β1 chains could be detected in sense-treated cultures at days 3-6, as well as in a positive control (T98G glioma cell lysate [15]). Antisense treatment of either chain resulted in a decreased signal for both chains. Again, maximum inhibition for both chains was achieved by a combined α4+β1 antisense treatment in a concentration of 0.25 mM for each oligo (FIG. 6B). These results were in complete agreement with cell immunostaining data. FIGS. 6C and 6D show reprobing of the membranes to detect fibronectin. Only human fibronectin was detected. T98G, cell lysate of a laminin-8 expressing GBM cell line T98G, used as positive control. Very similar results were obtained using co-culture of HBMVEC with cells another glioma line, U-87MG (data not shown). Matrigel Invasion Assay. Matrigel invasion assay was used to study the influence of antisense oligos to α4 and β1 chains of laminin-8 on the invasive parameters of co-cultures. Corresponding sense oligos were used in control chambers. Another set of controls included endothelial or glioma cells alone. Two glioma cell lines, U-87MG and M059K, alone had, respectively, 91% and 76% of invasion potential with or without treatment with either single or combined sense oligos against α4 and β1 chains. HMBVEC cells demonstrated only 11% invasion. Each experiment was repeated three times in triplicate. In the next set of experiments, co-cultures of glioma and endothelial cells were treated for three days with α4 and β1 antisense oligonucleotides, alone or in combination. Each antisense used in this study significantly inhibited invasion of two different co-culture types (FIG. 7). In this study, 842 microscopic fields with a total of 64,276 cells were evaluated. Specific endothelial staining has demonstrated that both endothelial and glioma cells migrated through Matrigel, with clear prevalence of glioma cells (data not shown). Co-cultures treated with sense oligos to the α4 and β1 chains of laminin-8 were considered as controls equal to 100%. When co-cultures were treated with α4 antisense oligo, invasion was blocked by 40% for U-87MG (FIG. 7 right; p<0.02 vs. control) and by 41% for M059K (FIG. 7 left; p<0.03) cell lines compared to cultures treated with sense oligos (taken as 100%). β1 antisense oligo also blocked the invasion by 40% for U-87MG (p<0.04) and by about 47% for M059K (p<0.001) co-cultures. When co-cultures were treated with both antisense oligos against α4 and β1 chains, invasion was reduced on average by 62% for U-87MG (p=0.0005) and by 53% for M059K (p<0.0001) co-cultures. In two of five experiments, the inhibition exceeded 75% (not shown here). A combination of α4+β1 antisense was more efficient at blocking laminin expression than α4 or β1 antisense in U-87MG cells and almost equal to β1 antisense in M059K cells. Interestingly, α4 and β1 chain expression was inhibited more efficiently with lower concentrations of antisense oligos (0.25+0.25 mM) than with higher ones (0.5+0.5 mM). This shows that careful optimization of Morpholino oligo concentrations is important for in vitro and in vivo studies. It is also important to emphasize the fact that only living cells can penetrate the Matrigel in the invasion assay. Discussion This is the first study to examine the role of laminin-8 in human tumor cell invasion using antisense inhibitors that block synthesis of this complex trimeric protein. We showed that normal brain endothelial cells expressed small amounts of laminin-9 chains, α4 and β2. The expression of laminin-8 chain, β1, however, was not detected. Normal astrocytes did not express any of these chains. This in vitro system is similar to in vivo normal brain, where there was a low expression of predominantly laminin-9 [5]. At the same time, glioma cells expressed chains of laminin-8 in culture in accordance with our previous in vivo data [5]. Moreover, in co-cultures with glioma cells, brain endothelial cells also started expressing laminin β1 chain (compatible with laminin-8 production) in agreement with the finding of laminin-8 overexpression in GBM in vivo (FIG. 3). These data clearly show that normal and tumor in vivo patterns of α4 chain-containing laminin isoform expression were retained in the culture setting. Therefore, we were able to validate the respective co-cultures for the patterns of laminin chain expression as a system similar to that observed in vivo, both in normal brain tissue and during glioma growth. In combination with several new well-characterized proteins associated with glioma progression, such as tenascin-C, MMP-2 and MMP-9, [5, 12, 25-29], laminin-8 is an important tool for potential diagnosis or treatment of gliomas. Previously, only laminin-5 was shown to play a role in melanoma invasion [30]. Our present data show that “vascular” laminin-8 also plays a significant role in glioma cell invasiveness. Since matrix-degrading proteinases are also important for glioma invasion [31], future research should explore whether proteolysis of laminin is required for glioma invasion. To probe the role of laminin-8 in glioma invasion, we used antisense oligos to block its expression. The potential of antisense is widely recognized, but it remained largely unfulfilled since, until recently, the available oligos suffered from poor specificity, instability, and undesirable non-antisense effects [32,33]. These problems have been largely solved by the new generation of antisense oligos that offer the promise of safe and effective therapeutics for various diseases including cancer [33,34]. The most promising types of oligos are Morpholino and peptide nucleic acid (PNA; they have nucleobases attached to a neutral “peptide-like” backbone) oligos [32,34]. Morpholino oligos function independently of RNase H and are soluble in aqueous solutions. They work well in the presence or absence of serum, are totally resistant to nucleases, and remain intact in culture medium and in cells indefinitely. Morpholino oligos have a high affinity for RNA and efficiently invade even quite stable secondary structures in mRNAs. They have the highest sequence specificity of all antisense types over a very broad concentration range and appear to be free of non-antisense effects [34,35]. They have high activity in a cell-free translation system and can block target protein production in cultured cells [36]. Morpholino are also effective in vivo [37]. Given these properties, Morpholino oligos have been chosen here to inhibit the expression of laminin-8 chains. Special experiments have demonstrated that Morpholino treatment did not affect the viability of any cell line used. Recently, promising data on the use of antisense technology in glioma cells were obtained. The blocking of matrix metalloproteinase-9 reduced the invasiveness of glioma cells in vitr [31,38]. Glioma growth in vitro and in vivo (as xenotransplants in nude mice) could be inhibited by antisense to telomerase [39]. A recent pilot study showed that antisense to the IGF-I receptor induced glioma cell apoptosis and resulted in clinical improvement in patients [40]. Several clinical trials are currently using antisense oligos for the treatment of other cancers [41]. To examine the involvement of laminin-8 in glioma invasion, we needed reliable systems where it was possible to quantify invasion rates and to optimize the dosage of antisense laminin oligos. We used a cell culture system to meet these important needs. One could potentially use glioma cultures. To better mimic the in vivo situation, however, and because laminin-8 seems to be produced by both glioma and endothelial cells [15, FIG. 3], we needed to combine glioma cells with brain endothelium in a co-culture [44]. In such a situation, endothelial cells can develop capillary-like structures, and this process is faster when endothelial cells are cultured with tumor astrocytes than with normal embryonic brain astrocytes [45]. We hypothesized that in glioma-endothelium co-cultures there would be more laminin-8 βroduced, and that this laminin might increase glioma invasion in a Matrigel assay. Research into these issues should facilitate both GBM diagnosis and prognosis, and increase survival of brain cancer patients. Matrigel invasion assay was developed for quantitative measurement of the invasiveness of tumor cells through a BM matrix. Most tested cells characterized as invasive and metastatic in vivo are able in vitro to invade Matrigel, which is a BM-like material from the mouse Engelbreth-Holm-Swarm tumor [21,22]. When glioma-endothelial co-cultures were treated by antisense, the inhibition of invasiveness on Matrigel was 62% for U-87MG+HBMVEC and 53% for M059K+HBMVEC of that seen in the control cells treated with corresponding sense oligonucleotides. In our experiments, α4 and β1 expression was inhibited more efficiently with a lower concentration of antisense oligos (0.25+0.25 mM) than with a higher concentration (0.5+0.5 mM), although no apparent toxicity was noticed at either concentration. These data may be explained by previous findings, where oligonucleotide receptors on membranes of HepG2 cells were blocked. It was shown that at relatively high oligonucleotide concentrations, these receptors were saturated and the pinocytotic process assumed larger importance [46]. A similar mechanism may occur in our system, which would explain the obtained results. The use of antisense technology offers an effective future tumor treatment because of its efficiency, specificity and ease of delivery to tumor cells [42,43]. This technology is being continuously developed and refined not only for the drug validation and diagnostic purposes but also for the development of future treatments. The present results demonstrate the effectiveness of antisense approach using laminin-8 as a target for treatment of brain gliomas. Reduction of tumor invasion by antisense to laminin-8 slows the growth and spread of aggressive GBMs. In combination with other treatment methods or with blocking of other targets as well (EGFR, MMPs) it prolongs disease-free periods and increases survival of glioma patients. Laminin-8 blocking for therapeutic purposes may also include the use of specific monoclonal antibodies and/or small interfering RNA (siRNA) and or other drugs specific to Laminin-8 production. It remains to be established how laminin-8 promotes glioma invasiveness. One possible mechanism may be stimulation of cell migration. It was previously shown that at least one form of laminin-8 containing α4A splice variant rather weakly supported cell adhesion and spreading compared to laminin-5 or laminin 10/11 [15, 47]. At the same time, laminin-8 stimulated cell migration better than several other laminin isoforms [15]. Increased expression of laminin-8 in both glioma cells and glioma-adjacent capillary endothelial cells [5, 15, this report] may reduce glial cell adhesion and enhance migration, which is necessary for local tumor invasiveness. Many alterations and modifications may be made by those having ordinary skill in the art. Therefore, it must be understood that the illustrated embodiment has been set forth only for the purposes of example and that it should not be taken as limiting the invention as defined by the following claims. The words used in this specification to describe the invention and its various embodiments are to be understood not only in the sense of their commonly defined meanings, but to include by special definition in this specification structure, material or acts beyond the scope of the commonly defined meanings. Thus if an element can be understood in the context of this specification as including more than one meaning, then its use in a claim must be understood as being generic to all possible meanings supported by the specification and by the word itself. In addition to the equivalents of the claimed elements, obvious substitutions now or later known to one with ordinary skill in the art are defined to be within the scope of the defined elements. The claims are thus to be understood to include what is specifically illustrated and described above, what is conceptually equivalent, and what can be obviously substituted. REFERENCES 1. American Cancer Society: Brain and Spinal Cord Tumors in Adults (2003). 2. Shapiro W R, Shapiro J R. Biology and treatment of malignant glioma. Oncology, 12: 233-240, 1998. 3. Kaye A H, Laws E R. (eds). Brain Tumors, pp. 990. Churchill Livingstone, 1997. 4. Ljubimova J Y, Khazenzon N M, Chen Z, Neyman Y I, Turner L, Riedinger M S, Black K L. Gene array analysis of differentially expressed genes in human glial tumors. Int J Oncol, 18: 287-295, 2001. 5. Ljubimova J Y, Lakhter A J, Loksh A,Yong W H, Riedinger M S, Miner J H, Sorokin M L, Ljubimov A V, Black K L. Overexpression of α4 chain-containing laminins in human glial tumors identified by gene microarray analysis. Cancer Res, 61: 5601-5610, 2001. 6. Sehgal A. Molecular changes during the genesis of human gliomas. Seminars Surg Oncol, 14: 3-12, 1998. 7. Lal A, Lash A E, Altschul S F, Velculescu V, Zhang L, McLendon R E, Marra M A. Prange C, Morin P J, Polyak K, Papadopoulos N, Vogelstein B, Kinzler K W, Strausberg R L, Riggins G J. A public database for gene expression in human cancers. Cancer Res, 59: 5403-5407, 1999. 8. Miner J H, Patton B L, Lentz S I, Gilbert D J, Snider W D, Jenkins N A, Copeland N G, Sanes J R. The laminin alpha chains: expression, developmental transitions, and chromosomal locations of α1-5, identification of heterotrimeric laminins 8-11, and doning of a novel α3 isoform. J Cell Biol, 137: 685-701, 1997. 9. Colognato H, Yurchenco P D. Form and function: The laminin family of heterotrimers. Dev Dyn, 218: 213-234, 2000. 10. Patarroyo M, Tryggvason K, Virtanen I. Laminin isoforms in tumor invasion, angiogenesis and metastasis. Semin Cancer Biol, 12: 197-207, 2002. 11. Belkin A M, Stepp M A. Integrins as receptors for laminins. Microsc Res Tech, 51: 280-301, 2000. 12. Kulla A, Liigant A, Piirsoo A, Rippin G. Asser T. Tenascin expression patterns and cells of monocyte lineage: relationship in human gliomas. Mod Pathol, 13: 56-67, 2000. 13. Sixt M, Engelhardt B, Pausch F, Hallmann R, Wendler 0, Sorokin L M. Endothelial cell laminin isoforms, laminins 8 and 10. βlay decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol, 153: 933-946, 2001. 14. Thyboll J, Kortesmaa J, Cao R, Soininen R, Wang L, livanainen A, Sorokin L, Risling M, Cao Y, Tryggvason K. Deletion of the laminin α4 chain leads to impaired microvessel maturation. Mol Cell Biol, 22:1194-1202, 2002. 15. Fujiwara H, Kikkawa Y, Sanzen N. Sekiguchi K. Purification and characterization of human laminin-8. Laminin-8 stimulates cell adhesion and migration through α3β1 and α6β1 integrins. J Biol Chem, 276: 17550-17558, 2001. 16. Gonzalez A M, Gonzales M, Herron G S, Nagavarapu U, Hopkinson S B, Tsuruta D, Jones J C. Complex interactions between the laminin α4 subunit and integrins regulate endothelial cell behavior in vitro and angiogenesis in vivo. Proc Natl Acad Sci USA, 99: 16075-16080, 2002. 17. Astriab-Fisher A, Sergueev D S, Fisher M, Shaw B R, Juliano R L. Antisense inhibition of P-glycoprotein expression using peptide-oligonucleotde conjugates. Biochem Pharmacol, 60: 83-90, 2000. 18. McKean D M, Sisbarro L, llic D, Kaplan-Alburquerque N, Nemenoff R, Weiser-Evans M, Kern M J, Jones P L. FAK induces expression of Prx1 to promote tenascin-C-dependent fibroblast migration. J Cell Biol, 161: 393-402, 2003. 19. Petäjäniemi N, Korhonen M, Kortesmaa J. Tryggvason K, Sekiguchi K, Fujiwara H, Sorokin L, Thomell L E, Wondimu Z, Assefa D, Patarroyo M, Virtanen I. Localization of laminin α4-chain in developing and adult human tissues. J Histochem Cytochem, 50: 1113-1130, 2002. 20. Ljubimov A V, Burgeson R E, Butkowski R J, Michael A F, Sun T T, Kenney M C. Human comeal basement membrane heterogeneity: Topographical differences in the expression of type IV collagen and laminin isoforms. Lab Invest, 72: 461473, 1995. 21. Albini A, Iwamoto Y. Aaronson S A, Kozlowski J M, McEwan R N. A rapid in vitro assay for quantitabng the invasive potential of tumor cells. Cancer Res, 47: 3239-3245, 1987. 22. Kleinman H K, McGarvey M L, Hassell J R, Star V L, Gannon F B, Laurie G W, Martin G R. Basement membrane complexes with biological activity. Biochemistry, 25: 312-318, 1986. 23. Minakawa T, Bready J, Berliner J, Fisher M, Cancilla P A. In vitro interaction of astrocytes and pericytes with capillary-like structures of brain microvessel endothelium. Lab Invest, 65: 32-40, 1991. 24. Voyta J, Via D, Butterfield E, Zetter B. Identification and isolation of endothelial cells based on their increased uptake of acetylated-low density lipoprotein. J Cell Biol, 99: 2034-2040, 1984. 25. Herold-Mende C, Mueller M M, Bonsanto M M, Schmitt H P, Kunze S, Steiner H H. Clinical impact and functional aspects of tenascin-C expression during glioma progression. Int J Cancer, 98: 362-369, 2002. 26. Zagzag D, Capo V. Angiogenesis in the central nervous system: a role for vascular endothelial growth factor/vascular permeability factor and tenascin-C. Common molecular effectors in cerebral neoplastic and non-neoplastic “angiogenic diseases”. Histol Histopathol, 17: 301-321, 2002. 27. Qin H, Sun Y, Benveniste E N. The transcription factors Sp1, Sp3, and AP-2 are required for constitutive matrix metalloproteinase-2 gene expression in astroglioma cells. J Biol Chem, 274: 29130-29137, 1999. 28. Kachra Z, Beaulieu E, Delbecchi L, Mousseau N, Berthelet F, Moumdjian R, Del Maestro R, Beliveau R. Expression of matrix metalloproteinases and their inhibitors in human brain tumors. Clin Exp Metastasis, 17: 555-566, 1999. 29. MacDonald T J, DeClerck Y A, Laug W E. Urokinase induces receptor mediated brain tumor cell migration and invasion. J Neurooncol, 40: 215-226,1998. 30. Tsuj T, Kawada Y, Kai-Murozono M, Komatsu S, Han S A, Takeuchi K, Mizushima H, Miyazaki K, Irimura T. Regulation of melanoma cell migration and invasion by laminin-5 and α3β1 integrin (VLA-3). Clin Exp Metastasis, 19:127-134, 2002. 31. Kondraganfi S. Mohanam S, Chintala S K, Kin Y, Jasfi S L, Nirmala C, Lakka S S, Adachi Y, Kyritsis A P, Ali-Osman F. Sawaya R, Fuller G N, Rao J S. Selective suppression of matrix metalloproteinase-9 in human glioblastoma cells by antisense gene transfer impairs glioblastoma cell invasion. Cancer Res, 60: 6851-6855, 2000. 32. Nielsen P E. Peptide nucleic acid targeting of double-stranded DNA. Methods Enzymol, 340: 329-340, 2001. 33. Dias N, Stein C A. Antisense oligonucleotides: basic concepts and mechanisms. Mol Cancer Ther, 1: 347-355, 2002. 34. Summerton J, Weller D. Morpholino antisense oligomers: Design, preparation and properties. Antsense Nucleic Acid Drug Dev, 7: 187-195, 1997. 35. Lacerra G, Sierakowska H, Carestia C, Fucharoen S, Summerton J, Weller D, Kole R. Restoration of hemoglobin A synthesis in erythroid cells from peripheral blood of thalassemic patients. Proc Natl Acad Sci USA, 97 :9591-9596, 2000. 36. Taylor M F, Paulauskis J D, Weller D D, Kobzik L. Comparison of efficacy of antisense oligomers directed toward TNF-α in helper T and-macrophage cell lines. Cytokine, 9: 672-681, 1997. 37. Arora V, Knapp D C, Smith B L, Statdfield M L, Stein D A, Reddy M T, Weller D D, Iversen P L. c-Myc antsense limits rat liver regeneration and indicates role for c-myc in regulating cytochrome P-450 3A activity. J Pharmacol Exp Ther, 292: 921-928, 2000. 38. Bello L, Ludni V, Carrabba G, Giussani C, Machluf M, Pluderi M, Nikas D, Zhang J, Tomei G, Villani R M, Carroll R S, Bikfalvi A, Black P M. Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2. Cancer Res, 61: 8730-6, 2001. 39. Komata T, Kondo Y, Koga S, Ko S C, Chung L W, Kondo S. Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53. Gene Ther, 7: 2071-2079, 2000. 40. Andrews D W, Resnicoff M, Flanders A E, Kenyon L, Curtis M, Merli G, Baserga R, Iliakis G, Aiken R D. Results of a pilot study involving the use of an antisense oligodeoxynucleoide directed against the insulin-like growth factor type I receptor in malignant astrocytomas. J Clin Oncol, 19: 2189-2200, 2001. 41. Jansen B. Wacheck V, Heere-Ress E, Schlagbauer-Wadl H, Hoeller C, Lucas T, Hoermann M, Hollenstein U, Wolff K, Pehamberger H. Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet, 356: 1728-1733, 2000. 42. Shi N, Boado R J, Pardridge W M. Antsense imaging of gene expression in the brain in vivo. Proc Natl Acad Sci USA, 97: 14709-14714, 2000. 43. Boado R J, Kazantsev A, Apostol B L, Thompson L M, Pardridge W M. Antisense-mediated down-regulation of the human huntingtin gene. J Pharmacol Exp Ther, 295: 239-243, 2000. 44. Minakawa T, Bready J, Berliner J, Fisher M, Cancilla P A. In vitro interaction of astrocytes and pericytes with capillary-like structures of brain microvessel endothelium. Lab Invest, 65: 32-40, 1991. 45. Knott J C, Mahesparan R. Garcia-Cabrera I, Bolge Tysnes B, Edvardsen K, Ness G O, Mork S, Lund-Johansen M, Bjerkvig R. Stimulabon of extracellular matrix components in the normal brain by invading glioma cells. Int J Cancer, 75: 864-872, 1998. 46. de Diesbach P, Berens C, N'Kuli F, Monsigny M, Sonveaux E, Wattiez R. Courtoy P J. Identification, purification and partial characterisation of an oligonucleotide receptor in membranes of HepG2 cells. Nucleic Acids Res, 15: 868-74, 2000. 47. Hayashi Y, Kim K H, Fujiwara H, Shimono C, Yamashita M, Sanzen N, Futaki S, Sekiguchi K. Identification and recombinant production of human laminin α4 subunit splice variants. Biochem Biophys Res Commun, 299: 498-504, 2002.

<SOH> INTRODUCTION <EOH>Glial tumors are the leading cause of cancer death in children [1]. Overall, they account for 1.4% of all cancers and 2.4% of all cancer deaths. Average survival time for low-grade astrocytoma or oligodendroglioma patients is 6 to 8 years. It decreases to 3 years for patients with anaplastic astrocytoma and drops to 12-18 months for glioblastoma multiforme (GBM). Currently, these tumors are treated by surgical removal, radiation therapy, chemotherapy or combinations of these treatments. The majority of GBMs is highly invasive and rapidly develops recurrences at the primary site. Tumor prognoses and responses to therapy can vary greatly even with the same histological diagnosis [2]. It is generally recognized that the improvement of prognosis, prediction of response to treatment, and development of novel effective therapeutic approaches for glial tumors may largely depend upon the introduction into clinical practice of novel specific markers involved in the development of different gliomas and their subsequent recurrences. Attempts have been made to establish and characterize a number of glioma markers, such as glial fibrillary acidic protein, vimentin, synaptophysin, and nestin. Determination of differential expression of these markers (immunophenotyping) in gliomas, however, has thus far not altered existing therapeutic approaches, treatment success rates, or disease outcome prediction [2, 3]. Researchers next sought to identify novel glioma markers using powerful gene array technology [4-7]. Recently, our group described a new molecular marker of glial tumors, laminin-8, that was differentially expressed in malignant tumors compared to benign tumors and normal brain tissues [5]. All laminins consist of three covalenfly linked chains, α, β and γ. To date, 15 members (isoforms) of this family that are present in different basement membranes (BMs) have been described [8-10]. Laminins interact with cells through various receptors. Most of these receptors belong to the family of integrin heterodimers, although other molecules including dystroglycan complex and Lutheran blood group glycoprotein have also been shown to bind to laminins. In different cell types, integrins α 1 β 1 , α 2 β 1 , α 3 β 1 , α 6 β 1 , α 6 β 4 and α 7 β 1 have been reported to have the capability to bind to laminins. Specific laminin isoforms bind some but not all of these different integrins, and each integrin can bind to more than one laminin isoform [10, 11]. Along with type IV collagens, nidogens and perlecan, glycoproteins of the laminin family are the major constituents of brain microvessel BMs [8, 12, 13]. These BMs have a complex structure and are produced by both endothelial and glial cells [13]. Endothelial cells contribute laminins containing α4 and α5 chains to these BMs, whereas glial cells synthesize laminins containing α1 and α2 chains [13]. In human brain capillary BMs we have recently observed a weak expression of the α4 chain-containing laminin-9. Interestingly, during progression of human gliomas, the expression of capillary BM laminins containing α4 chain switches from the predominant laminin-9 (α4β2γ1) to laminin-8 (α4β1γ1) [5]. Laminin-8 and its receptors, integrins α 3 β 1 and α 6 β 1 , appear to be important to the functioning of endothelial cell BMs, which play a role in the maintenance of the blood-brain barrier [14, 15]. Recently, the association of the laminin α4 chain with angiogenesis has been demonstrated in vivo and in vitro [16]. Some cultured glioma cell lines can also produce α4-containing laminins. Laminin-8 is thought to play a role in cell migration during development, wound healing, and angiogenesis [8, 10, 14].

<SOH> BRIEF DESCRIPTION OF THE FIGURES <EOH>FIG. 1 shows uptake of Ac-LDL by various cultures and co-cultures; endothelial cells (HBMVEC) are positive (green fluorescence) but glioma cells (M59K) and normal astrocytes (HAST 040) are negative; in co-cultures HBMVEC+M059K and HBMVEC+HAST040, endothelial cells are positive, whereas other cells are negative (DAPI was used to counterstain cell nuclei (blue fluorescence)). FIG. 2 shows Laminin α4, β1, and β2 chain expression in cells and conditioned media of pure cultures: FIG. 2A . Immunolocalization of laminin chains in cells where normal brain endothelium (HBMVEC) expresses α4 and β2 chains (consistent with laminin-9, α4β2γ1), whereas astrocytes (HAST 040) do not express these laminin chains; M059K glioma cells, however, express α4 and β1 chains consistent with laminin-8 (α4β1γ1). Indirect immunofluorescence. FIG. 2B . Western blot analysis of conditioned media shows that endothelial cells (HBMVEC) secrete chains of laminin-9 (α4 and β2), astrocytes (HAST 040) show little to no secretion of any studied chains, and M059K glioma cells secrete chains of laminin-8 (α4 and β1) (T98G, lysate of T98G glioma cells expressing laminin-8 chains only (α4 and β1) were used as positive control; equal amounts of conditioned media protein were applied to each lane. Note complete agreement between the results of immunostaining ( FIG. 2A ) and Western blotting ( FIG. 2B )). FIG. 3 shows the Laminin α4, β1, and β2 chain staining of co-cultures; live co-cultures were exposed to Ac-LDL (green color, to reveal endothelial cells) and then fixed and simultaneously stained for select laminin chains (red color) and nuclei (DAPI, blue color); in endothelial-astrocyte co-cultures (HBMVEC+HAST040) α4 and β2 chains are expressed in Ac-LDL-positive endothelial cells only but not in Ac-LDL-negative astrocytes (arrows); β1 chain is largely absent; in endothelial-glioma co-cultures (HBMVEC+M059K), α4 chain is expressed by both cell types and β2 chain, only by endothelial cells; significantly, β1 chain is expressed not only by Ac-LDL-negative glioma cells (arrowheads) but also by Ac-LDL-positive endothelial cells. FIG. 4 shows the Cell viability assay; viability of glioma cell lines M059K and U-87MG as well as of normal endothelial cell line HBMVEC after treatment with Morpholinos sense or antisense oligos and delivery factor is higher than 90%; no significant difference from parallel untreated control cultures was detected with any treatment (cell viability without treatment was taken as 100% and cell numbers were determined using MTS assay). FIG. 5 shows indirect immunofluorescence Laminin α4 and β1 staining of antisense-treated co-cultures; co-cultures of M059K or U-87MG with HBMVEC treated with sense oligos to laminin α4 and β1 chains for 5 days, and the patterns of laminin chain expression are similar to untreated cultures (upper row, cf. FIG. 3 ), whereas treatment with antisense oligos to either laminin α4 (antisense α4) or laminin β1 (antisense β1) chain partially inhibits both α4 and β1 chain expression (middle rows); finally, treatment with antisense oligos for both chains (antisense α4+β1) abolishes staining (lower row). FIG. 6 shows Western blot analysis of laminin-8 α4 and β1 chains in conditioned media of co-cultured M059K and HBMVEC cells where incubation with Morpholino sense and antisense oligos was for 3 or 6 days. FIG. 6A , a 200-kDa band corresponding to laminin α4 chain in co-culture on days 3 and 6, and the amount of immunoreactive α4 laminin was diminished by antisense oligos to either α4 or β1 or, especially, α4+β1. FIG. 6B , a 230-kDa band corresponding to laminin β1 chain in co-cultures on days 3 and 6, and the combination of antisense oligos (α4+β1) was efficient in decreasing the amount of immunoreactive β1 chain band at both time points. FIGS. 6C and 6D , Western blots of fibronectin (240 kDa band) on day 6 after stripping the respective membranes from α4 and β1 chain detection and reprobing them for fibronectin (these lanes are shown for loading control purpose), and only human (but not serum) fibronectin was detected by this antibody: Lane 1, sense oligos for α4+β1 chains; Lane 2, antisense oligo for α4 chain; Lane 3, antisense oligo for β1 chain; Lane 4, antisense oligos for α4+β1 chains. FIG. 7 shows measurement of invasion in co-cultures after antisense treatment using the Matrigel invasion assay which demonstrates a significant decrease in the fraction of cells that invaded through Matrigel in antisense-treated cultures (an even more pronounced effect is seen with a combination of antisense oligos; similar results were obtained with M059K and U-87MG glioma cell lines; *, p<0.04; **, p<0.001 by ANOVA with invasion in sense-treated cultures was taken as 100%). detailed-description description="Detailed Description" end="lead"?

20070130

20090616

20070510

96357.0

A61K4800

GIBBS, TERRA C

ANTISENSE INHIBITION OF LAMININ-8 EXPRESSION TO INHIBIT HUMAN GLIOMAS

SMALL

ACCEPTED

A61K

ACCEPTED

Stethoscope apparatus

[Object]To provide a stethoscope apparatus that can contribute to medical cares that can eliminate anxieties of a patient as much as possible. [Means for Solving]A stethoscope apparatus 10 according to the embodiment integrally mounts a speaker 9 and a microphone 8; accordingly, the speaker 9 can reproduce sounds obtained with the microphone 8. For instance, when a physician explains the pathology and so on to a patient with the patient allowed hearing sounds from a speaker, the patient can be diagnosed at ease more than ever.

1. A stethoscope apparatus, comprising: a microphone; a speaker that outputs a sound in accordance with an electrical signal generated by the microphone; and a housing that integrally mounts the microphone and speaker. 2. The stethoscope apparatus, as set forth in claim 1, further comprising: a diaphragm capable of vibrating supported by the housing. 3. The stethoscope apparatus as set forth in claim 1, wherein the housing has: a first housing on which the microphone is mounted; a second housing on which the speaker is mounted; and an adjusting mechanism capable of adjusting an angle of the second housing to the first housing. 4. The stethoscope apparatus as set forth in claim 3, wherein the adjusting mechanism has a uniaxial hinge mechanism. 5. The stethoscope apparatus as set forth in claim 4, wherein the first housing has a contact portion that is brought into contact with a patient; and wherein the contact portion and the speaker, respectively, are disposed to the first and second housings so that the speaker outputs the sound to an opposite side of the contact portion when the first and second housings are closed with the hinge mechanism. 6. The stethoscope apparatus as set forth in claim 3, wherein in the adjusting mechanism is a universal joint. 7. The stethoscope apparatus as set forth in claim 1, further comprising: a sensor that is disposed to the housing and detects that the stethoscope mechanism has come into contact with a patient; and a power supply portion that inputs electric power in accordance with a signal detected by the sensor. 8. The stethoscope apparatus as set forth in claim 1, further comprising: a memory portion that memorizes a sound obtained by the microphone; and a memory controller that controls the memory operation. 9. The stethoscope apparatus as set forth in claim 1, further comprising: an interface provided on the housing having a slot capable of being loaded with a portable recording medium: the interface is capable of communicating sound data obtained by the microphone to the recording medium when the recording medium loaded in the slot; and a controller that controls at least one of recording of the data in the recording medium through the interface and reproducing of data recorded in the recording medium through the interface. 10. The stethoscope apparatus, as set forth in claim 1, further comprising: a clip mechanism disposed to the housing. 11. The stethoscope apparatus, as set forth in claim 10, wherein the clip mechanism has a plane table-shaped or frame-shaped pressure member. 12. The stethoscope apparatus as set forth in claim 1, further comprising: storing means for storing data of patterns of a plurality of biological sounds; and pattern-matching means for pattern-matching a biological sound obtained from a patient with the microphone with the respective pattern data storing with the storing means. 13. The stethoscope apparatus as set forth in claim 12, wherein the storing means store a plurality of informations on a pathology so that each of the information corresponds to the respective pattern data; and the stethoscope apparatus further comprises: pathology output means for outputting the information of the pathology corresponding to at least one pattern data matched by the pattern-matching means is extracted from the storing means and outputted through the speaker. 14. The stethoscope apparatus as set forth in claim 12, wherein the storing means store a plurality of information on pathology so that each of the information corresponds to the respective pattern data; and the stethoscope apparatus further comprises: display means; and display control means that control so that information of the pathology corresponding to at least one pattern data matched by the pattern-matching means is extracted from the storing means and displayed through the display means.

FIELD OF THE INVENTION The present invention relates to a stethoscope apparatus that is used for medical practices. BACKGROUND OF THE INVENTION In medical practices, a physician frequently employs a stethoscope for diagnosing patients. Owing to the diagnosis with a stethoscope, from biological sounds of patients such as vesicular breath sounds, bronchial breath sounds, low tone continuous sounds, squawks and bubbling rales, various pathologies can be grasped. Owing to the biological sounds from a stethoscope, not only pathologies of a heart and a respiratory system, but also various pathologies of other organ and bowel can be grasped. Recently, there is a stethoscope in which biological sounds are electrically converted and amplified, followed by outputting with a speaker or the like (Published Application in JP: JP-A No. 2005-52521 (paragraph No. [0011] and FIG. 1). DISCLOSURE OF INVENTION PROBLEMS TO BE SOLVED In recent years, in medical practices, an idea called an informed consent where a physician explains pathology, a method of treatment and advantages and risks of the treatment to a patient and thereby obtains patient's consent of the treatment becomes important. However, since the medical cares are specialized, in some cases, patients cannot sufficiently understand an explanation of the physician. As a result, there are cases where the patients conceive anxiety of their own pathologies. MEANS FOR SOLVING THE PROBLEM In view of the above circumstances, the invention intends to provide a stethoscope apparatus that contributes to a medical care that can eliminate patient's anxiety as much as possible. In order to achieve the above object, the stethoscope apparatus according to the invention, comprising: a microphone, a speaker that outputs a sound in accordance with an electrical signal generated by the microphone, and a housing that integrally mounts the microphone and speaker. According to the invention, the microphone and the speaker are integrally mounted on the housing and the speaker can reproduce sounds obtained by the microphone. For instance, when a physician explains the pathology and so on to a patient with the patient allowing hearing sounds from the speaker, the patient can be diagnosed at ease more than ever. In the invention, the stethoscope apparatus may further comprise a diaphragm capable of vibrating supported by the housing. In the invention, the housing has a first housing on which the microphone is mounted, a second housing on which the speaker is mounted, and a adjusting mechanism capable of adjusting an angle of the second housing to the first housing. Thereby, a direction in which the sounds from the speaker are outputted can be appropriately adjusted. For instance, the physician can appropriately adjust a direction so that the physician or the patient may easily hear the sounds from the speaker. The angle of the second housing to the first housing means angles in various planes and is not restricted to an angle only in one plane. For instance, when the adjusting mechanism has a uniaxial hinge mechanism, the angle of the second housing to the first housing can be adjusted in one plane. In the invention, the first housing has a contact portion that is brought into contact with a patient, and the contact portion and the speaker, respectively, are disposed to the first and second housings so that the speaker outputs the sound to an opposite side of the contact portion when the first and second housings are closed with the hinge mechanism. Thereby, a physician who faces a patient can listen to the patient with a stethoscope apparatus in a state where sounds from the speaker of the stethoscope apparatus can be easily heard. Furthermore, the physician can listen to the patient with the first and second housings closed, that is, with the stethoscope apparatus rendered relatively compact. In the invention, the adjusting mechanism is a universal joint. Therewith, the physician can adjust the second housing to the first housing in all angle directions. In the invention, the stethoscope apparatus further comprises a sensor that is disposed to the housing and can detect when the stethoscope apparatus comes into contact with the patient; and a power supply of which electric power is inputted in accordance with a signal detected by the sensor. Thereby, the power saving can be realized. For instance, when the power supply of the stethoscope apparatus is a battery type, being particularly demanded to save power, the invention is particularly effective. Furthermore, since the power is not inputted until the stethoscope apparatus comes into contact with the patient, the stethoscope apparatus does not pick up noises and so on before the stethoscope apparatus comes into contact with the patient. In the invention, the stethoscope apparatus further comprising a memory portion that memorizes a sound obtained by the microphone, and a memory controller that controls the memory operation. The stethoscope apparatus may still further comprise a function of reproducing sounds memorized by the memory portion with the speaker. The memory portion is convenient when it is one that memorizes digital data. However, without necessarily restricting to the digital data, the memory portion may be one that memorizes analog data. The memory portion may be one incorporated in the stethoscope apparatus or may be a portable memory as shown below. In the invention, the stethoscope apparatus includes a slot where a portable recording medium can be loaded in the housing. The stethoscope apparatus further includes an interface that, in a state where the recording medium is loaded in the slot, can transmit sound data obtained by the microphone to the recording medium; and a controller that controls at least one of recording the data on the recording medium through the interface and reproducing data recorded on the recording medium through the interface. In this case, the data recorded on the portable recording medium are conveniently digital data. Thereby, data of biological sounds can be copied on a computer and a physician can analyze the biological sounds with a computer in more detail. In the invention, the stethoscope apparatus further comprising a clip mechanism disposed to the housing. So far, a stethoscope is provided with an auditory tube; accordingly, a physician, when hooking the auditory tube on a neck of the physician, can carry the stethoscope without using a hand. In the invention, such an auditory tube and other cables are not included. Accordingly, a physician can conveniently carry the stethoscope apparatus with it clipped with such a clip mechanism to a pocket of a physician's cloth. In the invention, the clip mechanism has a plane table-shaped or frame-shaped pressure member. When a shape of the housing that has the speaker and so on is considered, the plane table-shaped or frame-shaped pressure member can stabilize a clipped state. In the invention, the stethoscope apparatus further comprising storing means for storing data of patterns of a plurality of biological sounds, and pattern-matching means for pattern-matching a biological sound obtained from a patient with the microphone with the respective pattern data storing with the storing means. When a diagnosis due to the pattern matching is utilized, a physician, being inhibited from misdiagnosing, can effectively diagnose. On the other hand, the diagnosis with the pattern matching can be used also complementarily in the physician's diagnosis. In the invention, the storing means store a plurality of informations on pathology so that each of the information corresponds to the respective pattern data. The stethoscope apparatus further comprising pathology output means for outputting information of the pathology corresponding to at least one pattern data matched by the pattern-matching means is extracted from the storing means and outputted through the speaker. Alternatively, the stethoscope apparatus may further comprising, display means; and display control means that control so that information of the pathology corresponding to at least one pattern data matched by the pattern-matching means is extracted from the storing means and displayed through the display means. Thereby, the patient can know the pathologies from both the physician and the stethoscope apparatus and can be diagnosed at more ease. EFFECTS OF THE INVENTION As mentioned above, according to the invention, the medical care that can eliminate the patient's unease and is due to more satisfied informed consent can be realized. BEST MODE FOR CARRYING OUT THE INVENTION In what follows, embodiments according to the invention will be described with reference to the drawings. FIG. 1 is a perspective view showing a stethoscope apparatus involving a first embodiment according to the invention. The stethoscope apparatus 10 includes a diaphragm portion 1 and a speaker portion 2. FIG. 2 is a diagram seen from a diaphragm portion 1 side of the stethoscope apparatus 10 shown in FIG. 1. FIG. 3 is an exploded perspective view showing the diaphragm portion 1, and FIG. 4 is an exploded perspective view showing the speaker portion 2. Furthermore, FIG. 5 is a side view showing the stethoscope apparatus 10. As shown in FIG. 3, the diaphragm portion 1 includes a housing 11. The diaphragm 6 is vibratably mounted to an opening 11a disposed to the housing 11. A biological sound of, for instance, a patient obtained owing to a vibration of the diaphragm 6 is constituted so as to be collected with a sound collecting plate 7, and the sound collecting plate 7 is disposed so as to be supported with a supporter 13 fixed to for instance the housing 11. Since the diaphragm 6 is a vibrating member, the diaphragm 6 and the sound collecting plate 7 are disposed so as not to come into contact with each other. At a substantial center of the sound collecting plate 7, a hole-like sound passage 7a is disposed to allow sounds due to the vibration of the diaphragm 6 to pass and a microphone 8 is disposed to the sound passage 7a. Thereby, the microphone 8 converts sounds collected by the sound collecting plate 7 into electrical signals. For the microphone 8, when it is required to be for instance a smaller size, an electrostatic type or a piezoelectric type is used. However, without restricting thereto, it may be an electromagnetic type like a speaker. As shown in FIG. 4, the speaker portion 2 is constituted with a circuit board 17 and a speaker body 9 (hereinafter, simply referred to as a speaker 9) incorporated in the housing 12 and with a cover 19 loaded to the opening 12a of the housing 12. The speaker 9 may have a general structure where a conical vibrating plate 9a is attached to a frame 9b. A planar shape of the speaker 9 may not be a circular one such as exemplified but may be for instance an elliptical one or an oval one. On the circuit board 17, electronic components such as an IC22 and a capacitor are mounted. The speaker 9 is electrically connected to the electronic components such as the ICs of the circuit board 17 through a not shown cable or the like. On a front surface of the cover 19, an operation input portion 4 is disposed to carry out recording or reproduction of sounds obtained by the microphone. When the operation input portion 4 is touched with for instance a human finger, a not shown contact point disposed to the operation input portion 4 comes into contact with an electrode 21 of the circuit board 17 to trigger an operation such as the reproduction. A power switch may be disposed to the operation input portion 4 or to a separate position. To a surface of the cover 19, a speaker cover 3 provided with a plurality of holes is attached. With reference to FIG. 3, an electric cable and so on of the microphone 8 are wired through a hole 13a opened in the support 13 and a hole 12b opened in the housing 12 to the circuit board 17. As shown in FIG. 5, for instance, the diaphragm portion 1 and the speaker portion 2 are connected with a uniaxial hinge mechanism 5. As shown in FIG. 6, by use of the hinge mechanism 5, for instance, with a shaft 5a as a rotation axis, an angle of the speaker portion 2 can be appropriately varied to the diaphragm portion 1 to fix positions of both at a desired angle. With the hinge mechanism 5, the diaphragm portion 1 and the speaker portion 2 can be constituted so as to open at an angle less than 180° or more than 180° at maximum. The electrical cables and so on of the microphone 8 are wired for instance inside of a shaft 5a of the hinge mechanism 5 and connected to the circuit board 17 of the speaker portion 2. The housings 11 and 12 or the diaphragm 6 are constituted of for instance a resin. However, without restricting to such a material, the housing 11 may be formed of metal or other materials. The housing 11 and the support 13 can be integrally molded; however, these may be formed from separate members respectively followed by connecting. The speaker cover 3 is formed also of a resin or metal. Though not shown in the drawing, a power supply of the stethoscope apparatus 10 can be constituted into for instance a rechargeable or exchangeable battery type. In the case of the rechargeable type, on the circuit board 17, an electrode or the like electrically connected to a rechargeable battery is disposed and the electrode may be exposed from the housing 12. Alternatively, without disposing such an electrode, a non-contact rechargeable battery may be adopted. On the other hand, in the case of the exchangeable battery, when a generally used coin battery is used, the stethoscope apparatus 10 can be miniaturized or thinned. FIG. 7 is a block diagram showing an electrical configuration of the stethoscope apparatus 10. The stethoscope apparatus 10 includes a CPU (Central Processing Unit) 31, a recording/reproducing controller 32, a memory 33 and a power supply 34. The CPU 31 collectively and totally controls an operation of the stethoscope apparatus 10. The recording/reproducing controller 32, based on an operation input portion instruction from the operation input portion 4, controls an operation of recording or reproduction. In particular, the recording/reproducing controller 32 converts sounds that are analog inputted from the microphone 8, for instance at an appropriate sampling frequency, into digital data at a quantized bit number of 4 bits, 8 bits or more. The recording/reproducing controller 32 may compress the data being recorded. The memory 33 memorizes for instance digital data of the sound. As the memory 33, a flash memory is used; however, a recording medium other than this, for instance, a magnetic disc such as a hard disc may be used. A signal that drives the speaker 9 may be an analog signal; however, based on data digitalized as shown above, a speaker output may be controlled. The electrical signal from the microphone 8 is preferably passed through a not shown amplifier or noise filter. When a physician diagnoses a patient with the stethoscope apparatus 10, the physician holds the housing 11 of the diaphragm portion 1 and, while bringing a diaphragm 6 into contact with the patient, listens to biological sounds of the patient generated from the speaker portion 2. In this case, since the stethoscope apparatus 10 is provided with the hinge mechanism 5, an angle of the speaker portion 2 can be varied so that the physician may easily listen to sounds. In particular, as shown in FIG. 5, in a state where the diaphragm portion 1 and the speaker portion 2 are closed and the diaphragm 6 is brought into contact with a skin of the patient, a direction in which sounds are outputted from the speaker portion 2 is constituted so as to be opposite to a side on which the diaphragm 6 is disposed. That is, when, with the first and second housings closed to make the stethoscope apparatus compact, a physician faces a patient and diagnoses with the stethoscope apparatus 10, a state where the physician can easily listen to speaker sounds results. Furthermore, the housing 11 has a vibration plate 6 as a contact portion that is brought into contact with a patient. As shown in FIG. 5, in a state where the stethoscope apparatus 10 is closed, the biological sounds are outputted from a speaker 9 toward a side opposite to the vibration plate 6. Thereby, the physician who faces the patient can listen to speaker sounds of the stethoscope apparatus 10 in an easily audible state. Furthermore, in that case, the physician can, with the stethoscope apparatus 10 closed as shown in FIG. 5, that is, with the stethoscope apparatus 10 rendered relatively compact, listen to the patient with the stethoscope apparatus 10. Still furthermore, the physician can operate the operation input portion 4 at the time of auscultation to record sounds on the memory 33 and reproduce the recorded sounds later. A volume can be preferably controlled. As mentioned above, since the stethoscope apparatus 10 according to the embodiment integrally mounts the microphone 8 and the speaker 9, sounds obtained with the microphone 8 can be reproduced by use of the speaker 9. For instance, the physician, while allowing the patient to listen to the sounds from the speaker portion 2, can diagnose the patient and explain the pathologies to the patient. Accordingly, the patient can be diagnosed at more ease than ever. When the physician listens to the patient with a stethoscope in a state shown in FIG. 5, an output direction of sounds of the speaker portion 2 is in a direction opposite to the patient; however, the patient can easily listen to the sounds of the speaker portion 2. When the patient is difficult to listen to the sounds, in order to make easy to listen to, the physician may appropriately vary an angle of the speaker portion 2. Alternatively, for instance, when the diaphragm portion 1 and the speaker portion 2 are opened so as to be substantially vertical to each other (so that an output plane of the speaker sounds and a vibration direction of the diaphragm 6 may be substantially in parallel with each other), with the diaphragm portion 1 brought into contact with the patient, an output direction of the speaker portion 2 can be directed upward. Thereby, both the patient and physician can easily listen to the speaker sounds. FIG. 8 is a perspective view showing a stethoscope apparatus involving another embodiment of the invention. FIG. 9 is a block configuration diagram of the stethoscope apparatus. In the descriptions after this, of the members and functions of the stethoscope apparatus 10 according to the above-mentioned embodiment, similar ones will be simplified in or omitted from describing and different points therefrom will be mainly described. As shown in FIG. 8, the stethoscope apparatus 20 includes a slot 12c to which a portable external memory 41 is detachably attached. As the portable external memory 41, for instance, a semiconductor memory such as a flash memory can be cited. With reference to FIG. 9, the stethoscope apparatus 20 includes an interface 36 accessible to the external memory 41. Thereby, with the portable external memory 41 loaded in the slot 12c, data of sounds obtained by the microphone 8 can be communicated to the memory 41. In this case, the recording/reproducing controller 32 controls a recording or reproducing operation to the memory 41. With such a configuration, the physician can connect the portable external memory 41 to an external device such as a computer and thereby can copy data of biological sounds recorded in the memory 41 in the computer. As a result, the physician can analyze the biological sounds in more detail with the computer. The stethoscope apparatus 20 may have, in place of the external memory interface 36, an interface for a USB (Universal Serial Bus). In this case, a USB cable is connected to the stethoscope apparatus, and through the USB interface, data communication is carried out between the stethoscope apparatus and the external device. FIG. 10 is a partial sectional view showing a stethoscope apparatus involving still another embodiment of the invention. FIG. 11 is a block configuration diagram of the stethoscope apparatus. A diaphragm 6 provided to a diaphragm portion 51 of a stethoscope apparatus 30 is loaded with a contact sensor 24 that detects, for instance, that the stethoscope apparatus 30 came into contact with a patient. The contact sensor 24 is disposed, for instance, at a substantial center of the diaphragm 6. As the contact sensor 24, for instance, an electrostatic sensor or a piezoelectric sensor can be used. As shown in FIG. 11, a power supply controller 35 controls based on a signal detected by the contact sensor 24 a power supply portion 34 so as to input power. According to such a stethoscope apparatus 30, when a physician brings the stethoscope apparatus 30 into contact with a patient, electric power is inputted; accordingly, power saving can be realized. The stethoscope apparatus 30, being a battery type as mentioned above, is particularly strong in demand for power saving; accordingly, in this case, an advantage is very large. Furthermore, the electric power is not inputted until the contact sensor 24 comes into contact with the patient; accordingly, the stethoscope apparatus does not collect noises before the stethoscope apparatus 30 is brought into contact with the patient. Still furthermore, for the physician, since an operation of pushing a power switch can be omitted, the stethoscope apparatus 30 can be used with a sense as if an existing non-electronic stethoscope apparatus is used. In the stethoscope apparatus 30, the contact sensor 24 can be disposed to any place thereof as far as it comes into contact with the patient. For instance, an attachment portion of the contact sensor 24 is formed to a housing 11 and the contact sensor 24 may be attached to the attachment portion. The stethoscope apparatus 30 may have a timer function of the power supply portion 34. For instance, as mentioned above, a signal detected by the contact sensor 24 triggers to input electric power. Thereafter, at a predetermined time after a signal became not to be detected with the contact sensor 24, the power controller 35 can control so that a power supply of the power supply portion 34 may be turned off. FIG. 12 is a partial sectional view showing a stethoscope apparatus involving further still another embodiment of the invention. As shown in FIG. 12(A), in a stethoscope apparatus 40, an angle adjusting mechanism that connects a diaphragm portion 1 and a speaker portion 2 is constituted of a universal joint 25. In the universal joint 25, a spherical body 25a fixed to a housing 12 of, for instance, the speaker portion 2 is rotatably fitted in a receiving body 25b disposed to the housing 11 of the diaphragm portion 1. According to such a configuration, although a range of angle of the speaker portion 2 to the diaphragm portion 1 is limited, the speaker portion 2, without being restricted in a direction in which it moves, can conveniently move in all directions. For instance, a state shown in FIG. 12(B) is a state where an angle and a direction similar to FIG. 6 are taken. A state shown in FIG. 12(C) is a state where the speaker portion 2 is upside down. Other than the states shown in FIGS. 12(A) through 12(C), for instance, with a posture of the diaphragm portion 1 kept as it is, an output surface of the speaker sound of the speaker portion 2, among FIGS. 12(A) through 12(C), can be made a state that faces toward a front side (a state where the cover 19 shown in FIG. 4 faces a front side in FIG. 12). The universal joint is not restricted to one that uses the spherical body 25a shown in FIG. 12. For instance, a structure where the diaphragm portion 1 and the speaker portion 2 move in at least two planes is called a universal joint. The structure where the diaphragm portion 1 and the speaker portion 2 move in two planes can be realized with for instance a biaxial hinge mechanism. FIG. 13 is a perspective view showing a stethoscope apparatus involving another embodiment of the invention. The stethoscope apparatus 50 includes substantially parallelepiped housings 151 and 152, and the housings 151 and 152 are rotatably connected through a hinge mechanism 65. The housing 151 incorporates a not shown speaker body and from a plurality of slits 151a disposed on a surface of the housing 151 sounds are outputted. Holes therefrom the sounds are outputted are not necessarily slit-like ones but may be mesh-like ones or a plurality of round-holes such as shown in FIG. 1. FIG. 14 is a perspective view showing an opposite side of the stethoscope apparatus 50 shown in FIG. 1. The housing 152 is vibratably loaded with a diaphragm 56 as shown in FIG. 14. FIG. 15 is a side view showing the stethoscope apparatus 50. The housing 151 is provided with a pressure member 54 that plays a function of a clip. Specifically, one end 54a of the pressure member 54, supported by the housing 151, forms a fixed end, and the other end 54b of the pressure member 54 forms a free end. Thereby, the pressure member 54 is imparted with the spring properties and thereby a clip mechanism is realized. So far, since a stethoscope is provided with an auditory tube, when a physician hooks the auditory tube on own neck, without using a hand, the stethoscope can be carried with. The stethoscope apparatus 50 involving the embodiment does not have such an auditory tube and cables. Accordingly, when it has such a clip mechanism, for instance, by clipping the stethoscope apparatus 50 with the pressure member 54 to a pocket of clothing that the physician wears, the physician can conveniently carry the stethoscope apparatus 50. In particular, when the pressure member 54 is formed into a frame-shape so as to fit to a shape of the housing 151, a clipped state can be stabilized. FIG. 16 is a side view showing a state where the stethoscope apparatus 50 is opened, that is, the housings 151 and 152 are opened. Thus, by use of the hinge mechanism 65, the housings 151 and 152 can be constituted so as to be opened at an angle less than 180° at most or 180° or more. In addition to the hinge mechanism 65, the housings 151 and 152 may be constituted twistably. That is, the housing 151 may be constituted so as to move against the housing 152 in a direction (in a direction deviating from a direction in parallel with the axial direction) where a surface (an output surface of speaker sounds) on which the slit 151a (FIG. 13) is disposed twists to an axial direction (a vertical direction to a page space in FIG. 16) of a rotation axis 65a of the hinge mechanism 65. FIG. 17 is a block configuration diagram of a stethoscope apparatus involving still another embodiment of the invention. The stethoscope apparatus 60 includes a ROM (Read Only Memory) 37 that stores for instance a predetermined program and database. The ROM may be a semiconductor memory, a memory such as a magnetic disc, or memories other than the above. As shown in FIG. 18, specifically, the ROM 37 stores a pattern-matching program 45, a pathological information output program 46 and a pathological pattern database 47. The pathological pattern database 47 is a database where all patterns of biological sounds obtained with the stethoscope apparatus 60 (for instance, typical waveform patterns of the biological sounds) are stored in association with pathological information (for instance, a disease name or a symptom due to the disease). The pattern-matching program 45 extracts one or a plurality of pathological patterns most similar to a pattern of a biological sound actually obtained with the microphone 8 from the pathological pattern database 47. The pathological information output program 46 is a program for outputting, with a speaker 9 as sounds, pathological information corresponding to thus extracted pathological pattern. As a method with which the pattern-matching program 45 extracts a pathological pattern, for instance, a frequency of a waveform obtained with the microphone 8, a kind of a continuous sound, a kind of a discontinuous sound, combinations thereof, number of times or frequency of continuous or discontinuous sounds, or sound pressure levels thereof are used. A threshold value for these values is determined to extract. However, other than these, various methods can be considered. By use of the diagnosis due to the pattern-matching method, a physician, inhibited from misdiagnosing, can effectively diagnose. Furthermore, since the pathologies are notified as sounds from the speaker 9, a patient, being able to acknowledge the pathologies from both of the physician and the stethoscope apparatus 60, can be diagnosed at more ease. In recent years, medical accidents due to physicians are not scarce. It is important to inhibit the physicians from misdiagnosing at an early stage from the time of diagnosis with a stethoscope apparatus, which is an early stage of a medical process. The invention, without restricting to the embodiments described above, can be variously modified. In the stethoscope apparatus according to the respective embodiments, an angle of a speaker portion can be controlled by use of a hinge or a universal joint. However, a microphone and a speaker may be mounted in one integral housing that does not have such an angle adjusting mechanism. Furthermore, the stethoscope apparatus according to the respective embodiments are constituted with a diaphragm; however, the diaphragm is not necessarily required. The stethoscope apparatus 10 shown in FIG. 1 and so on and other stethoscope apparatus 20, 30 and 40 are not provided with the clip mechanism (pressure member 54) shown in FIG. 13 and so on; however, these may be provided therewith. In this case, the pressure member preferably has a dimension same or smaller than a width of the housing 11 or 12 of the stethoscope apparatus 10 from a viewpoint of design. In the stethoscope apparatus involving embodiments shown in FIGS. 17 and 18, the speaker outputs the pathological information as sounds. However, when a stethoscope apparatus is provided with, for instance, a liquid crystal, an EL (Electro-Luminescence) or other display, the pathological information may be displayed on the display as characters or images. At least one of features of the stethoscope apparatus involving the respective embodiments may be combined to constitute a stethoscope apparatus. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a perspective view showing a stethoscope apparatus involving one embodiment according to the invention. FIG. 2 is a view seen from a diaphragm portion side of the stethoscope apparatus shown in FIG. 1. FIG. 3 is an exploded perspective view of the diaphragm shown in FIG. 1, and FIG. 4 is an exploded perspective view showing a speaker portion of the stethoscope apparatus. FIG. 5 is a side view of the stethoscope apparatus. FIG. 6 is a side view showing a state where the stethoscope apparatus is opened with a certain angle. FIG. 7 is a block diagram showing an electrical configuration of the stethoscope apparatus. FIG. 8 is a perspective view showing a stethoscope apparatus involving another embodiment according to the invention. FIG. 9 is a block configuration diagram of the stethoscope apparatus shown in FIG. 8. FIG. 10 is a partial sectional view showing a stethoscope apparatus involving a still another embodiment according to the invention. FIG. 11 is a block configuration diagram according to the stethoscope apparatus. FIG. 12 is a partial sectional view showing a stethoscope apparatus involving a further still another embodiment according to the invention. FIG. 13 is a perspective view showing a stethoscope apparatus involving another embodiment according to the invention. FIG. 14 is a perspective view shown from an opposite side of the stethoscope apparatus shown in FIG. 13. FIG. 15 is a side view showing the stethoscope apparatus shown in FIG. 13. FIG. 16 is a side view showing a state where the stethoscope apparatus shown in FIG. 13 is opened. FIG. 17 is a block configuration diagram of a stethoscope apparatus according to still another embodiment of the invention. FIG. 18 is a block diagram showing data stored in a ROM shown in FIG. 17. EXPLANATION OF CODES 1, 51 . . . diaphragm portion 2 . . . speaker portion 5, 65 . . . hinge mechanism 6, 56 . . . diaphragm 8 . . . microphone 9 . . . speaker body 10, 20, 30, 40, 50, 60 . . . stethoscope apparatus 11, 12, 151, 152 . . . housing 12c . . . slot 17 . . . circuit board 24 . . . contact sensor 25 . . . universal joint 31 . . . CPU 32 . . . recording/reproducing controller 33 . . . memory 34 . . . power supply 35 . . . power supply controller 36 . . . external memory interface 37 . . . ROM 41 . . . portable external memory 45 . . . pattern matching program 46 . . . pathology information output program 47 . . . pathology pattern data base

<SOH> BACKGROUND OF THE INVENTION <EOH>In medical practices, a physician frequently employs a stethoscope for diagnosing patients. Owing to the diagnosis with a stethoscope, from biological sounds of patients such as vesicular breath sounds, bronchial breath sounds, low tone continuous sounds, squawks and bubbling rales, various pathologies can be grasped. Owing to the biological sounds from a stethoscope, not only pathologies of a heart and a respiratory system, but also various pathologies of other organ and bowel can be grasped. Recently, there is a stethoscope in which biological sounds are electrically converted and amplified, followed by outputting with a speaker or the like (Published Application in JP: JP-A No. 2005-52521 (paragraph No. [0011] and FIG. 1 ).

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a perspective view showing a stethoscope apparatus involving one embodiment according to the invention. FIG. 2 is a view seen from a diaphragm portion side of the stethoscope apparatus shown in FIG. 1 . FIG. 3 is an exploded perspective view of the diaphragm shown in FIG. 1 , and FIG. 4 is an exploded perspective view showing a speaker portion of the stethoscope apparatus. FIG. 5 is a side view of the stethoscope apparatus. FIG. 6 is a side view showing a state where the stethoscope apparatus is opened with a certain angle. FIG. 7 is a block diagram showing an electrical configuration of the stethoscope apparatus. FIG. 8 is a perspective view showing a stethoscope apparatus involving another embodiment according to the invention. FIG. 9 is a block configuration diagram of the stethoscope apparatus shown in FIG. 8 . FIG. 10 is a partial sectional view showing a stethoscope apparatus involving a still another embodiment according to the invention. FIG. 11 is a block configuration diagram according to the stethoscope apparatus. FIG. 12 is a partial sectional view showing a stethoscope apparatus involving a further still another embodiment according to the invention. FIG. 13 is a perspective view showing a stethoscope apparatus involving another embodiment according to the invention. FIG. 14 is a perspective view shown from an opposite side of the stethoscope apparatus shown in FIG. 13 . FIG. 15 is a side view showing the stethoscope apparatus shown in FIG. 13 . FIG. 16 is a side view showing a state where the stethoscope apparatus shown in FIG. 13 is opened. FIG. 17 is a block configuration diagram of a stethoscope apparatus according to still another embodiment of the invention. FIG. 18 is a block diagram showing data stored in a ROM shown in FIG. 17 .

20060307

20091222

20070315

63766.0

A61B704

MONIKANG, GEORGE C

STETHOSCOPE APPARATUS

SMALL

ACCEPTED

A61B

ACCEPTED

Use of extracts from pelargonium species

The present invention relates to the use of extracts from Pelargonium species or plant parts thereof, particularly from P. sidoides and P. reniforme for the prophylaxis or treatment of disease-related behavioural changes, the chronic or post-viral asthenia syndrome and/or stress-induced chronic pathological conditions as well as pharmaceutical preparations containing these extracts.

1-14. (canceled) 15. A method for treating a subject suffering from or susceptible to one or more of disease-related behavioural change, chronic or post-viral asthenia syndrome and/or stress-induced chronic pathological conditions, the method comprising administering to the subject one or more extracts from Pelargonium species selected from P. sidoides and P. reniforme or plant parts thereof. 16. The method of claim 15 wherein the plant parts are roots. 17. The method of claim 15 wherein the one or more extracts are is an aqueous-ethanolic extract from roots of Pelargonium sidoides and/or reniforme. 18. The method of claim 15 wherein the subject is suffering from or susceptible to a disease-related behavioural change. 19. The method of claim 15 wherein the subject is suffering from or susceptible to a disease-related behavioural change associated with symptoms of episodes of depression, listlessness, feeling of weakness, fatigue, anergy, anorexia, social isolation, weakness of concentration, sleep disorders, anxiety, indifferentism and hyperalgesia, which occur in a temporal correlation with infectious disease, injuries, traumata, tumor disease, inflammatory reaction or autoimmune disease. 20. The method of claim 15 wherein the subject is suffering from or susceptible to a disease-related behavioural change in connection with the therapeutic application of a cytokine, or with the application of a cytostatic agent or other cell or tissue-damaging medicament or therapeutic measure. 21. The method of claim 15 wherein the subject is suffering from or susceptible to a stress-induced chronic pathological condition. 22. The method of claim 21 wherein the subject is suffering from post-traumatic stress syndrome, fibromyalgia or multiple chemical sensitivity. 23. The method of claim 15 wherein the subject is identified as suffering from one or more of disease-related behavioural change, chronic or post-viral asthenia syndrome and/or stress-induced chronic pathological conditions, and the one or more extracts are administered to the identified subject. 24. The method of claim 15 wherein the subject is identified as susceptible to one or more of disease-related behavioural change, chronic or post-viral asthenia syndrome and/or stress-induced chronic pathological conditions, and the one or more extracts are administered to the identified subject. 25. A medicament for the prophylaxis or treatment of disease-related behavioural changes, chronic or post-viral asthenia syndrome and/or stress-induced chronic pathological conditions comprising an extract from Pelargonium species selected from P. sidoides and P. reniforme. 26. A pharmaceutical comprising comprising one or more extracts from Pelargonium species selected from P. sidoides and P. reniforme and one or more suitable adjuvants. 27. The pharmaceutical comprising of claim 26 wherein the composition consists of one or more extracts from Pelargonium species selected from P. sidoides and P. reniforme and one or more suitable adjuvants. 28. The pharmaceutical composition wherein the composition is in an oral administration form.

The present invention relates to the use of extracts from Pelargonium species or plant parts thereof, particularly from P. sidoides and P. reniforme for the prophylaxis or treatment of disease-related behavioural changes, chronic or post-viral asthenia syndrome and/or stress-induced chronic pathological conditions, as well as pharmaceutical preparations containing these extracts. Many patients know from their personal experience that infections and inflammations such as a cold, influenzal infections or infections of the upper respiratory tracts are accompanied by a plurality of unspecific and generalized disease symptoms. Besides phenomena such as fever and articular or muscular pain, also behavioural changes are among them. Thus, episodes of depression, listlessness, feeling of weakness, fatigue, anergy, anorexia, social isolation, weakness of concentration, sleep disorders, anxiety, indifferentism or hyperalgesia often occur in connection with infective diseases. In their totality, these symptoms and behavioural disorders are designated as “acute phase reaction”, “sickness behaviour” or “depression due to a generalized disease” (W. Kozak et al., Am. J. Physiol. 272, R1298-R1307 (1997); R. Dantzer, Brain Behav. Immun. 15, 7-24 (2001); K. W. Kelley et al., Brain Behav. Immun. 17, p. 112-p. 118 (2003); A. H. Miller, Brain Behav. Immun. 17, p. 132-p. 134 (2003)). On a molecular level these symptoms are caused by an increased synthesis of proinflammatory cytokines such as interleukuin-1 (IL-1), IL-6, tumor necrosis factor-α (TNFα) or interferons (INF). These mediators, which are produced in increased amounts after tissue damages, elicit behavioural changes indirectly via afferent nerve tracts or directly after transfer into the brain. Although sickness behaviour clearly appears mainly in cases of infectious diseases, it is also observed in connection with injuries, traumata, tumor diseases or inflammatory reactions such as autoimmune diseases (R. Dantzer, Brain Behav. Immun. 15, 7-24 (2001)). The importance of cytokines for the development of unspecific disease symptoms and behavioural changes was recognized for the first time in the scope of clinical studies. It turned out that the administration of, for example, IL-2 or interferons to patients with tumor diseases, hepatitis or multiple sclerosis causes influenza-like symptoms and psychiatric disorders (such as acute psychoses and serious depressions). Meanwhile, there is a plurality of indication that the cytokine-dependent mechanisms that contribute to disease-related behavioural changes play an important role also in the pathogenesis of depressions (L. Capuron and R. Dantzer, Brain Behav. Immun. 17, p. 119-p. 124 (2003)). In test animals sickness behaviour can be caused by direct injection of proinflammatory cytokines or by administration of a cytokine inducer such as a lipopolysaccharide, which are constituents of the cell walls of gram-negative bacteria. Like in human beings, typical symptoms in animals are, inter alia, a reduced uptake of food and water, loss of weight, reduced social interactions, decreasing sexual behaviour, limited kinesic and exploratory behaviour or also a lack of interest for sweetened drinks. The pathophysiologic importance of sickness behaviour presumably lies in an adaption of the organism to the modified needs of a diseased organism. As a result, exhausting physical activities (such as foraging and sexual behaviour) are avoided and temperature losses are limited (for example by physical rest). Simultaneously, the temperature production is increased, for example by trepidation. These behavioural changes in total shall ease the healing process for the body. However, this condition should only last until it is no longer necessary for the healing process. A number of mechanisms is known actually, which limit the biological effects of the proinflammatory cytokines such as the increased synthesis of gluco-corticoids, IL-10 or α-melanocyte-stimulating hormone (R. Yirmiya, Current Opinion in Psychiatry 10, 470-476 (1997)). Perturbations of these regulative mechanisms may contribute to a continuation of the immunologic and neuronal processes and may lead to a misdirected adaption reaction which manifests as chronic weakness syndrome (burnout syndrome, chronic fatigue syndrome, chronic exhaustion syndrome) or as post-viral weakness syndrome (post-viral fatigue syndrome). Various stress-induced chronic disease conditions such as the posttraumatic stress, syndrome, fibromyalgia or multiple chemical sensitivity syndrome (multiple chemical sensitivity, sick building syndrome, electrical allergy), exhibit very similar symptoms and many patients fulfil the diagnostic criteria for one or more of these diseases. It is common to all of them that they are elicited by a state of stress which is followed by a longer lasting pathological condition. The preliminary stress is obviously the elicitor for the cell-promoting “circulus vitiosus”. It becomes more and more evident that there are close relations between the nervous system, the immune system and the hormone system and that all these conditions are caused by a stress-induced reduced responsiveness of the immune system against anti-inflammatory signals (M. L. Pall (2001), Med. Hypotheses 57, 139-145; G. E. Miller et al. (2002), Health Psychol. 21, 531-541). Due to their frequent and regular appearance, the symptoms of the sickness behaviour are often ignored by physicians. They are rather considered to be unpleasant side effects of the actual disease process, which cannot be avoided. However, it is clear from the knowledge obtained in recent years that the disease-related behavioural changes and the physiological reactions associated therewith (e.g. fever) are a complex pathological condition in themselves. The symptoms of sickness behaviour can elicit a severe psychological strain in affected patients and impair the quality of life dramatically. In particular, the lethargic attitude associated therewith can significantly hamper the patient's cooperation in therapeutic measures, such as in case of tumor diseases, or challenge the overall success of the treatment. Furthermore, in cases of trivial diseases such as an influenzal infection, the degree of severity of the symptoms of the disease-related behavioural changes is often not in due proportion to the, actual physiological purpose of this defensive mechanism. The elucidation of the molecular mechanisms of sickness behaviour has led to new possible ways for a therapeutic intervention in recent years. Antidepressive agents have turned out to be suitable for the treatment of the depressive component of disease-related behavioural changes. However, antidepressive agents develop their therapeutic effect after a delay of several days or weeks and additionally often induce severe side effects. Therefore, for acute or less severe diseases these medicaments are hot suitable or are of limited suitability only. Furthermore, antidepressive agents do not exert any influence on the neurovegetative symptoms of sickness behaviour such as physical Weakness, exhaustion or anorexia. Therefore, there is an urgent need for effective treatment methods against disease-related behavioural changes that exhibit limited side effects. Extracts from the roots of the Pelargonium species P. sidoides and P. reniforme, which are domiciled in South Africa, are widely used in the African traditional medicine for the treatment of diarrhea, gastrointestinal complaints, dysmenorrhoea and liver diseases. However, the administration against respiratory tract diseases and, particularly, against tuberculosis of the lung is predominant. Since many years, also an extract from the roots of P. sidoides is distributed under the trade name Umckaloabo for the treatment of acute and chronic infections of the otorhinolaryngologic regions such as rhinopharyngitis, tonsillitis, sinusitis and bronchitis. The clinical efficacy of this extract appears to rely on antimicrobial and immuno-modulating effects. There are evidences from experimental investigations that an extract from Pelargonium sidoides increases the synthesis of TNF-α, INF-β and nitric oxide. (NO) (H. Kolodziej et al., Phytomedicine 10 (Suppl. 4), 18-24 (2003)). It now has been surprisingly observed that extracts from Pelargoniums positively influence LPS-induced behavioural changes in animal experiments despite the stimulating effect on the synthesis of proinflammatory cytokines and, thus, can be employed for the prophylaxis and therapy of disease-related behavioural changes (“sickness behaviour”) in human beings and animals. Examples for the disease-related behavioural changes are symptoms such as episodes of depression, listlessness, feeling of weakness, fatigue, anergy, anorexia, social isolation, weakness of concentration, sleep disorders, anxiety, indifferentism or hyperalgesia, which occur in a temporal correlation with infectious diseases, injuries, traumata, tumor diseases, inflammatory reactions or autoimmune diseases. Furthermore, the extracts are suitable for the prophylaxis and treatment of sickness behaviour in connection with the therapeutic application of natural or recombinant cytokines such as interleukins, interferons and the like or also with the application of cytostatic agents or other cell or tissue-damaging medicaments or therapeutic measures. Moreover, Pelargonium extracts can also be used for the prophylaxis and therapy of the chronic or post-viral asthenia syndrome (chronic or post-viral fatigue syndrome) and various stress-induced chronic pathological conditions such as the posttraumatic stress syndrome, fibromyalgia or multiple chemical sensitivity. Extracts from Pelargoniums or plant parts thereof can be obtained according to known production methods in various compositions using solvents such as water, methanol, ethanol, acetone and the like as well as mixtures thereof at temperatures from room temperature to 60° C. under slight to vigorous mixing or by percolation within 10 minutes to 24 hours. Preferred extraction solvents for this purpose are mixtures of ethanol and water, particularly preferred in a ratio ethanol/water=10/90 to 12/88 (w/w). In order to concentrate the active ingredients, further concentration steps can be carried out, such as liquid-liquid distribution using, for example, 1-butanol/water or ethylacetate/water, adsorption-desorption using ion exchangers, LH20, HP20. and other resins or chromatographic separations using RP18, silica gel and the like If desired, further processing to obtain dry extracts is carried out according to methods known per se by removing the solvent at an increased temperature and/or reduced pressure or by freeze-drying. The extracts according to the invention can be administered, preferably orally, in form of powders, granules, tablets, dragées (coated tablets) or capsules or as a solution such as that directly obtained by the extraction. For the preparation of tablets, the extract is mixed with suitable pharmaceutically acceptable adjuvants such as lactose, cellulose, silicon dioxide, croscarmellose and magnesium stearate and pressed into tablets which are optionally provided with a suitable coating made of, for example, hydroxymethylpropyl cellulose, polyethylene glycol, colorants (e.g. titanium dioxide, iron oxide) and talcum. The extracts according to the invention can also be filled into capsules, optionally after adding adjuvants such as stabilizers, fillers and the like. The dosage is such that 2 to 1000 mg, preferably 10 to 200 mg extract are administered per day. The efficacy of Pelargonium extracts against disease-related behavioural changes and/or chronic or post-viral asthenia syndrome are supported by the experiments described below. A dry extract from roots of P. sidoides, which was produced by means of a double maceration using seven times their amount made up of 11 percent by weight ethanol at 55° C., respectively, (yield: 11%), was used for the experiments. The extract was administered to male NMRI mice (20-25 g weight) by gavage in varying dosages in 0.2% agar suspension (10 ml/kg). Control animals received the agar suspension only. One hour after the treatment, the animals were injected intraperitoneally with 400 μg/kg lipopolysaccharide (LPS) (E. coli 0127:B8; Sigma, Deisenhofen) in 10 mg/kg physiological saline (0.9% NaCl). After a further two hours, the animals were transferred into the bright field of a dark-bright box and the motility as well as the exploration behaviour were observed over a period of 3 minutes. As nocturnal animals, mice prefer to stay in a dark surrounding. Therefore, an extended stay in the bright region of the bright-dark box and a decreasing frequency of changes between the two regions is to be assessed as an evidence for a reduced exploration behaviour, anergy and reduced interest. The results of the experiments are shown in the following table. It becomes evident that animals treated with LPS stay significantly longer in the bright region compared to control animals (NaCl) and change less often between the two regions. This effect is neutralized by the pre-treatment with the Pelargonium extract in dose-dependant manner. TABLE Influence of Pelargonium extract on the exploration behaviour of mice in a bright-dark box. Stay in the bright Number of Dose region (seconds) changes of Substance mg/kg p.o. MW ± S.D. the region agar + NaCl 83 ± 8 8.5 ± 2.8 agar + LPS 135 ± 34 4.4 ± 2.8 Pelargonium extract + LPS 100 119 ± 18 5.5 ± 0.8 Pelargonium extract + LPS 200 104 ± 18* 5.5 ± 1.4 Pelargonium extract + LPS 400 97 ± 11* 7.5 ± 1.9* *P < 0.05 (=probability of error), t-test

20060308

20091103

20070118

95017.0

A61K36185

MI, QIUWEN

USE OF EXTRACTS FROM PELARGONIUM SPECIES

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Method of producing a spring wire and wire thus produced

Method of producing spring wires shaped as a cylinder. The wire includes at least one first plurality of layers of wound fibres, the layers being disposed on top of one another and impregnated with a matrix. The first plurality of layers includes at least two stacked layers of fibres which are wound in opposing directions along two coaxial helices around the same axis to the left and right thereof respectively. The tangents to the two helices together with the axis (10) form respectively two angles having values βx−1 and βx which are respectively equal to Δ+kγ and −Δ−kγ, γ being a function of the value of the modulus of elasticity for the spring to be produced and k being a factor of between 0 and 1. The method is suitable for the production of helical cylindrical-type spring wires for the suspension systems of motor vehicles.

1. A method of making a spring wire comprising at least one layer (C) of a fiber wound helically on a cylindrical “primary” portion (12) of diameter equal to D, the tangent to said helix making an angle relative to the axis (100) of the primary portion (12) having a value β, said layer (C) also being suitable for being bonded to the primary portion (12) by a matrix (Rp), the fiber, once wound around the primary portion, presenting a cross-section that is substantially rectangular, of thickness E in the radial direction of the primary portion (12) and of width E′ in the direction perpendicular to the tangent to the helix, the method consisting in preparing a funnel (13) of frustoconical shape, said funnel having a small opening (14) corresponding to the small base of the frustoconical shape, in preparing a supply (15) to deliver the fiber (Fb1), in connecting one of the ends (16) of said fiber to the primary portion (12), and in imparting rotary movement (R) to said supply (15) at a speed ω about the axis (100) of said primary portion (12), said primary portion being moved in translation (17) at a speed T through the funnel (13) along its axis going from its large opening (24) towards its small opening (14), the method being characterized by the fact that it further consists in causing said fiber (Fb1) to penetrate into the funnel (13) via its large opening corresponding to the large base of the frustoconical shape before being rolled up around the primary portion so that it comes to lick the frustoconical interior wall of the funnel, the angle at the apex of said funnel (13) having a value that is substantially equal to 2β, the small base of the frustoconical shape of said funnel having a diameter equal to D+2E, the value ω of the speed in rotation of the supply (15) expressed in revolutions per second, and the value T of the speed in translation of the primary portion (12) expressed in meters per second being associated by the following relationship: ω = T D ⁢ ⁢ π ⁡ [ tan ⁢ ⁢ ( π 2 - β ) ] 2. A method according to claim 1, characterized by the fact that it consists in preparing X supplies (15-1, 15-2, . . . ) each of one fiber, one end of each fiber being connected to the primary portion (12), the X fibers penetrating into the funnel (13) via its large opening (24), and in driving said supplies in rotary movement (R) at the same speed of rotation of value ω about the axis (100) of the primary portion, while causing said primary portion (12) to move in translation at the speed of value T towards said small opening of the funnel, the number X of said supplies being equal to: X = π ⁢ ⁢ D E ⁢ sin ⁢ ⁢ ( π 2 - β ) 3. A method according to claim 1, characterized by the fact that said movement in translation is selected from one of the following two kinds of movement: continuous translation; stepwise translation. 4. A method according to claim 3, characterized by the fact that stepwise translation is obtained by applying oscillating motion to said funnel (13) along its axis, the small opening (14) presenting a shape that is substantially cylindrical and including biting teeth on the surface of its inside wall. 5. A method according to claim 1 for making a spring wire, the wire comprising “n” layers (C) of fibers (Fb) each having a thickness E and being wound in “n” helices on one another in coaxial manner, respectively in left-handed and in right-handed helices on a cylindrical “primary” portion (12) of diameter equal to D, the tangents to said “n” helices making angles relative to the axis (100) of the primary portion having respective values β1, β2, . . . , βn progressing from −Δ−γ to Δ+γ, said “n” layers (C) also being suitable for being bonded to one another and to the primary portion (12) by a matrix (Rp), the method being characterized by the fact that it consists: in preparing a funnel (13) of frustoconical shape having an angle at the apex substantially equal to 2(Δ+γ), said funnel having a small opening (14) corresponding to the small base of the frustoconical shape of diameter equal to D+2nE; in preparing “n” supplies (15) of fibers; in connecting one of the ends (16) of each of the “n” fibers to the primary portion (12), said “n” fibers penetrating into the funnel (13) via its large opening (24) corresponding to the large base of the frustoconical shape; and in driving the “n” supplies (15) in rotary movement (R) and in directions opposite to one another at respective speeds of rotation of values ω1, ω2, . . . , ωn about the axis (100) of the primary portion (12), said primary portion being moved in translation (17) through the funnel (13) along its axis going from its large opening (24) towards its small opening (14), the values ω1, ω2, . . . , ωn of the respective speeds of rotation of the “n” supplies (15) being functions of the value T of the speed in translation of the primary portion. 6. A method according to claim 1, characterized by the fact that it further consists in filing said funnel (13) in a liquid matrix (Rp) prior to setting at least one supply (15) in rotation and to setting the primary portion into translation. 7. A method according to claim 5, characterized by the fact that it consists in surrounding said small opening (14) of the funnel (13) with a sleeve (20) having an inlet orifice of substantially the same diameter as said small opening, and an outlet orifice (20) of a shape adapted to the shape of the section desired for the wire. 8. A wire for making a spring, the wire being obtained by the method according to claim 1, said wire being substantially cylindrical in shape (FR) and including at least a first plurality of layers (Cx−1, Cx, . . . , Cn) of wound fibers (Fb), said layers being situated on one another and being impregnated with a matrix (Rp), the wire being characterized by the fact that said first plurality of layers comprises at least two layers (Cx−1, Cx) of fibers situated on each other, the fibers of these two layers being wound in opposite directions relative to each other in two helical pitches about a common axis (10), respectively left-handedly and right-handedly, the tangents to these two helices forming angles relative to said axis (10) with respective values βx−1 and βx that are substantially equal respectively to Δ+kγ and −Δ−kγ, where γ is a function of the value of the modulus of elasticity for the spring to be obtained and “k” is a factor of having a value lying in the range zero to one, the value Δ being no greater than substantially 44.6°. 9. A wire according to claim 8 for making a spring suitable for working in compression, the wire being characterized by the fact that said first plurality of layers comprises an even number “n” of layers C1, . . . , Cn of fibers (Fb) situated on one another, the layer C1 being the closest to said axis (10), said fibers being wound in helices that are all coaxial about said axis (10), the helices of two consecutive layers C1, C2; . . . , Cn−1, Cn being respectively left-handed and right-handed, and the tangents to these helices forming angles relative to said axis having values respectively equal to: −Δ and Δ for the first pair of layers C1, C2; −(Δ+2α) and +Δ+2α for the second pair of layers C3, C4; −(Δ+4α) and Δ+4α for the third pair of layers C5, C6; and so on up to −(Δ+(n−2)α) and Δ+(n−2)α for the (n/2)th pair of layers Cn−1, Cn; where Δ is no greater than substantially 44.6°, and −α is substantially equal to γ n - 2 . 10. A wire according to claim 8 for making a spring suitable for working in compression, the wire being characterized in that said first plurality of layers comprises “n” layers C1, . . . , Cn of fibers (Fb) situated on one another, the layer C1 being the closest to said axis (10), the fibers being wound in helices that are all coaxial about said axis (10), the helices of two consecutive layers being respectively left-handed and right-handed, and the tangents to the helices forming angles relative to said axis having values respectively equal to: −Δ, +Δ+α, −(Δ+2α), Δ+3α, −(Δ+4α), Δ+5α, . . . , −(Δ+(n−2)α), Δ+(n−1)α; where Δ is no greater than substantially 44.6°, and −α is substantially equal to γ n - 1 . 11. A wire according to claim 8 for making a spring suitable for working in traction, the wire being characterized by the fact that said first plurality of layers comprises an even number “n” of layers C1, . . . , Cn of fibers (Fb) situated on one another, the layer C1 being the closest to said axis (10), said fibers being wound in helices that are all coaxial about said axis (10), the helices of two consecutive layers C1, C2; . . . , Cn−1, Cn; being respectively left-handed and right-handed, and the tangents to the helices forming angles with said axis having values respectively equal to: Δ and −Δ for the first pair of layers C1, C2; Δ+2α and −(Δ+2α) for the second pair of layers C3, C4; Δ+4α and −(Δ+4α) for the third pair of layers C5, C6; and so on up to Δ+(n−2)α and −(Δ+(n−2)α) for the (n/2)th pair of layers Cn−1, Cn; where Δ is no greater than substantially 44.6°, and −α is substantially equal to γ n - 2 . 12. A wire according to claim 8 for making a spring suitable for working in traction, characterized by the fact that said first plurality of layers comprises “n” layers C1, . . . , Cn of fibers (Fb) situated on one another, the layer C1 being the closest to said axis (10), the fibers being wound in helices that are all coaxial about said axis (10), the helices of two consecutive layers being respectively left-handed and right-handed, and the tangents to the helices forming angles with said axis having respective values equal to: Δ, −(Δ+1α), Δ+2α, −(Δ+3α), Δ+4α, −(Δ+5α), . . . , Δ+(n−2)α), −(Δ+(n−1)α); where Δ is no greater than substantially 44.6°, and −α is substantially equal to γ n - 1 . 13. A wire according to claim 8, characterized by the fact that said first plurality of layers is situated at the periphery of the cylinder (FR). 14. A wire according to claim 8, characterized by the fact that it further comprises a central core (Ac). 15. A wire according to claim 14, characterized by the fact that said central core (Ac) is made of a material having a low modulus of elasticity in twisting. 16. A wire according to claim 14, characterized by the fact that said central core (Ac) is made of a material having a low modulus of elasticity in twisting and a second plurality of layers of fibers situated concentrically on one another at the periphery of the central core, the fibers being wound in helices that are coaxial and the tangents to said helices forming angles with the axis (10) of the helices having absolute values that are no greater than substantially 44. 6°. 17. A wire according to claim 16, characterized by the fact that in the second plurality of layers of fibers (Fb), the number of left-handed helices is equal to the number of right-handed helices. 18. A wire according to claim 8, characterized by the fact that it further comprises a protective sheath (11) surrounding the outside and in contact with the last layer (Cn) of the first plurality of layers of fibers (Fb). 19. A wire according to claim 8, characterized by the fact that said fibers are glass fibers and said matrix (Rp) is a polymerizable resin. 20. A wire according to claim 8, characterized by the fact that the layer situated at the periphery of the cylinder (FR) is thicker than the layer situated inside. 21. A wire according to claim 8, characterized by the fact that the value Δ for the layer (Cx−1) of the layer closest to said axis (10) is greater than the value Δ for the layer (Cx) closest to the periphery of the cylinder (FR). 22. A wire according to claim 21, characterized by the fact that it has about ten layers in said plurality (C1, . . . , Cn), said value Δ decreasing substantially continuously from substantially 44.6° to 42° on going from the first layer (C1) at the central core to the last layer (Cn) at the periphery.

The present invention relates to wire substantially in the form of a cylinder for making springs, advantageously of the helically-wound cylindrical type, or the like, and also torsion bars or the like that find applications in numerous industrial fields, and are particularly advantageous for making suspensions for motor vehicles, trucks, rail vehicles, or the like. There exist substantially cylindrically-shaped wires for making springs, the wires including at least a first plurality of helically-wound fiber layers, said layers being situated on one another and impregnated by a matrix, the fibers generally being glass fibers, and the matrix generally being a polymerizable resin of the epoxy, vinylester, or polyester type. These spring wires are very advantageous since they present the advantage of a much smaller ratio of weight over volume occupied than applies to metal wires used for making springs enabling identical resilient forces to be delivered. An object of the present invention is to provide an industrial and particularly inexpensive method of providing an improvement to wires of the above-defined type as are known in the prior art, to give them a modulus of elasticity of much greater value, and to do so for wires of the same section. The present invention also provides a spring wire obtained by implementing the method of the invention. More precisely, the present invention provides a method of making a spring wire comprising at least one layer of a fiber wound helically on a cylindrical “primary” portion of diameter equal to D, the tangent to said helix making an angle relative to the axis of the primary portion having a value β, said layer also being suitable for being bonded to the primary portion by a matrix, the fiber, once wound around the primary portion, presenting a cross-section that is substantially rectangular, of thickness E in the radial direction of the primary portion and of width E′ in the direction perpendicular to the tangent to the helix, the method consisting in preparing a funnel of frustoconical shape, said funnel having a small opening corresponding to the small base of the frustoconical shape, in preparing a supply to deliver the fiber, in connecting one of the ends of said fiber to the primary portion, and in imparting rotary movement to said supply at a speed ω about the axis of said primary portion, said primary portion being moved in translation at a speed T through the funnel along its axis going from its large opening towards its small opening, the method being characterized by the fact that it further consists in causing said fiber to penetrate into the funnel via its large opening corresponding to the large base of the frustoconical shape, the angle at the apex of said funnel having a value that is substantially equal to 2β, the small base of the frustoconical shape of said funnel having a diameter equal to D+2E, the value ω of the speed in rotation of the supply expressed in revolutions per second, and the value T of the speed in translation of the primary portion expressed in meters per second being associated by the following relationship: ω = T D ⁢ ⁢ π ⁡ [ tan ⁢ ⁢ ( π 2 - β ) ] The present invention also provides a wire for making a spring, the wire being obtained by the above-defined method, said wire being substantially cylindrical in shape and including at least a first plurality of layers of wound fibers, said layers being situated on one another and being impregnated with a matrix, the wire being characterized by the fact that said first plurality of layers comprises at least two layers of fibers situated on each other, the fibers of these two layers being wound in opposite directions relative to each other in two helical pitches about a common axis, respectively left-handedly and right-handedly, the tangents to these two helices forming angles relative to said axis with respective values βx−1 and βx that are substantially equal respectively to Δ+kγ and −Δ−kγ, where γ is a function of the value of the modulus of elasticity for the spring to be obtained and “k” is a factor of having a value lying in the range zero to one, the value Δ being no greater than substantially 44.6°. Other characteristics and advantages of the invention appear from the following description given with reference to the accompanying drawings by way of non-limiting illustration, in which: FIG. 1 is a diagram showing the principle of a helical curve and the main parameters for defining it in application of mathematical relationships; FIGS. 2 and 3 are two views of an embodiment of a wire of the invention, FIG. 2 being a cutaway side view and FIG. 3 being a diagrammatic cross-section view; and FIG. 4 shows an embodiment of means enabling the method of the invention to be implemented for making the wire of the invention. It is specified that in the figures the same references are used to designate elements that are the same, regardless of the figure in which they appear and regardless of the way in which the elements are shown. Similarly, if elements are not specifically referenced in any one of the figures, their references can easily be found by referring to another figure. FIG. 1 is a diagram showing the main parameters for defining a helical curve in application of mathematical relationships. This curve is referenced He in the figure and its defining parameters, e.g. the helical pitch Pas are known. They are described in particular on page 272 of the book entitled “Guide du dessinateur industriel” [Industrial drawing guide] by A. Chevalier, 1984-1985 edition, published by Hachette Technique. That said, FIGS. 2 and 3 show an embodiment of a wire suitable for use in making a spring and having substantially the shape of a cylinder FR that is advantageously a circular cylinder, By way of example, the spring may be of the type mentioned in the introduction. The wire includes at least a first plurality of layers Cx−1, Cx, . . . , Cn of wound fibers Fb, the layers being situated on one another and impregnated in a matrix Rp. According to an important characteristic of the invention, the first plurality of layers comprises at least two layers Cx−1, Cx of fibers wound in opposite directions to each other following two coaxial helices about a common axis 10, respectively left-handedly and right-handedly (in other words: the algebraic sign of the helix angle βx is positive for one of them and negative for the other). The tangents to these two helices form two angles relative to the axis 10 of values βx−1 and βx that are substantially equal respectively to −(Δ+kγ) and Δ+kγ, where γ is a function of the modulus of elasticity for the spring that is to be made and “k” is a factor having a value lying in the range zero to one. As a result, the tangents to the helices of two consecutive layers may form angles relative to the axis 10 having values lying in the range Δ and respectively −(Δ+γ) and +(Δ+γ), and any intermediate value. The fibers Fb may be of different kinds, for example fibers of carbon, of Kevlar (registered trademark), of Deenema (registered trademark), of boron, etc. However they are advantageously glass fibers. The matrix may also be of various kinds, for example of light alloy or metal based on aluminum, magnesium, etc., or of a polymer material that is thermoplastic, thermosetting, etc. Nevertheless, when the fibers Fb are glass fibers, the matrix is advantageously a thermosetting polymerizable resin of the epoxy, polyester, vinylester, etc. type, such as the resin known in the trade under the reference Araldite (registered trademark). The essential characteristics of the invention described above enable the above-defined objects of the invention to be achieved. In an advantageous industrial application, in order to make a spring wire suitable for working in compression, the first plurality of layers comprises an even number “n” (n>2) of layers C1, . . . , Cx−1, Cx, . . . , Cn of fibers Fb situated on one another, the layer C1 being the closest to the axis 10. These fibers are wound in helices that are all coaxial about the axis 10, and the helices of two consecutive layers C1, C2; . . . ; Cx−1, Cx; . . . ; Cn−1, Cn, are respectively left-handed and right-handed (winding angles of positive and negative signs), the tangents to these helices advantageously forming angles relative to the axis 10 having values respectively equal to −Δ and Δ for the first pair of layers C1, C2; to −(Δ+2α) and Δ+2α for the second pair of layers C3, C4; to −(Δ+4α) and Δ+4α for the third pair of layers C5, C6; and so on up to values of (−Δ+(n−2)α) and Δ+(n−2)α for the n/2 pair of layers Cn−1, Cn; where Δ is no greater than substantially 44.6°, and −α is substantially equal to γ n - 2 . However, and preferably, still for a wire for making a spring for working in compression, this first plurality of layers comprises “n” (n≧2) layers C1, . . . , Cn of fibers Fb situated on one another, with the layer C1 being the closest to the axis 10. The fibers are wound in helices that are all coaxial about the axis, with the helices of any two consecutive layers being respectively left-handed and right-handed (winding angles of positive and negative signs) and the tangents to these helices forming relative to the axis angles having values that are respectively equal to: −Δ, +Δ+α, −(Δ+2α), Δ+3α, −(Δ+4α), Δ+5α, . . . , −(Δ+(n−2)α), Δ+(n−1)α; where Δ is no greater than substantially 44.6°, and −α is substantially equal to γ n - 1 . With a wire for making a spring suitable for working in traction, the first plurality of layers comprises a number “n” (n>2) of layers C1, . . . , Cn of fibers Fb situated on one another, the layer C1 being the closest to the axis 10, and the fibers being wound in helices that are all coaxial about the axis 10. The helices of two consecutive layers C1, C2, . . . ; Cn−1 Cn are respectively left-handed and right-handed (winding angles of positive and negative signs), and the tangents to these helices form angles relative to the axis 10 having values that are advantageously respectively equal to Δ and −Δ for the first pair of layers C1, C2; to Δ+2α and −(Δ+2α) for the second pair of layers C3, C4; to Δ+4α and −(Δ+4α) for the third pair of layers C5, C6; and so on up to Δ+(n−2)α and −(Δ+(n−2)α) for the (n/2)th pair of layers Cn−1, Cn; where Δ is no greater than substantially 44.6°, and −α is substantially equal to γ n - 2 . However, preferably, still for a wire for making a spring suitable for working in traction, the first plurality of layers comprises “n” (n≧2) layers C1, . . . , Cn of fibers Fb situated on one another with the layer C1 closest to the axis 10. The fibers are wound in helices that are all coaxial about the axis 10, with the helices of two consecutive layers being respectively left-handed and right-handed (winding angles of positive and negative signs), and the tangents to these helices form angles relative to said axis having values that are respectively equal to: Δ, −(Δ+1α), Δ+2α, −(Δ+3α), Δ+4α, −(Δ+5α), . . . , Δ+(n−2)α), −(Δ+(n−1)α); where Δ is no greater than substantially 44.6°, and −α is substantially equal to γ n - 1 . Wires having a first plurality of layers of fibers in accordance with the above-defined characteristics give the best looked-for results when the first plurality of layers is situated at the periphery of the cylinder FR, i.e. when the layer of rank “n” is the closest to the side wall of the wire and when the layer of rank “1” is the closest to the axis 10. As a result, it can be seen that the structure of the central portion of the wire is not of the greatest importance in obtaining a spring wire having a very good modulus of elasticity relative to its section. Thus, for reasons of economy, and as shown in FIGS. 2 and 3, the wire may have a central core Ac. In one possible embodiment, the central core Ac is made of a material having a low modulus of elasticity in twisting, e.g. an extruded tube or rod of a material that is metallic, thermoplastic, or thermosetting, or preferably of a material that is viscoelastic serving to confer vibration-damping properties on the spring, or indeed materials that are piezoelectric, or even a tube or rod comprising a matrix and reinforcing fibers forming an angle relative to the axis 10 with a value of less than 44.6°. Preferably, the value of this angle is equal to zero degrees, with the fibers then being substantially parallel to one another and to the axis 10. However, it is also possible for the central core Ac to be made out of a material having a low modulus of elasticity in twisting, as mentioned above, together with a plurality of fiber layers situated concentrically on one another at the periphery of the central core, the fibers being preferably wound in coaxial helices with the tangents to these helices forming angles relative to the axis of the helices with a value that is advantageously equal to or no greater than substantially 44.6°, these fibers advantageously being of the same kind as that mentioned above. Without this being absolutely necessary, it is also preferable in said plurality of fiber layers Fb, for the number of left-handed helices to be substantially equal to the number of right-handed helices, without it being essential for them to alternate between left-handed and right-handed. It is also advantageous for the layers situated at the periphery of the cylinder FR, i.e. the layer of rank “n”, and the layers immediately preceding it, to be thicker than the other layers situated further in, so as to give the outer layers greater resistance to twisting deformation and, for example, so as to avoid an effect of the wire swelling when subjected to loading once it constitutes a spring, it being specified that the layer of rank “n” may be a superposition of a plurality of layers having the same thickness but all wound in the same direction and with the same angle Δ as defined above. Given that the wire is for making springs as mentioned in the introduction to the present description, e.g. in order to make motor vehicle suspensions or the like, it is also preferable for the wire further to include a protective sheath 11 surrounding the outside of the wire, in contact with the last layer Cn of the first plurality of layers of fibers Fb. This sheath may be constituted by a layer of elastic material, e.g. of silicone, rubber, polyurethane, or more generically of any thermosettable, thermoplastic, or vulcanizable material. It may also be a composite material based on fibers of Kevlar, Deenema, carbon, glass, Teflon (registered trademark), etc., placed in helices at an angle having a value greater than 44.6°, and preferably close to 90°, it being specified that the term “composite material” is used to mean an intimate assembly of fibers and a matrix. It is specified that these wires for springs are advantageously made from layers of glass fibers bonded together by means of a polymerizable resin having the advantage of polymerizing slowly and at low temperature. As a result, it is possible, for example, to make a spring of the helically-wound cylindrical type, by winding the wire while the resin is not yet polymerized, the wire being wound on a mold or the like having the shape of the spring that is to be made. This technique is itself known and is not described in greater detail herein, merely to avoid making the present description too complicated. However, in a preferred embodiment, particularly with certain materials constituting the fibers Fb, since the value Δ must be equal to or must tend to be equal to 44.6° after the spring wire has deformed, e.g. under twisting, in order to achieve this result more reliably, it is desirable to wind the fibers with a “laying” angle having a value that is less than 44.6°. Given that an effect of twisting the wire can add up to 2° to the laying angle of the fibers situated at the periphery of the wire, but only 0.5° for the fibers situated close to the axis 10, e.g. when there are about ten layers, it is advantageous to ensure that the fibers situated at the surface of the wire have a laying angle equal to 44.6°-2°, while the fibers situated close to the central core or the axis 10 have a laying angle equal to 44.6°-0.5°. The Applicant has made such a spring wire with the materials defined below in which the value of this laying angle was decreased substantially continuously from the inner first layer of rank “1” to the outer layer of rank “n” over the range 44.5° to 42.1°, where “n” was substantially equal to ten. When the wire has a plurality of layers, as is the case in practice when making springs industrially, the value Δ is greater for the first layer situated towards the center of the wire, i.e. the layer of rank “1” which is the closest to the axis 10, and also for the following internal first layers, than for the layers situated at the surface of the wire, and it decreases down to a limit value for the layer of rank “n” that is closest to the side wall of the wire or to the periphery of the above-defined cylinder FR. When the number “n” of layers is about ten, the value Δ decreases substantially continuously from about 44.6° to about 42° on going from the first layer (C1) near the central core to the last layer (Cn) at the periphery. The present invention also provides a method of making a wire such as those described above. One possible implementation of the method is shown in FIG. 4. An implementation of the method of the invention is described below when the wire is to have at least one layer C of fiber helically wound on a cylindrical “primary” portion 12 of diameter equal to D, the tangent to the helix making an angle relative to the axis 100 of said primary portion 12 having a value β, the layer C also being suitable for being bonded to the primary portion 12 by a matrix Rp, the fiber, once wound around the primary portion, presenting a cross-section that is substantially rectangular, having a thickness E in the radial direction of the primary portion 12 and a width E′ in the direction perpendicular to the tangent to the helix. It should be understood that the primary portion can be of any type, e.g. the above-described central core Ac. With reference to FIG. 4, the method consists in preparing a funnel 13 of substantially frustoconical shape, advantageously of circular section, having an angle at the apex substantially equal to 2β, the funnel having a small opening 14, corresponding to the small base of the frustoconical shape, of diameter equal to D+2E, this small opening advantageously being surrounded by a sleeve 20 having an inlet orifice substantially of the same diameter as the opening 14 (or possibly a value that is very slightly greater). It is also advantageous for the outlet orifice of the sleeve 20 to be of a shape other than circular, for example to be elliptical or the like when it is necessary to obtain a wire of the invention that presents a section that is elliptical. Naturally, other shapes are possible, depending on the shape desired for the section of the wire. The method also consists in preparing a supply 15 for delivering the fiber Fb1, e.g. a reel of glass fiber in the above-mentioned advantageous option. One of the ends 16 of the fiber is connected to the primary portion 12, said fiber Fb1 penetrating into the funnel 13 through its large opening 24 corresponding to the large base of the frustoconical shape, prior to being wound around the primary portion 12 so as to lie flush with the frustoconical inside wall of the funnel, as shown in FIG. 4. The method then consists in causing the supply 15 to rotate R at a speed of rotation ω about the axis 100 of the primary portion 12, this primary portion simultaneously being moved in translation 17 through the funnel 13 along its axis going from its large opening 24 towards its small opening 14. In addition, the speed of rotation ω of the supply 14 is a function of the speed in translation T of the primary portion 12. In one possible implementation that gives advantageous results, the value of ω expressed in revolution per second and the value of T expressed in meters per second are associated by the following relationship: ω = T D ⁢ ⁢ π ⁡ [ tan ⁢ ⁢ ( π 2 - β ) ] The above-described implementation of the method is limited to making a layer C comprising only one helix. However, in order to obtain wires that are strong with a modulus of elasticity that makes them suitable for use in making springs, as mentioned above, it is clear that the layer C should have a finite number of helices situated in contact with one another and wound on the same primary portion 12 in order to obtain a layer C that is as solid as possible, as for making the spring wire shown in FIG. 2. Under such circumstances, the method consists: in preparing X supplies 15-1, 15-2, . . . , each of one or more fibers, one end of each fiber being connected to the primary portion 12, the X fibers penetrating into the funnel 13 through its large opening 24; and in causing the supplies to rotate R at the same speed of rotation ω about the axis 100 of the primary portion, while simultaneously causing the primary portion 12 to move in translation at the speed T towards the small opening of the funnel, with the number X of these supplies being equal to: X = π ⁢ ⁢ D E ⁢ sin ⁢ ⁢ ( π 2 - β ) As mentioned above, while the fiber is being wound helically around the primary portion 12, the primary portion carrying the wound fiber is moved in translation at the speed T. This movement in translation can be selected to implement one of the following two techniques: continuous translation; stepwise translation. Continuous translation can be envisaged, but it is clear that it can be obtained only by exerting continuous traction on the emerging end of the primary portion together with the wound fiber. This technique can present two drawbacks that can be troublesome in some circumstances, namely the primary portion together with the wound fiber can become stretched involuntarily, and during this stretching, even if the stretching is eliminated when the traction ceases to be applied, the primary portion with the wound fiber is subjected to a wringing effect, that runs the risk of changing the value of the fiber laying angle, of losing polymerizable resin, and thus of impeding proper manufacture of the wire. Thus, under certain circumstances, it is advantageous to impart translation movement stepwise to the primary portion together with the wound fiber. By way of example, such stepwise movement in translation can be obtained by applying oscillating motion to the funnel 13 along its axis, the small opening 14 presenting a kind of sleeve 20 that is substantially cylindrical with biting teeth on the surface of its inside wall, preferably microteeth. By way of example, these biting teeth may be constituted by one or more rows of teeth 40 of sawtooth shape, each sawtooth (shown magnified in FIG. 4) having a flank 41 of small slope on its upstream side and an opposite flank 42 on its downstream side that is preferably perpendicular to the axis of the funnel 13, these sawteeth also being distributed continuously or discontinuously on the inside wall of the sleeve 20, either being disposed parallel to one another or in one or more helices having the same pitch as the helices formed by the fibers Fb. These microteeth may be continuous or discrete, and they may be made from etching or striping in the material lining the bore of the sleeve 20. They may also be constituted by bristles or scales sloping towards the axial outlet, parallel to the axis of the sleeve 20 or preferably perpendicular to the helices formed by the fibers Fb, or the microrelief in the last surface layer of the wire. The teeth are preferably on the same scale as the microrelief on the surface formed by the fibers Fb or the microrelief of the last layer at the surface of the wire. With teeth made in this way, and by imparting micro-oscillations to the funnel along its axis, the primary portion 12 together with the fiber Fb thereon is caused to move stepwise in translation. The oscillations “skip” from one microtooth to the immediately following microtooth along the bore of the sleeve 20. If the amplitude of the oscillations is small, typically the pitch size of the microrelief, the movement in translation can be considered as being continuous translation of average speed T, in which case it is possible to drive the supply(ies) 15 in rotation R at a speed of continuous value ω as defined above. The description above relates to an implementation of the method of the invention for making one layer C on a primary portion 12, the layer comprising one or more helically-wound fibers, all of these fibers being wound in the same direction. However, as mentioned above, a spring wire of the invention advantageously has a plurality of fiber layers wound helically in opposite directions in alternation from one layer to the next. Portion I of FIG. 4 shows how a first layer of helically-wound fibers is made on the primary portion 12 with the fibers being wound in the direction given by arrow R. Portion II in the same figure shows a second layer of fibers being wound helically on the first layer and in the opposite direction as indicated by arrow R′. When making the second layer, the primary portion is constituted by the primary portion 12 for making the first layer plus said first layer. Overall, FIG. 4 shows how two layers of fibers can be wound in opposite-direction helices, thus requiring two different funnels. In another implementation of the method, it is possible to wind at least two layers of fibers helically in opposite directions one on the other, while using only one funnel. Thus, for a wire that is to have “n” layers C of fibers Fb, each having a thickness E and being wound as “n” helices one on another in coaxial manner, respectively left-handedly and right-handedly on a cylindrical “primary” portion 12 of diameter equal to D, the tangents to the “n” helices being at angles relative to the axis 100 of the primary portion having respective values β1, β2, . . . , βn progressing between −Δ−γ and Δ+γ, the “n” layers C also being suitable for being bonded to one another and to the primary portion 12 by a matrix Rp, the method of the invention consists: in preparing a frustoconical funnel 13 having an angle at the apex equal to 2(Δ+γ), said funnel having a small opening 14 corresponding to the small base of its frustoconical shape of diameter equal to D+2nE; in preparing “n” supplies 15 of fibers; in connecting one of the ends 16 of the “n” fibers to the primary portion 12, the “n” fibers penetrating into the funnel 13 via its large opening 24 corresponding to the large base of its frustoconical shape; and in imparting rotary movement to the “n” supplies 15 in directions that are opposite from one to another and at respective speeds of rotation ω1, ω2, . . . , ωn about the axis 100 of the primary portion 12, the primary portion being moved in translation 17 through the funnel 13 along its axis going from the large opening 24 towards its small opening 14, the values ω1, . . . ω2, . . . , ωn of the respective speeds of rotation of the “n” supplies 15 being functions of the speed in translation T of the primary portion and of the corresponding local laying angle β. As mentioned above, the fibers could be bonded to the primary portion 12 and to one another by means of a liquid matrix such as the polymerizable resin if the fibers are glass fibers. It is therefore desirable to wet the primary portion 12 and the fibers themselves with the matrix prior to winding the helices. Each fiber can be impregnated by any method known to the person skilled in the art, in particular at a point upstream from the convergence in the funnel(s). The method preferably further consists in filling the funnel 13 with a liquid matrix Rp prior to setting at least one supply 15 in rotation and moving the primary portion 12 in translation. It is advantageous to position the funnels 13 in such a manner that their axes are vertical and coincide. Under such circumstances, the matrix remains fully contained in the funnel since the small opening 14 is of section equal to the total section of the primary portion covered in the layers of fibers. Consequently, the matrix does not run out through the opening 14, even in the event of production stopping, but is entrained only by the movements of the primary portion 12 and of the fibers being wound thereon, while impregnating them thoroughly so as to ensure they are properly bonded together. By running flush over the inside wall of the funnel as mentioned above, the fibers keep the funnel clean and prevent a layer of “dead” resin forming thereon which run the risk of polymerizing and thus of clogging the wall of the funnel. It is advantageous to operate at a relatively low temperature, typically about 10° C., in order to benefit from the best working conditions for making the matrix. Finally, it should be observed that when the drive is applied finally to the protective sheath 11 when that is constituted by fibers and a matrix as mentioned above, the bore of the sleeve 20 may present a surface similar to the fastener known under the trademark “Velcro” or the like.

20060309

20071225

20070419

62373.0

D02G336

TOLAN, EDWARD THOMAS

METHOD OF PRODUCING A SPRING WIRE AND WIRE THUS PRODUCED

UNDISCOUNTED

ACCEPTED

D02G

ACCEPTED

Lithography Lens System And Projection Exposure System Provided With At Least One Lithography Lens System Of This Type

An optical imaging system for a microlithography projection exposure system is used for imaging an object field arranged in an object plane of the imaging system into an image field arranged in an image plane of the imaging system. A projection objective or a relay objective to be used in the illumination system can be involved, in particular. The imaging system has a plurality of lenses that are arranged between the object plane and the image plane and in each case have a first lens surface and a second lens surface. At least one of the lenses is a double aspheric lens where the first lens surface and the second lens surface is an aspheric surface. Lenses of good quality that have the action of an asphere with very strong deformation can be produced in the case of double aspheric lenses with an acceptable outlay as regards the surface processing and testing of the lens surfaces.

1-31. (canceled) 32. An illumination system for a microlithography projection exposure system comprising: an optical imaging system for imaging an object field arranged in an object plane of the imaging system into an image field arranged in an image plane of the imaging system, the optical imaging system including a plurality of lenses that are arranged between the object plane and the image plane and in each case have a first lens surface and a second lens surface, at least one of the lenses being a double aspheric lens where the first lens surface and the second lens surface is an aspheric surface. 33. The illumination system as claimed in claim 32, wherein the first lens surface and the second lens surface of the double aspheric lens are shaped to be substantially symmetrical relative to one another. 34. The illumination system as claimed in claim 32, wherein the first lens surface and the second lens surface of the double aspheric lens have substantially the same surface description with reference to curvature and aspheric constants. 35. The illumination system as claimed in claim 32, wherein the first lens surface and the second lens surface of the double aspheric lens are shaped such that they can substantially be transformed into one another by means of an orthotomic projection. 36. The illumination system as claimed in claim 32, wherein the first lens surfaces and the second lens surface of the double aspheric lens are similar aspheres in the sense that they can be tested with the same test optics. 37. The illumination system as claimed in claim 32, wherein the double aspheric lens is arranged in the vicinity of a field plane of the imaging system. 38. The illumination system as claimed in claim 37, wherein the double aspheric lens is arranged in a lens region close to a field in which the principal ray height is large by comparison with the marginal ray height of the imaging. 39. The illumination system as claimed in claim 32, wherein the imaging system is an objective for imaging an illumination field, arranged in an intermediate field plane of the illumination system, into an exit plane of the illumination system. 40. The illumination system according to claim 39, wherein the imaging system has a linear magnification between approximately 1:1 and 1:5. 41. The illumination system as claimed in claim 32, wherein the double aspheric lens is the last lens of the imaging system, closest to the image plane. 42. The illumination system as claimed in claim 32, wherein the double aspheric lens is a substantially symmetrical biconvex lens. 43. The illumination system as claimed in claim 32, wherein the double aspheric lens is shaped as a meniscus lens. 44. The illumination system as claimed in claim 43, wherein the meniscus lens has an image-side convex surface. 45. An optical imaging system for a microlithography projection exposure system for imaging an object field arranged in an object plane of the imaging system into an image field arranged in an image plane of the imaging system, comprising: a plurality of lenses that are arranged between the object plane and the image plane, the plurality of lenses having a first aspheric lens surface and at least one second aspheric lens surface, and the first aspheric lens surface and the second aspheric lens surface being deformed similarly in such a way that they can be tested with the same test optics. 46. The optical imaging system as claimed in claim 45, wherein the first aspheric lens surface and the second aspheric lens surface have substantially the same surface description with reference to curvature and aspheric constants. 47. The optical imaging system as claimed in claim 45, wherein the first aspheric lens surface and the aspheric second lens surface are shaped such that they can substantially be transformed into one another by means of an orthotomic projection. 48. The optical imaging system as claimed in claim 45, wherein the first aspheric lens surface and the second aspheric lens surface are formed on the same lens, whereby a double aspheric lens is formed. 49. The optical imaging system as claimed in claim 45, wherein the first aspheric lens surface and the second aspheric lens surface are formed on different lenses. 50. The optical imaging system as claimed in claim 49, wherein at least one other optical surface is arranged between the first aspheric lens surface and the second aspheric lens surface. 51. The optical imaging system as claimed in claim 45, wherein the imaging system is a projection objective for imaging a pattern of a mask arranged in an object plane of the projection objective into the image plane of the projection objective. 52. The optical imaging system according to claim 45, wherein the imaging system is a subsystem integrated in an illumination system of a microlithography exposure apparatus.

The invention relates to an optical imaging system for a microlithography projection exposure system for imaging an object field arranged in an object plane of the imaging system into an image field arranged in an image plane of the imaging system, and to a microlithography projection exposure system comprising at least one such optical imaging system. Microlithography projection exposure systems are used for the microlithographic production of semiconductor components and other finely structured subassemblies. A projection exposure system has an illumination system and a projection objective downstream of the illumination system. The task of the illumination system is to prepare the light of a primary light source, for example a laser, such that a mask (reticle) that is arranged in an exit plane of the illumination system and has a pattern to be imaged can be illuminated in a way that can be prescribed in definite terms. The mask is located in the object plane of the downstream projection objective whose task it is to image the pattern of the mask with the highest possible resolution onto an object coated with a photosensitive layer, for example a semiconductor wafer coated with a photoresist layer, with the highest possible resolution. A projection objective for microlithography is a complex diffraction-limited optical imaging system comprising a plurality of lenses whose number and diameter typically increase the higher the requirements made of the resolving capability and of the optical correction. Modern projection objectives that are designed for resolving typical structure sizes of 100 nm or below and operate with ultraviolet light from the deep ultraviolet (DUV) region frequently have more than twenty lenses that are further supplemented by at least one imaging concave mirror in the case of catadioptric systems. At least one optical imaging system is likewise normally provided inside the illumination system in order to image an illumination field arranged in an intermediate field plane of the illumination system into the exit plane of the illumination system. An essential task of such an imaging system is to adapt the properties of the illumination light with regard to field size and beam path to the entrance-end requirements of the downstream projection objective. The setting of the telecentricity of the illumination light plays an essential role here. Such imaging systems are frequently denoted as relay objectives. If the object is used to image an intermediate field plane, equipped with a reticle masking device (REMA), of the illumination system into the exit plane of the illumination system or onto the reticle, the designation REMA objective is also used. These imaging systems also have a complex design comprising a plurality of lenses, which in some cases can have larger diameters. Attempts have already been made for some time to achieve a more advantageous design of the imaging systems mentioned at the beginning by using aspheric surfaces (aspheres). An aspheric surface is an optical surface that is used to reflect or refract a light bundle and is neither spherical nor flat. It is known that aspheric surfaces produce additional degrees of freedom in the possibilities of correction that can be used for an improved optical correction and/or for a reduction in the number of surfaces, and/or in order to provide particular optical properties. U.S. Pat. No. 4,906,080 exhibits a projection exposure system comprising an illumination system and a downstream projection objective. In order to adapt the light provided by the illumination system to the projection objective, the illumination system includes an imaging system having at least one aspheric surface that is calculated such that the principal ray angles of the radiation output by the illumination system substantially correspond to the principal ray angles of the downstream projection objective. In order to ensure this adaptation to the telecentricity requirements of the projection objective, in one embodiment the last lens surface facing the exit plane or image plane of the imaging system is an aspheric surface whose surface form substantially determines the ray angle adaptation. Patent application EP 1 316 832 (corresponding to WO 02/14924) exhibits a relay objective for an illumination system of a projection exposure system in which in order to reduce the number of lenses and to reduce weight while retaining its optical properties, a number of aspheric surfaces are provided, at least one of the aspheres being arranged in the vicinity of the object plane or in the vicinity of the image plane, that is to say in the vicinity of a field plane. Patent application US 2002/0171944 A1 exhibits an illumination system for a projection exposure system in which a relay objective is provided that is subdivided into three lens groups. A first lens group closest to the object plane has a negative lens with a concave surface pointing toward the object plane, a second lens group with a positive lens, and a third lens group. At least one of the lens surfaces in the first lens group is aspheric. German patent application DE 196 53 983 (corresponding to U.S. Pat. No. 6,366,410) exhibits a REMA objective where the use of fewer aspheric surfaces succeeds in reducing the number of the interfaces inside the system that lead to reflection losses, and in reducing the glass path inside the system that determines the absorption by comparison to the prior art such that a substantially improved transmission efficiency is achieved. One lens surface is respectively aspheric in the case of the aspherized lenses. In some embodiments, aspheric surfaces are arranged both in the vicinity of a pupil plane of the imaging system and in the vicinity of the object plane and/or the image plane. Patent EP 0 869 383 B1 exhibits a double-focusing catadioptric projection objective with an intermediate image where a lens with an aspheric lens surface is arranged in the vicinity of a field plane, and a lens with an aspheric lens surface is arranged at a vast distance from a field plane in the vicinity of a pupil plane. The aim of using these aspheric lenses is to be able to correct the distortion and the aspherical aberration simultaneously without other aberrations being disadvantageously influenced. European patent application EP 1 079 253 (corresponding to WO 99/52004) exhibits catadioptric projection objectives for a wavelength region of less than 180 nm in the case of which four or more aspheric surfaces are provided for supporting the optical correction. Because of the high number of aspheres, the mutually facing lens surfaces of adjacent lenses are aspheric surfaces at a number of points in the case of some embodiments. Patent application U.S. 2003/0030916 A1 exhibits various refractive projection objectives that are designed as three-belly systems with three bellies and two waists lying therebetween, and have a plurality of aspheres. The aspheric surfaces are concentrated in the waist regions, four consecutive aspheres being provided in the vicinity of the waist in one embodiment. EP 0 851 304 A2 discloses the adjacent arrangement of aspheric lens surfaces of adjacent lenses in a projection objective. The mutually facing, aspheric surfaces are positioned in the region of a pupil plane of the projection objective, and are not rotationally symmetrical. They are mounted such that they can be displaced relative to one another in a radial direction. The difference between the mutually facing aspheric surfaces, and thus the combined action of the aspheric surfaces, is varied by the relative displacement. The aim thereby is to be able to set the optical imaging properties of the projection objective in a variable fashion. The international patent application WO 01/50171 (corresponding to EP 1 242 843) exhibits refractive projective objectives that are designed as three-belly systems having three bellies and two waists lying between the bellies. There is a pair of lenses with mutually facing, aspheric lens surfaces in the region of the waist between a first lens group, following the object plane, of positive refractive power and a second lens group, following thereupon, of negative refractive power. This arrangement of aspheric lens surfaces arranged adjacent to one another on various lenses is also denoted there as a “double asphere”. By comparison with precursor systems, the use of at least one double asphere in the region of the first belly rendered it possible to correct input telecentricity and distortion with the aid of modest means over a short distance, an increase in the image-side numerical aperture having been achieved at the same time. The advantageous actions of aspheres result essentially because it is possible with the aid of aspheric lens surfaces to set a specific variation, which cannot be achieved by spherical lens surfaces, in the radial refractive power profile by suitable deformation of the asphere. In order here to achieve an optimum degree of freedom for the optical design by the use of aspheres, aspheres with strong deformations are increasingly becoming required. However, this results in problems, since the fabrication of aspheric lens surfaces with strong deformations comes up against technological limits both with regard to the processing of the aspheric lens surface and with regard to the testing of the aspheric lens surface. It is an object of the invention to provide an optical imaging system for a microlithography projection exposure system that includes a number of aspheric lens surfaces for influencing its imaging properties, the production and testing of the aspheric surfaces being simplified by comparison with the prior art. The invention provides an optical imaging system having the feature of claim 1 in order to achieve this object. Advantageous developments are specified in the dependent claims. The wording of all the claims is incorporated in the description by reference. An optical imaging system according to the invention for a microlithography projection exposure system is used to image an object field arranged in an object plane of the imaging system into an image field arranged in an image plane of the imaging system. The optical imaging system comprises: a plurality of lenses that are arranged between the object plane and the image plane and in each case have a first lens surface and a second lens surface, at least one of the lenses being a double aspheric lens where the first lens surface and the second lens surface is an aspheric surface. The optical imaging system that is also denoted below as a “lithography objective” therefore has at least two aspheric surfaces that are provided at one and the same lens such that both the entrance surface of the lens, and the exit surface of the lens are aspherically curved Such a lens is also denoted below as a “biasphere”. The inventors have found that it is possible by using double aspheric lenses of this type to provide lenses that have the action of an asphere with very strong deformation, and that can nevertheless be designed so that they can be produced with good quality and an acceptable outlay by using conventional methods for finishing and for testing the surfaces. If appropriate, a strong radial profile of the refractive power of an asphere can be produced by aspherization of the two lens surfaces of a lens. The contribution of the individual aspherical lens surfaces to the refractive power profile, and the deformation, attendant thereon, of the individual surfaces can nevertheless be kept so small that the surfaces can be produced and tested with an acceptable outlay. In some embodiments, the first lens surface and the second lens surface of the double aspheric lens are shaped to be symmetrical relative to one another. A strong aspheric action can be achieved in this way in conjunction with minimal deformation. Symmetrical double aspheric lenses are also advantageous with regard to fabrication and testing, since substantially the same production and testing process can be used for both lens surfaces. The double aspheric lens can be a biconvex positive lens or a biconcave negative lens. Also possible are embodiments where the double aspheric lens is a meniscus lens, that is to say a lens in which the first lens surface and the second lens surface have the same sense of curvature. Double aspheres can also be formed as a planarconvex lens or planarconcave lens with a substantially flat, yet aspherized first lens surface and an aspherically curved second lens surface as well as a plane-parallel plate with an aspheric component on both sides. It has proved to be advantageous with regard to simplified fabrication and testing when the first lens surface and the second lens surface of the double aspheric lens have substantially the same surface description with reference to curvature and aspheric constants. They can thus be substantially of identical shape. A simplified testing can be achieved by shaping a first aspheric lens surface and a second aspheric lens surface such that they can substantially be transformed into one another by means of an orthotomic projection. With reference to a surface of prescribed surface shape, an orthotomic light bundle is a light bundle whose rays are in each case normals to the surface onto which the light bundle falls. If use is made when testing aspheres of test optics that are shaped such that the emerging light falls substantially perpendicular to the aspheric surface to be tested, such a test optics can be used unchanged for the purpose of testing aspheres of different size as long as their aspheric surfaces can be transformed into one another by an orthotomic projection. In general, first and second aspheric lens surfaces are advantageous when both surfaces are “similar” aspheres in the sense that they can be tested with the same test optics, if appropriate given a different working distance or testing distance. The advantages that are afforded thereby, namely that at least two aspheric lens surfaces inside an optical imaging system have an essentially identical surface description with reference to curvature and aspheric constants, and/or can substantially be transformed into one another by means of an orthotomic projection, and/or are substantially shaped such that they can be tested with the same test optics, can be utilized not only when using double aspheric lenses according to the invention. Rather, mutually similar or identical aspheres can also be arranged on various lenses of an imaging system, if appropriate at a large distance from one another and/or with at least one optical surface lying therebetween. The advantages are retained with regard to the ability to produce and test. In one development of the invention, the double aspheric lens is arranged in a region of the imaging system close to a field and therefore acts as a field lens. A “region close to a field” in this sense is, in particular, a region that lies in the vicinity of a field plane of the imaging system and in which the marginal ray height of the optical imaging is smaller than or small by comparison with the principal ray height. In the region close to a field, the marginal ray height is typically less than 50%, 40%, 30%, 20% or 10% of the marginal ray height in the region of an aperture-limiting stop. An effective correction of distortion as well as a setting of the telecentricity in the closest field plane is possible with the aid of double aspheric lenses close to a field. There are embodiments in which the imaging system is a relay objective or REMA objective for imaging an illumination field arranged in an intermediate field plane of an illumination system into an exit plane of the illumination system. It has proved to be advantageous here when the double aspheric lens is the last one of the imaging system, closest to the image plane. As a result, the central function of such objectives, specifically the compensation of the telecentric error of the subsequent projection objective, is optimally fulfilled without the need to fabricate aspheric lenses with excessively strong deformation. The symmetrical shaping already mentioned has proved to be advantageous in order to achieve the desired aspheric action by comparison with conventional systems having a substantially lesser local curvature at the surface. Since the aspheres enable a large variation in the radial refractive power profile in conjunction with moderate deformation of the individual surfaces within a short installation space, biaspheres close to a field enable the generation and/or compensation of large telecentric errors. Whereas in some embodiments the exit-side double asphere is, if appropriate, a symmetrical biconvex lens, other embodiments the double asphere closest to the exit plane is shaped as a meniscus lens, in particular with a concave side directed toward the object, that is to say with an image-side convex surface. In accordance with one development, the imaging system is a projection objective for imaging a pattern of a mask arranged in an object plane of the projection objective into the image plane of the projection objective. The projection objective can be a rotationally symmetrical, purely refractive projection objective. Although systems with three or more bellies between the object plane and image plane are also possible, a preferred projection objective is designed as a two-belly system having an object-side belly, an image-side belly and a waist lying therebetween. Such a system has a first lens group, following the object plane, of negative refractive power, a second lens group, following thereupon, of positive refractive power, a third lens group, following thereupon, of negative refractive power, a fourth lens group, following thereupon, of positive refractive power, and a fifth lens group, following thereupon, of positive refractive power, a system aperture being arranged in the transition region between the fourth and fifth lens group. The double aspheric lens can be arranged in the vicinity of the object plane, in particular inside the first lens group. In one embodiment, the double aspheric lens has negative refractive power, it being shaped as a biconcave meniscus lens, in particular. If a double aspheric lens is the lens of the imaging system that is closest to the object plane, a particularly strong influence on telecentricity and the correction of distortion is possible in a small installation space. The invention can also be used in catadioptric systems with or without an intermediate image, in particular in systems having a geometric beam splitter or a physical, polarization-selective beam splitter. For example, a double aspheric lens close to a field can be present in the entrance region close to the object plane or in the vicinity of the intermediate image. The invention can equally well be used for “air objectives” and for “immersion objectives”. An air objective in this sense is a projection objective in which during operation an interspace filled with air or another gas exists between the image-side exit surface and the image plane. By contrast, an immersion objective is distinguished by the fact that during operation the interspace between an exit side of the objective and the image plane is filled with an immersion medium of high refractive index, for example an immersion liquid such as water, perfluoropolyether (PFPE) or the like. Image-side numerical apertures of NA≦1 are possible in this case. The aim when shaping the aspheric lens surfaces with regard to fabrication and testing is as slight as possible deformations. The “deformation” of an aspheric lens surface is defined here as the extent of the deviation of a spherical lens surface (enclosing sphere), adapted in the best way to the aspheric surface, of the aspheric lens surface. The enclosing sphere is laid in this case such that it touches the aspheric lens surface at its apex and at the outer edge. With regard to fabrication, it is customary to determine the extent of the deformation, that is to say the distance between the enclosing sphere and aspheric surface, in a radial direction of the enclosing sphere. From the point of view of optical design, the deformation is alternatively specified as distance in the axial direction. The last-named definition is used in this application. In the sense of this application, aspheres are, in particular, so-called “design aspheres” that are provided from the beginning in the optical design for the purpose of optimizing the system. Such design aspheres typically have maximum deformations of clearly more than 1 to 5 μm, and differ from so-called “correction aspheres”, which are inserted subsequently, if appropriate, into optical imaging systems in order to correct aberrations. Aspheres are, in particular, all optical surfaces with a rotationally symmetrical deviation from the enclosing sphere where the deviation is more than 5 μm. Useful deviations are predominantly of the order of magnitude of 0.1 mm to 1 mm. In the case of advantageous embodiments, aspheric surfaces are. possible for which the maximum deformation is less than 500 μm, in particular less than 400 μm or less than 300 μm. This facilitates the fabrication and testing of the aspheres. The invention also relates to a design method for producing an optical imaging system for a microlithography projection exposure system, the imaging system being provided for imaging an object field arranged in an object plane of the imaging system into an image field arranged in an image plane of the imaging system, and having a plurality of lenses that are arranged between the object plane and the image plane, and it being permitted to provide an aspheric effect of at least one aspheric optical surface in order to influence the imaging. In the method, a first aspheric lens surface and at least one second aspheric lens surface are calculated by means of appropriate algorithms in a calculation program such that a combination of the first and the second aspheric lens surfaces is formed in order to produce the aspheric effect, and that the first aspheric lens surface and the second aspheric lens surface are deformed similarly in such a way that they can be tested with the same test optics. The method can be integrated into existing computer programs by means of suitable programming. Apart from proceeding from the claims, the existing and further features also proceed from the description and the drawings, it being respectively possible to implement the individual features on their own or severally in the form of subcombinations in one embodiment of the invention and in other fields, and to constitute advantageous designs that are patentable per se. FIG. 1 shows a schematic of an embodiment of a projection exposure system for microlithography; FIG. 2 shows an embodiment of an inventive imaging system that is designed as a refractive two-belly projection objective; FIGS. 3 and 4 show reference systems relating to the projection objective in accordance with FIG. 2; FIG. 5 shows a first embodiment of an inventive imaging system that is designed as a REMA objective for an illumination system of a projection exposure system; FIGS. 6 and 7 show schematics relating to the dependence of the local curvature C on the relative aperture on aspheric lens surfaces of a symmetrical double aspheric lens; FIG. 8 shows a diagram relating to the pupil function of the REMA objective in accordance with FIG. 5; FIG. 9 shows a diagram that illustrates the dependence of the telecentric error on the image height of the REMA objective in accordance with FIG. 5, for various settings; FIG. 10 shows a diagram that illustrates the dependence of the uniformity error of the image height of the REMA objective in accordance with FIG. 5, for various settings; FIG. 11 shows a second embodiment of an inventive imaging system configured as a REMA objective; FIG. 12 shows a third embodiment of an inventive imaging system configured as a REMA objective; FIG. 13 shows a fourth embodiment of an inventive imaging system configured as a REMA objective; FIG. 14 shows a schematic of the effect of various shapings of aspheres on the shape of a wavefront passing through; FIG. 15 shows a lens section through the image-side end region of a catadioptric immersion projection objective; and FIG. 16 shows a variant of the projection objective shown in FIG. 15, with aspheric lens surfaces similar to one another. In the following description of preferred embodiments, the term “optical axis” denotes a straight line through the centers of curvature of the spherical optical components or through the axes of symmetry of aspheric elements. Directions and distances are described as being on the image side or as toward the image when they are pointed in the direction of the image plane, and as on the object side or toward the object when they are directed toward the object with reference to the optical axis. FIG. 1 shows an exemplary embodiment of a projection exposure system 1 for microlithographic production of integrated semiconductor components and other finely structured subassemblies at resolutions of up to 0.1 μm or below. The projection exposure system 1 comprises an illumination system 2 for illuminating a photomask 5 (reticle) arranged in the exit plane or image plane 4 of the illumination system, as well as a projection objective 6 that is provided for the purpose of imaging the pattern of the photomask arranged in its object plane 4 into the image plane 7 of the projection objective on a reducing scale. A semiconductor wafer coated with a photosensitive layer is located in the image plane 7 as an object to be exposed. Serving as a light source of the illumination system 2 is a laser 8, for example an excimer laser, customary in the deep ultraviolet (DUV) region and having an operating wavelength of 248 nm, 193 nm or 157 nm. The light of the output light beam is largely linearly polarized. A subsequent optical device 9 shapes the light of the light source and transmits it into a subsequent light mixing device 10. In the example shown, the optical device 9 comprises a beam expander that is downstream of the laser 8 and serves the purpose of reducing coherence and shaping the beam to a rectangular beam cross section with an aspect ratio x/y of its side lengths of more than one. A first diffractive optical raster element subsequent to the beam expander is seated in the object plane of a subsequent zoom objective, in whose exit pupil a second optical raster element is provided. From the latter, the light enters an encoupling optics that transmits the light into the light mixing device. The light is mixed and homogenized inside the light mixing device 10 by multiple internal reflection, and exits at the exit 11 of the light mixing device in a largely homogenized fashion. Arranged directly at the exit of the light mixing device is an intermediate field plane in which a reticle masking system (REMA) 12, an adjustable field stop, is arranged. The subsequent objective 13, which is also denoted as REMA objective, has a number of lens groups, a pupil plane 14 and a deflecting mirror 15, and images the intermediate field plane of the reticle masking system onto the reticle or the photomask 5. The design of the previously described illumination system can substantially correspond to the design described in EP 0 747 772, the disclosure content of which is incorporated in this description by reference. The entrance plane 21 of the light mixing device 10, which coincides with the rear focal plane of the upstream encoupling optics is a field plane of the illumination system. The exit plane of the light mixing device, in the region of which the reticle masking system 12 is arranged, is likewise a field plane. In other embodiments with a similar basic design, the optical devices present up to the exit plane of the encoupling optics are shaped such that the illumination distribution within this field plane is sufficiently uniform. No separate light mixing device is provided in the case of these embodiments, and so the reticle masking system can be arranged directly in the region of the exit plane of the encoupling optics. A typical design of an embodiment of an inventive, purely refractive reduction objective 200 is shown in FIG. 2. It serves the purpose of imaging a pattern, arranged in its object plane 202, of a reticle or the like into an image plane 203 on a reduced scale, for example, on the scale 4:1 (linear magnification β=0.25). This is a rotationally symmetrical one-wayist system or two-belly system with five consecutive lens groups that are arranged along the optical axis 204 perpendicular to the object plane and image plane. The first lens group LG1 following the image plane 202 has negative refractive power (with a focal length of −546.86 mm). A second lens group LG2 following thereupon has positive refractive power (with a focal length of 205.97 mm). A third lens group LG3 following thereupon has negative refractive power (and a focal length of −55.62 mm). A fourth lens group, following thereupon, has positive refractive power (and a focal length of 216.53 mm). A fifth lens group LG5, following thereupon, has positive refractive power (and a focal length of 121.10 mm). This distribution of refractive power produces a two-belly system that has an object-side belly 206, an image-side belly 208 and a waist 207 that lies therebetween and in which a site of constriction X with a minimum beam diameter lies. The system aperture 205 lies in the region of relatively large beam diameters in a transition region from the fourth lens group to the fifth lens group. The imaging possible with the aid of the projection objective can be characterized by the course of its principal rays and marginal rays. Denoted here as principal ray A is a ray that runs from an outer marginal point of the object field in a fashion parallel, or at an acute angle, to the optical axis, and cuts the optical axis 204 in the region of the system aperture 205. A marginal ray B leads from the middle of the object field, that is to say from an axial field point, to the edge of an aperture stop that is normally seated at the location of the system aperture 205 or in the immediate vicinity thereof. A ray C, that leads from an outer field point to the opposite edge of the aperture stop, is denoted here as a coma ray. The perpendicular distance of these rays from the optical axis yields the corresponding ray heights hA, hB and hC. A first lens region LB1 begins at the object plane 202 and ends in the plane in which the marginal ray B and the coma ray C intersect such that the condition |hB/hC|<1 is fulfilled in the first lens region LB1. The principal ray height is large by comparison with the marginal ray height in this lens region LB1. The lens surfaces arranged here are denoted as “particularly close to a field”. A second lens region LB2 extends from the object plane 202 as far into the region in which the principal ray height and the marginal ray height are approximately equal in terms of magnitude, it applying, in particular, that |hB/hA|<1.2. In typical variants of inventive projection systems, the length of the second lens region LB2 is smaller than one third of the distance L between the object plane 202 and image plane 203. This object/image distance is also denoted as the design length of the projection objective. The first lens group LG1 following the object plane 202 is substantially responsible for expanding the light bundles in the first belly 206. A negative lens 211 with a convex entrance side relative to the object plane and a concave exit side on the image side is provided as first lens directly following the object plane 202. Both lens surfaces (surfaces 2 and 3 in Table 1) are aspheric surfaces, and so the negative lens 211 is also denoted here as a “double aspheric lens” or “biasphere”. There follows a double spherical meniscus lens 212 of weak refractive power and, downstream thereof, a positive meniscus 213 with an object-side aspheric concave surface. The aspheric surfaces, arranged particularly close to the field, of the double aspheric lens 211 contribute to the good correction of the distortion and of the astigmatism, and provide support for the correction with regard to telecentricity. The second lens group LG2 comprises four positive lenses 214, 215, 216, 217. An entrance-side meniscus lens 214 with a virtually flat, object-side concave entrance surface and spherical exit surface is followed by a further virtually planarconvex positive lens with a spherical entrance surface and a virtually flat aspheric exit surface. Following thereupon are a double spherical positive meniscus 216, a thick positive meniscus lens 217 with a spherical entrance surface and an aspheric exit surface that is concave on the image side. This design, in which the curvatures of the lens surfaces on the object side and image side of a plane lying between the lenses 214, 215 run in opposite directions and with concave surfaces averted from one another, ensures small surface loadings for the meniscuses and the positive lenses and thus slight aberrations. The third lens group LG3 comprises three negative lenses 218, 219, 220. A double spherical meniscus lens 218 with a concave surface on the image side is followed by a negative meniscus lens 219 which is concave on the object side and has an image-side asphere and a double spherical biconcave lens 220. The location X of narrowest constriction inside the waist 207 lies in the entrance region of the lens 219. The fourth lens group LG4 starts with a positive meniscus lens 221, concave relative to the object plane, with an aspheric entrance surface that is followed by a negative meniscus 222 with a virtually flat entrance surface and spherical exit surface concave on the image side. Seated behind a subsequent double spherical biconvex lens 223 is a positive meniscus 224, concave relative to the image plane, with a spherical entrance side and aspheric exit side. Striking inter alia are the large incident angles, occurring on the exit side of the meniscus 222, in the region of the divergent ray bundle, which contribute to the correction. The fifth lens group LG5 starts with a double spherical negative meniscus 225 with an image-side concave side that projects into the region of the system aperture. Following this are six positive lenses 226, 227, 228, 229, 230, 231, of which the first lens 226 is biconvex, while the remaining are designed as positive meniscuses concave on the image side. The exit sides of the lenses 227 and 229 are aspheric, while the other lens surfaces are spherical. The system ends with a plane-parallel plate 232. The double telecentric system has an object-side operating distance of approximately 32 mm and an image-side operating distance of 5 mm. The specification of the design is summarized in Table 1 in tabular form in a known way. Here, column 1 specifies the number of a surface distinguished as refractive or in some other way, column 2 specifies the radius r of the surface (in mm), column 3 specifies the distance d, denoted as thickness, of the surface from the subsequent surface (in mm) and column 4 specifies the material of the optical components. Column 5 specifies the refractive index of the lens material, and column 6 specifies the useful, free radii or half the free diameter of the lenses (in mm). Eleven of the surfaces, particularly the surfaces 2, 3, 6, 11, 15, 19, 22, 29, 36, 38 and 40, are aspheric in the embodiment. Table 2 specifies the corresponding aspheric data, the aspheric surfaces being calculated using the following rule: p(h)=[((1/r)h2)/(1+SQRT(1−(1+K)(1/r)2h2))]+C1*h4+C2*h6+ . . . Here, the reciprocal (1/r) specifies the radius of the surface curvature, and h the distance of a surface point from the optical axis (that is to say the ray height). p(h) therefore provides the so-called sagitta, that is to say the distance of the surface point from the apex of the surface in the z-direction, that is to say in the direction of the optical axis. The constants K, C1, C2, . . . are reproduced in Table 2. The optical system reproducible with the aid of these data is designed for an operating wavelength of approximately 193 nm, at which the synthetic silica glass used for all lenses has a refractive index n=1.5608. The image-side numerical aperture is NA=0.95. The objective has a design length L (distance between the image plane and object plane) of 1101 mm. Given an image size of approximately 14 mm, a light conductance value (product of numerical aperture and image size) of approximately 13.3 mm is reached. Particular features of this design are now explained in conjunction with FIGS. 3 and 4, which show reference systems that have a virtually identical lens sequence except for the region of the objective entrance. The specifications of the embodiment in FIG. 3 is specified in Tables 3 and 4, those of the embodiment in accordance with FIG. 4 being specified in Tables 5 and 6. All three systems have substantially the same, good correction state. In the reference system in FIG. 3, the first lens, next to the object plane 202, is formed by a planarconcave negative lens 311 where the flat entrance surface is followed by a strongly deformed, aspheric exit surface (surface 3 in Table 3). This aspheric surface has a maximum deformation of approximately 1037 μm. The system can be effectively corrected, in particular, even with regard to telecentricity and distortion, with the aid of this strong deformation. However, the deformation is so large as to present difficulties in producing and testing such an asphere. In the reference system 400 in accordance with FIG. 4, two negative lenses 411, 411′ are provided instead of one negative lens 311 in the region close to an object or close to a field. In both negative meniscuses, the entrance side respectively assigned to the object plane is aspherized, while the exit side that is concave relative to the image plane is spherically curved. Since the total deformation in the region near a field that is required for correction is distributed here over two aspheric surfaces (on different lenses), the deformations of the individual aspheric surfaces can be kept substantially smaller than in the example in accordance with FIG. 3, fabrication and testing thereby being facilitated. However, two additional surfaces that can cause light losses are introduced. In addition, stringent requirements are placed on the relative positioning of the aspheric surfaces lying closely next to one another. The problems occurring with the reference systems can be avoided in the inventive embodiment in accordance with FIG. 2. In the negative lens 211, the total deformation is distributed over the two aspheric lens surfaces such that a biasphere is formed. The deformations of the individual lens surfaces lie in the range below 500 μm. Deformations in this range can be effectively mastered during production and testing, and so such a biasphere can be produced with high quality. The arrangement of the double aspheric lens, acting as field lens, in the direct vicinity of the object plane 202 permits an effective correction of field aberrations. Alternatively, or in addition, one or more biaspheres can also be provided in other regions of the projection objective, for example in the region of the image-side exit. FIGS. 5 to 13 are used to describe by way of example the use of biaspheres in the field lens part of REMA objectives with the aid of which in the region of the adjustable stop formed by the REMA system can be imaged inside the illumination system onto the reticle to be exposed on a suitable scale (typically between approximately 1:1 and approximately 1:4 to 1:5). The images are therefore enlarging as a rule, but can also be performed substantially without a change in field size, or even in a slightly reducing fashion. FIG. 5 shows an embodiment of such a REMA objective 500 that is designed for an operating wavelength of 193 nm and an approximately 1:1 imaging (β=0.98). The specification is set forth in Tables 7 and 8. The objective has an object plane 502 in which the reticle masking system is arranged. There follows a condenser part 550 that is upstream of the aperture stop 505 and designed as a partial objective. Beginning downstream of the aperture stop 505 is an intermediate part 560 that extends between the aperture stop and an imaginary plane 506 in which a deflecting mirror for example can be arranged. Beginning downstream thereof is a field lens part 570 that, in the vicinity of the image plane 503 in which a reticle to be exposed is located during operation of the system, comprises a number of lenses arranged in the vicinity of the image field. The air spaces in the region of the object plane 502, in the region of the aperture stop 505, between the intermediate part 560 and the field lens part 570 as well as in the region of the reticle plane or image plane 503 are so generously dimensioned that the parts to be arranged there and, in particular, the REMA system (reference numeral 12 in FIG. 1), correction elements in the stop plane, a deflecting mirror (reference numeral 15 in FIG. 1) and a reticle stage for moving the masks to be arranged in the image plane can be accommodated without a problem. A principal function of the REMA objective 500 is to image a bright/dark edge, defined by the cutting of the REMA stop, sharply from the object plane 502 onto the reticle plane 503. A further core function of the REMA objective is to adapt the direction of the centroid ray of the emerging rays, down to a few mrad (for example 3 mrad) to the directions of the principal rays of the downstream projection objective. This is equivalent to the requirement of reproducing a prescribed pupil function with the least deviations in the exit plane (reticle plane 503). The condenser part 550 comprises a positive meniscus lens 511, concave on the object side, with a spherical entrance surface and exit-side aspheric surface, and a further positive meniscus lens 512 with a spherical entrance surface and exit-side aspheric surface. The intermediate part 560 following downstream of the aperture stop comprises a further positive meniscus lens 513 with a spherical entrance surface and exit-side aspheric surface. The field lens part 570 has a positive meniscus lens 514, concave on the image side, with an aspheric entrance surface and spherical exit surface, a positive meniscus lens 515, concave on the image side, with a spherical entrance surface and spherical exit surface, a diverging planar-concave lens 516 with a flat entrance surface and aspheric exit surface. A double aspheric lens 517 with an aspheric entrance surface and aspheric exit surface is provided at the last, exit-side lens of the REMA objective. Still following downstream thereof are two plane-parallel plates 518, 519 and the reticle 520. The biasphere 517 is of substantially symmetrical design with reference to a plane of symmetry lying perpendicular to the optical axis, such that the aspheric entrance surface and the aspheric exit surface are formed in an essentially mirror-symmetric fashion relative to one another. For the purposes of illustration, in this regard FIG. 6 shows schematically the typical profile of the local curvature C of the entrance side as a function of the relative aperture (Re. Ap.) for the case of a comparable embodiment. FIG. 7 shows the corresponding illustration for the exit side of the biasphere. A comparison of the figures shows the far-reaching symmetry of the curvature profiles. The system has numerous special features, some of which are described in more detail below. The linear magnification is 1:0.98. All the elements with a center thickness of less than 10 mm are made from CaF2 (n=1.501403 at 193 nm) in order to minimize compaction there. This relates to the filter plates 518, 519, the reticle 520 and the penultimate lens 516. This can be advantageous, because there is the suspicion that thin lenses, in particular, suffer more severely under birefringence owing to compaction. Other lenses are made from synthetic silica glass (n=1.560318). The concave asphere on the exit side of lens 515 is controlled such that its deviations from the curvatures of a sphere do not contain points of inflection. The aspheric surfaces of the double aspheric lens 517, which are principally responsible for the telecentric profile are controlled such that their tangents always preserve the same sign. In order to simplify fabrication, the aspheres of the first four lenses 511 to 514 are respectively on the convex side. The sagging of the lens 513 is kept small in order to save material. The lens 513 close to the pupil is made from CaF2 in order to ensure radiation resistance for small settings. The pupil is optimized to a transverse deviation of less than 0.75 mm. It is thereby possible to introduce a stop in order to limit the settings in order, if appropriate, to minimize scattered light in the case of small settings. The overall length is 1418 mm. FIG. 8 shows that pupil function which is to be set in the field plane 503 (reticle plane). The telecentric angle [mrad] is illustrated to this end as a function of the image height r[mm]. FIG. 9 shows the dependence of the telecentric error [mrad] on the image height y. It may be seen that the maximum telecentric error is <0.2 mrad for an annular setting of <0.3 mrad. It is to be seen from FIG. 10 that the maximum uniformity error plotted on the ordinate is <0.05%, a field profile of up to 100.5% being set in order to maintain the transmission or the layer influences. The planar-concave negative lens 516 serves as manipulator for compensating uniformity errors with a linear field profile. The biasphere 517 enables a large variation in the radial refractive power profile in the case of moderate deformation of the individual surfaces inside a very short installation space that is determined by the axial thickness of the biasphere. If such a biasphere is positioned in the immediate vicinity of the image field, it is possible to correct large telecentric errors, or to set any desired pupil functions within wide limits. Despite the strong aspheric action, the biasphere is relatively unproblematic with regard to the fabrication of its surfaces and to the testing of the surfaces, since only relatively slight surface deformations occur. In addition, testing can be carried out using one and the same test optics owing to the symmetry of the two aspheric surfaces, and this substantially eases the outlay on testing. FIG. 11 shows another variant of an inventive lithography objective 600 that is designed as REMA objective for 248 nm. The exit-side biasphere 690 is shaped here as a positive meniscus lens with a concave surface on the object side in conjunction with basically the same division into a condenser part 650, an intermediate part 660 and a field lens part 670. The system has an enlarging linear magnification β=−4.73. The object field diameter is 27 mm. The object-side numerical aperture is 0.127. The design length is 1200 mm. An edge sharpness of 0.1-99.9%—exactly 0.253 mm is achieved. The pupil function (desired value and actual value) is specified in Table 9, while the specification comes from Tables 10 and 11. Another variant of an inventive lithography objective 700, which is designed as a REMA objective for 248 nm, is shown in FIG. 12. Here, in conjunction with basically the same division into a condenser part 750, an intermediate part 760 and a field lens part 770, the exit-side biasphere 790 is shaped as a positive meniscus lens with a concave surface on the object side and a relatively strong curvature. The system has an enlarging linear magnification β=−=4.73. The object field diameter is 27 mm. The object-side numerical aperture is 0.127. The design length is 1200 mm. An edge sharpness of 0.1-99.9%—exactly 0.251 mm is achieved. The pupil function (desired value and actual value) is specified in Table 12, while the specification comes from Tables 13 and 14. Another variant of an inventive lithography objective 800, which is designed as a REMA objective for 248 nm, is shown in FIG. 13. Here, in conjunction with basically the same division into a condenser part 850, an intermediate part 860 and a field lens part 870, the exit-side biasphere 890 is shaped as a positive meniscus lens with a concave surface on the object side. The system has an enlarging linear magnification β=−4.73. The object field diameter is 27 mm. The object-side numerical aperture is 0.127. The design length is 1200 mm. An edge sharpness of 0.1-99.9%—exactly 0.244 mm is achieved. The pupil function (desired value and actual value) is specified in Table 15, while the specification comes from Tables 16 and 17. The examples so far show possibilities for using a plurality of aspheric surfaces in the case of lithography objectives without coming up against technological limits in fabrication and testing because of strong deformations of the aspheres. Further measures for avoiding such problems are proposed in conjunction with FIGS. 14 to 16. As mentioned at the beginning, in optical design a customary approach to reducing aspheric deformation is to introduce further aspheres at a point with strongly deformed aspheres in order to distribute the strong deformation over a number of more weakly deformed aspheres. The inventors have now found out that great technological advantages can be yielded in the case of this procedure when, instead of one strongly deformed aspheric surface, use is made of two or more identically or at least similarly aspherized surfaces with a correspondingly weaker deformation. It is true that a division into two or more identical or similar aspheric surfaces slightly increases the outlay on fabrication, since a number of surfaces need to processed. However, the surface processing of all the identical aspheres can substantially proceed in accordance with the same program. In particular, identical and similar aspheric surfaces can be tested with the same test optics such that a substantial outlay on testing can be saved. This basic idea will be explained in more detail with the aid of FIG. 14. FIG. 14(a) shows a plane-parallel plate 900 that is transirradiated by a plane wave. It is to be seen with the aid of the schematically depicted wavefront 901 that the plane wave upstream of the plane-parallel plate and downstream of the plane-parallel plate has no aberrations and that therefore a plane wave remains. If, according to FIG. 14(b), one side of the plane-parallel plate is now deformed with a deformation d (x, y), the continous wavefront acquires a wave aberration such that a slightly deformed wave 901′ results. The wave aberration can be described substantially in the zero order immediately downstream of the “thin” plate by the product (n-11)*d(x, y), n being the refractive index of the plate. If, in accordance with FIG. 14(c) the asphericity is doubled starting from FIG. 14(b), there is also a doubling of the wave deformation. However, if, in turn, starting from the situation in FIG. 14(b), an identical aspheric surface is once again also applied to the exit side of the plane-parallel plate, it is possible as a result for the wave aberration likewise to rise to 2*(n-1)*d(x, y) (FIG. 14(d)). The effects of the entrance-side aspheric surface and the exit-side aspheric surface of the double aspheric lens 911 formed thereby are added together so that the effect seems to gradually form an asphere with a deformation of 2*d(x, y). It is therefore conceivable in principle to distribute an asphere with the deformation 2*d(x,y) over two aspheres each having identical deformations of d(x,y). It is likewise possible in an optical imaging system, for example a projection objective for microlithography, to distribute an asphere with a large deformation over two aspheres with a lesser, but the same or similar deformation, or to relieve an asphere with deformation that is threatening to become greater than a permissible limit value by a second, identical or similar asphere. This can be carried out such that the entire deformation corresponds substantially to the sum of the two deformations so that it is possible to reach apparently larger, effective deformations. If the surface curvatures of the mutually supplementary aspheric surfaces are in agreement completely or at least predominantly, an identical test optics can be used for testing the additional aspheric surface. As a result, no extra outlay is generated in the case of testing, it merely being necessary to increase the number of the surfaces to be aspherized. Starting from this basic principle, it will be necessary in a real design to support the result of the method by subsequent optimization in order to take account of a finite spacing between the two resulting aspheres. It is, in addition, not mandatory for the mutually corresponding, identical or similar aspheric surfaces to be directly adjacent. It is also possible for at least one optical surface, for example a spherical lens surface to be situated between the mutually corresponding aspheric surfaces. In a further development of the method, it is not necessary in principle for the mutually corresponding aspheric surfaces to be exactly identical. It has emerged that it is also possible for the mutually supplementary or corresponding aspheric surfaces to be shaped “similarly” in such a way that they can be tested with the same test optics (given a different working distance or testing distance). The substantial technological advantages further ensue for testing in this case, as well. It is provided in one variant of the method to produce a desired aspheric action in which provision is made of at least two aspheric surfaces that substantially emerge from one another or are transformed into one another by means of an orthotomic projection. This means that the surface normals to the aspheric surfaces that are similar in this sense form a “substantially orthotomic system”. It is possible in this way even to test aspheres having different absolute dimensions with the aid of an identical test optics, since it is possible in the case of all the aspheric surfaces belonging to an orthotomic system of the testing radiation provided by the test optics to impinge perpendicularly on these aspheric surfaces, thus facilitating testing. Two or more aspheric surfaces to be compared need not form a perfect orthotomic system. It suffices when they form a “substantially orthotomic system” in the sense explained below: assuming that two aspheric surfaces to be compared are firstly arranged concentrically about a point with reference to the apex radius, a surface normal to the first surface then encloses an angle α at the respective intersection point with the surface normal to the second surface. It holds for an exactly orthotomic system that α=0 for all possible surface normals. It holds for a “substantially orthotomic system” in the sense of the application that sin ⁡ ( α ) ≤ N ( D / λ D being the optically free diameter of the aspheric surface, and λ the wavelength (for example 633 nm) used for testing. The apex spacing of the two surfaces now need no longer be given by the difference between the apex radii, but is to be selected so as to minimize the maximum angle α that occurs. In the sense of the application, “substantially orthotomic systems” are involved, in particular, whenever it holds that N=50, in particular N=10 or N=2. This means that the residual compensation of 50 or 10 or 2 interference fringes/diameters then occurs in an interferogram in the case of interferometric measurement. FIG. 15 shows an image-side end region of a catadioptric immersion projection objective 1000, designed for 193 nm, as an example of the advantages of this design method. In a region close to the stop between the 1005 and image plane 1003 a relatively strongly deformed aspheric surface (surface 53) is positioned on the exit side of an approximately planarconvex positive meniscus (maximum deformation approximately 400 μm). In the corresponding system in FIG. 16, the strongly deformed aspheric surface was relieved by positioning on the exit surface, likewise concave relative to the image plane, of the positive meniscus lens following thereupon, a further aspheric surface (surface 55) that has substantially the same surface description as that of the aspheric surface upstream thereof. It was possible to halve the maximum deformation from approximately 400 μm to circa 200 μm by means of this measure, thus simplifying fabrication and testing. Moreover, it was even possible to substantially improve the system performance from 12.0 mλ to 10.6 mλ. It is assumed that the improvement to the system performance results in part from the fact that higher-order deformations at the aspheric surfaces can be reproduced when asphericity is distributed over more than one surface. The specification of the systems is quoted in Tables 18 and 19 (re FIG. 10) and 20 and 21 (refigure 11). TABLE 1 r217v REFRACTIVE INDEX ½ FREE SURFACE RADII THICKNESSES LENSES 193.368 nm DIAMETER 0 0.000000000 32.320000000 LUFTV193 1.00030168 56.080 1 0.000000000 0.000000000 LUFTV193 1.00030168 63.974 2 −1459.164104982AS 10.883642136 SIO2V 1.56078570 63.974 3 180.619581350AS 39.156911315 N2VP950 1.00029966 67.044 4 −107.911220584 84.781901584 SIO2V 1.56078570 68.729 5 −213.989607599 1.000000000 N2VP950 1.00029966 111.823 6 −412.845153739AS 45.792045149 SIO2V 1.56078570 120.332 7 −190.379523326 1.000000000 N2VP950 1.00029966 126.132 8 −4614.877843160 27.708693812 SIO2V 1.56078570 134.795 9 −457.274001084 1.000000000 N2VP950 1.00029966 135.949 10 420.000000000 30.000000000 SIO2V 1.56078570 137.193 11 35602.890285272AS 1.000000000 N2VP950 1.00029966 136.246 12 270.000000000 26.475451634 SIO2V 1.56078570 131.917 13 502.754294891 1.000000000 N2VP950 1.00029966 129.430 14 173.244893529 85.000000000 SIO2V 1.56078570 120.248 15 214.130898591AS 20.540800473 N2VP950 1.00029966 92.443 16 1272.514093441 39.820596617 SIO2V 1.56078570 90.281 17 110.781466896 74.295506424 N2VP950 1.00029966 68.947 18 −104.989672476 9.000000000 SIO2V 1.56078570 65.198 19 730.287776054AS 22.486936747 N2VP950 1.00029966 71.895 20 −307.597097235 9.262679110 SIO2V 1.56078570 75.360 21 451.935383561 17.226875006 N2VP950 1.00029966 83.667 22 −1494.299186899AS 38.937578772 SIO2V 1.56078570 87.442 23 −148.722559000 1.035639602 N2VP950 1.00029966 92.689 24 −3752.461411339 9.000000000 SIO2V 1.56078570 103.329 25 258.882844388 20.496820411 N2VP950 1.00029966 111.025 26 784.281838265 42.249678112 SIO2V 1.56078570 115.317 27 −299.834096576 1.000000000 N2VP950 1.00029966 119.214 28 252.743271757 38.035650313 SIO2V 1.56078570 152.454 29 462.923229099AS 46.891093164 N2VP950 1.00029966 151.679 30 0.000000000 −33.756526966 N2VP950 1.00029966 154.358 31 330.495802864 9.500000000 SIO2V 1.56078570 155.347 32 231.289261882 40.469468987 N2VP950 1.00029966 153.254 33 571.711143658 76.794483240 SIO2V 1.56078570 155.511 34 −290.609715959 1.000000000 N2VP950 1.00029966 157.318 35 237.617551020 57.120134799 SIO2V 1.56078570 153.853 36 1696.873918301AS 1.000000000 N2VP950 1.00029966 151.130 37 157.356137136 46.718690084 SIO2V 1.56078570 127.954 38 293.488395013AS 1.000000000 N2VP950 1.00029966 121.868 39 151.671762316 59.722817409 SIO2V 1.56078570 107.894 40 208.655839861AS 4.385810273 N2VP950 1.00029966 80.177 41 204.831099129 21.287882831 SIO2V 1.56078570 77.985 42 804.557271249 6.470098061 N2VP950 1.00029966 70.895 43 475.191683660 12.337210713 SIO2V 1.56078570 57.127 44 1142.238156752 5.049134278 N2VP950 1.00029966 48.974 45 0.000000000 9.468750000 SIO2V 1.56078570 36.676 46 0.000000000 5.000014319 LUFTV193 1.00030168 29.397 47 0.000000000 −0.000014316 1.00000000 14.020 TABLE 2 ASPHERIC CONSTANTS SURFACE NO. 2 K 0.0000 C1 1.09119463e−007 C2 −5.30689084e−012 C3 −1.09315970e−016 C4 4.82752139e−020 C5 −2.47155650e−023 C6 1.58501935e−027 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 3 K 0.0000 C1 −1.56384505e−007 C2 1.06996314e−011 C3 −1.05376927e−015 C4 1.85697980e−019 C5 −3.19176766e−023 C6 2.00274942e−027 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 6 K 0.0000 C1 3.83956125e−009 C2 3.47868288e−013 C3 −1.28803865e−017 C4 1.18910850e−021 C5 −4.25647183e−026 C6 5.77188832e−031 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 11 K 0.0000 C1 4.81120275e−009 C2 4.13520576e−014 C3 −5.36254054e−018 C4 3.56325685e−022 C5 −9.96093521e−027 C6 1.64692958e−031 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 15 K 0.0000 C1 −1.61331019e−008 C2 3.52919257e−014 C3 3.06661268e−017 C4 −7.22002268e−021 C5 4.16057249e−025 C6 −2.31207963e−029 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 19 K 0.0000 C1 1.27878859e−008 C2 −4.13979560e−012 C3 −4.07208879e−016 C4 5.26377145e−020 C5 −8.68076114e−025 C6 −6.17849743e−029 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 22 K 0.0000 C1 −3.87264754e−008 C2 1.81612882e−012 C3 −1.09323759e−016 C4 2.55204344e−021 C5 −1.38859668e−025 C6 4.37920480e−030 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 29 K 0.0000 C1 1.55648594e−009 C2 7.87201037e−014 C3 −7.46227893e−019 C4 −8.47715974e−023 C5 3.94573522e−027 C6 −5.27152158e−032 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 36 K 0.0000 C1 1.38463693e−009 C2 9.34105890e−014 C3 −3.31978125e−018 C4 1.98461745e−022 C5 −5.31913432e−027 C6 7.36614617e−032 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 38 K 0.0000 C1 1.23494614e−009 C2 4.07836082e−013 C3 5.52319264e−018 C4 −1.06214092e−021 C5 5.56801394e−026 C6 −1.09523279e−030 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 40 K 0.0000 C1 1.76315794e−008 C2 3.90180649e−012 C3 1.77550556e−017 C4 −3.14301026e−021 C5 4.39156108e−025 C6 8.08125064e−030 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 TABLE 3 r218v REFRACTIVE INDEX ½ FREE SURFACE RADII THICKNESSES LENSES 193.368 nm DIAMETER 0 0.000000000 32.000000000 LUFTV193 1.00030168 56.080 1 0.000000000 0.000000000 LUFTV193 1.00030168 63.909 2 0.000000000 17.844950703 SIO2V 1.56078570 63.909 3 141.364869321AS 42.976532865 N2VP950 1.00029966 68.570 4 −106.379969384 78.027724995 SIO2V 1.56078570 70.336 5 −166.687860454 1.000000000 N2VP950 1.00029966 108.096 6 −453.543565041AS 26.035967427 SIO2V 1.56078570 118.587 7 −232.687652830 1.000000000 N2VP950 1.00029966 122.253 8 −4175.612871634 34.571195540 SIO2V 1.56078570 132.347 9 −339.014596070 1.000000000 N2VP950 1.00029966 134.146 10 500.000000000 34.007738554 SIO2V 1.56078570 137.817 11 −1979.358317517AS 1.000000000 N2VP950 1.00029966 137.328 12 275.000000000 38.615595029 SIO2V 1.56078570 131.717 13 713.420881508 1.000000000 N2VP950 1.00029966 127.146 14 219.840025272 85.000000000 SIO2V 1.56078570 118.935 15 321.375540921AS 4.922289739 N2VP950 1.00029966 92.215 16 408.796272617 25.823140797 SIO2V 1.56078570 89.829 17 101.545676471 72.090709976 N2VP950 1.00029966 70.185 18 −113.185080136 9.000000000 SIO2V 1.56078570 65.216 19 −6276.526315852AS 30.855400278 N2VP950 1.00029966 68.772 20 −137.418484927 17.333137381 SIO2V 1.56078570 70.621 21 413.789552546 20.404389259 N2VP950 1.00029966 84.304 22 −625.367774639AS 35.350033804 SIO2V 1.56078570 87.244 23 −140.888106901 1.000000000 N2VP950 1.00029966 91.874 24 2331.984028426 9.000000000 SIO2V 1.56078570 105.044 25 250.875405170 22.125324131 N2VP950 1.00029966 111.593 26 835.343130512 39.746104742 SIO2V 1.56078570 115.758 27 −326.784324219 1.000000000 N2VP950 1.00029966 119.638 28 255.433855640 46.317736953 SIO2V 1.56078570 153.611 29 490.028436327AS 42.760537386 N2VP950 1.00029966 152.582 30 0.000000000 −32.760537386 N2VP950 1.00029966 154.980 31 341.273585728 9.000000000 SIO2V 1.56078570 156.026 32 236.023249432 38.136711957 N2VP950 1.00029966 154.319 33 538.352989022 76.926527135 SIO2V 1.56078570 156.695 34 −303.854952853 1.000000000 N2VP950 1.00029966 158.497 35 242.471332890 55.345758805 SIO2V 1.56078570 156.649 36 1273.475455674AS 1.000000000 N2VP950 1.00029966 154.009 37 165.078804777 51.848716746 SIO2V 1.56078570 133.227 38 360.689088970AS 2.381005965 N2VP950 1.00029966 127.273 39 155.800125543 60.708631213 SIO2V 1.56078570 109.767 40 257.289833789AS 3.059278416 N2VP950 1.00029966 83.432 41 214.574391728 23.013966672 SIO2V 1.56078570 79.983 42 581.722478991 7.376730203 N2VP950 1.00029966 70.287 43 432.957343908 11.524326583 SIO2V 1.56078570 56.460 44 953.963555708 5.255374130 N2VP950 1.00029966 48.919 45 0.000000000 9.375000000 SIO2V 1.56078570 36.611 46 0.000000000 5.000014179 LUFTV193 1.00030168 29.403 47 0.000000000 0.000014174 1.00000000 14.020 TABLE 4 ASPHERIC CONSTANTS SURFACE NO. 3 K 0.0000 C1 −2.86481339e−007 C2 1.33428721e−011 C3 −1.15140908e−015 C4 9.48184306e−020 C5 −5.08944755e−024 C6 1.72476575e−028 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 6 K 0.0000 C1 −1.00040949e−008 C2 1.91234847e−014 C3 −3.08640325e−018 C4 2.26769898e−022 C5 −1.40237554e−027 C6 3.92572161e−031 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 11 K 0.0000 C1 −1.62545449e−009 C2 −8.02017004e−014 C3 9.07741798e−019 C4 6.22361354e−023 C5 7.91274435e−029 C6 −2.44533345e−032 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 15 K 0.0000 C1 −5.34383332e−008 C2 2.24730624e−012 C3 2.71223685e−018 C4 −5.23845943e−021 C5 1.96396121e−025 C6 −1.58673005e−030 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 19 K 0.0000 C1 1.79672442e−009 C2 −6.77223099e−012 C3 −3.96951402e−016 C4 2.97275706e−020 C5 1.64172060e−024 C6 −2.76013991e−028 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 22 K 0.0000 C1 −3.46618935e−008 C2 1.24390269e−012 C3 −4.83656616e−017 C4 1.75302648e−022 C5 1.21150441e−025 C6 −1.12186612e−029 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 29 K 0.0000 C1 2.91242380e−009 C2 5.36672462e−014 C3 −3.84138467e−019 C4 −5.83775573e−023 C5 3.05838142e−027 C6 −4.39732968e−032 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 36 K 0.0000 C1 1.34059170e−009 C2 1.06725317e−013 C3 −3.54947088e−018 C4 1.30852468e−022 C5 −2.68379318e−027 C6 3.47219208e−032 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 38 K 0.0000 C1 2.63154343e−009 C2 2.84724714e−013 C3 1.03599926e−018 C4 −5.71879023e−022 C5 3.15244493e−026 C6 −4.20712791e−031 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 40 K 0.0000 C1 9.80415755e−009 C2 4.75026576e−012 C3 −1.99060433e−016 C4 9.51377978e−021 C5 −4.27716194e−025 C6 −5.70277764e−030 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 TABLE 5 r221v REFRACTIVE INDEX ½ FREE SURFACE RADII THICKNESSES LENSES 193.368 nm DIAMETER 0 0.000000000 32.320000000 LUFTV193 1.00030168 56.080 1 0.000000000 0.000000000 LUFTV193 1.00030168 63.987 2 −1414.283119543AS 8.000000000 SIO2V 1.56078570 64.113 3 424.792851760 5.648215816 N2VP950 1.00029966 65.856 4 1299.539331232AS 8.000000000 SIO2V 1.56078570 67.145 5 235.797454960 42.846403790 N2VP950 1.00029966 69.121 6 −102.370191138 69.189096195 SIO2V 1.56078570 70.860 7 −172.393415521 1.000000000 N2VP950 1.00029966 107.074 8 −311.506629059AS 37.876409079 SIO2V 1.56078570 116.081 9 −198.729331749 1.000000000 N2VP950 1.00029966 122.907 10 10618.353983725 37.816832272 SIO2V 1.56078570 134.690 11 −345.414077618 1.000000000 N2VP950 1.00029966 136.145 12 400.000000000 25.074567519 SIO2V 1.56078570 137.066 13 1543.425862196AS 1.000000000 N2VP950 1.00029966 136.002 14 250.000000000 44.417771731 SIO2V 1.56078570 132.858 15 424.538863322 1.000000000 N2VP950 1.00029966 125.810 16 174.877745836 70.000000000 SIO2V 1.56078570 118.444 17 243.447507091AS 14.188161571 N2VP950 1.00029966 98.000 18 484.930164939 48.000000000 SIO2V 1.56078570 95.965 19 111.938442661 77.053811810 N2VP950 1.00029966 71.061 20 −109.460895056 9.000000000 SIO2V 1.56078570 65.591 21 438.039183085AS 23.422549148 N2VP950 1.00029966 71.158 22 −202.054583818 9.000000000 SIO2V 1.56078570 72.631 23 465.572943863 16.082181763 N2VP950 1.00029966 82.930 24 −1172.049223927AS 36.326480405 SIO2V 1.56078570 86.214 25 −145.267929878 1.000000000 N2VP950 1.00029966 90.911 26 1353.417341936 9.000000000 SIO2V 1.56078570 105.237 27 254.308618512 21.441664729 N2VP950 1.00029966 111.540 28 808.549194446 40.139409419 SIO2V 1.56078570 115.722 29 −324.795643495 1.000000000 N2VP950 1.00029966 119.584 30 259.623325413 30.156883912 SIO2V 1.56078570 152.402 31 442.106202542AS 49.702134449 N2VP950 1.00029966 152.056 32 0.000000000 −35.918141056 N2VP950 1.00029966 155.705 33 321.189339694 13.200000000 SIO2V 1.56078570 156.875 34 235.938498925 38.959238636 N2VP950 1.00029966 154.952 35 548.092450535 78.619078346 SIO2V 1.56078570 157.303 36 −295.129602720 1.000000000 N2VP950 1.00029966 159.105 37 257.343015350 56.517809884 SIO2V 1.56078570 155.780 38 3502.742343640AS 1.000000000 N2VP950 1.00029966 153.286 39 153.633385258 50.277016535 SIO2V 1.56078570 128.279 40 298.509028204AS 1.000000000 N2VP950 1.00029966 122.045 41 149.675345185 60.980134477 SIO2V 1.56078570 107.243 42 190.178192400AS 5.453949973 N2VP950 1.00029966 77.382 43 197.572510486 20.628074249 SIO2V 1.56078570 75.169 44 718.043747110 5.783836616 N2VP950 1.00029966 68.036 45 479.704970402 11.372838185 SIO2V 1.56078570 56.262 46 1276.727595948 4.938062857 N2VP950 1.00029966 48.931 47 0.000000000 9.468750000 SIO2V 1.56078570 36.649 48 0.000000000 5.000014315 LUFTV193 1.00030168 29.372 49 0.000000000 −0.000014316 1.00000000 14.020 TABLE 6 ASPHERIC CONSTANTS SURFACE NO. 2 K 0.0000 C1 2.08525794e−007 C2 −3.19987515e−011 C3 3.56280613e−015 C4 −3.77486884e−019 C5 2.10578968e−023 C6 −2.70937745e−028 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 4 K 0.0000 C1 3.64477027e−008 C2 2.00816645e−011 C3 −2.98745270e−015 C4 2.91202348e−019 C5 −1.79522903e−023 C6 3.55575104e−028 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 8 K 0.0000 C1 8.55962248e−009 C2 2.04733903e−013 C3 −6.43943314e−018 C4 5.73836441e−022 C5 −1.59385846e−026 C6 4.68346251e−031 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 13 K 0.0000 C1 7.03699560e−009 C2 −1.52661867e−014 C3 −3.99418159e−018 C4 1.88604871e−022 C5 −4.98713537e−027 C6 1.16946921e−031 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 17 K 0.0000 C1 −9.76738019e−009 C2 1.42039979e−013 C3 2.09426135e−017 C4 −3.11005072e−021 C5 1.30236376e−025 C6 −9.13097296e−030 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 21 K 0.0000 C1 1.14826642e−008 C2 −5.23285076e−012 C3 −3.60906300e−016 C4 4.17780521e−020 C5 4.11241516e−025 C6 −1.26961570e−028 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 24 K 0.0000 C1 −3.11670458e−008 C2 1.40028813e−012 C3 −1.04629804e−016 C4 9.68145933e−022 C5 −8.29015519e−026 C6 −2.79089191e−030 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 31 K 0.0000 C1 2.31274915e−009 C2 5.27830899e−014 C3 −2.07768704e−018 C4 −6.60919096e−023 C5 4.30024872e−027 C6 −5.82559285e−032 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 38 K 0.0000 C1 1.22133020e−009 C2 9.82170002e−014 C3 −4.08875155e−018 C4 2.25637760e−022 C5 −5.76550179e−027 C6 7.24587177e−032 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 40 K 0.0000 C1 2.01766742e−009 C2 3.58703800e−013 C3 1.38458390e−017 C4 −1.65456142e−021 C5 8.49511243e−026 C6 −1.87184616e−030 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 SURFACE NO. 42 K 0.0000 C1 2.38088222e−008 C2 4.23623902e−012 C3 3.32178613e−017 C4 9.51247573e−021 C5 −1.75917666e−024 C6 2.13969194e−028 C7 0.00000000e+000 C8 0.00000000e+000 C9 0.00000000e+000 TABLE 7 Center Half Surface Radius thickness diameter No. Type [mm] [mm] Material [mm] Object 79.2500 plane 1 Sphere −99.4350 48.0000 ‘SIO2HL’ 69.6 2 Asphere −101.0810 156.6400 86.1 A(1) 3 Sphere −723.0640 70.0000 ‘SIO2HL’ 120.7 4 Asphere −183.9000 340.9100 126.9 A(2) Stop 124.2000 73.5 5 Sphere −180.6640 40.0000 ‘CAF2HL’ 93.6 6 Asphere −141.0650 107.0000 102.1 A(3) Mirror ∞ 138.7300 150.2 7 Asphere 172.4900 50.0000 ‘SIO2HL’ 136.0 A(4) 8 Sphere 596.7120 47.4580 133.5 9 Sphere 170.4950 56.0000 ‘SIO2HL’ 117.3 10 Asphere 194.7400 30.7260 107.5 A(5) 11 Sphere infinity 7.2500 ‘CAF2HL’ 93.4 12 Sphere 107.4480 30.7500 75.8 13 Asphere 413.1300 24.6400 ‘SIO2HL’ 74.8 A(6) 14 Asphere −199.5060 1.2500 72.9 A(7) 15 Sphere ∞ 3.0500 ‘CAF2HL’ 70.8 16 Sphere ∞ 1.2500 70.3 17 Sphere ∞ 3.0500 ‘CAF2HL’ 70.0 18 Sphere ∞ 51.4480 69.6 19 Sphere ∞ 6.3000 ‘SIO2HL’ 57.3 20 Sphere ∞ 0.0000 56.8 Image plane 0.0000 56.8 TABLE 8 Asphere Curvature K A B C D E A(1) −0.00989306 −1.016679 −6.011E−08 −2.104E−12 −8.452E−17 −9.101E−21 0.000E+00 A(2) −0.00543774 0.172377 1.415E−08 5.799E−13 −5.406E−18 8.810E−22 0.000E+00 A(3) −0.00708893 −0.740223 −1.794E−08 1.226E−13 −3.779E−17 1.585E−21 0.000E+00 A(4) 0.00579744 −0.487512 −1.532E−08 8.915E−14 −3.181E−19 −1.307E−22 0.000E+00 A(5) 0.00513505 −1.224675 −1.442E−07 7.613E−13 1.473E−16 −3.805E−21 0.000E+00 A(6) 0.00242055 −5.404462 −1.062E−07 8.090E−12 −3.350E−16 7.063E−19 −1.193E−22 A(7) −0.00501238 1.430927 1.452E−07 1.114E−11 1.352E−15 5.307E−19 −9.312E−23 TABLE 9 Pupil function: Image field height Actual value Actual- [mm] [mrad] desired [mrad] 63.6 5.34 0.09 57.3 1.59 −0.10 51.0 −0.90 0.06 44.6 −2.65 0.10 38.3 −3.76 −0.01 31.9 −4.21 −0.10 25.5 −4.00 −0.08 19.1 −3.29 0.01 12.8 −2.28 0.09 6.4 −1.15 0.08 TABLE 12 Pupil function: Image field height Actual value Actual- [mm] [mrad] desired [mrad] 63.6 5.34 0.09 57.3 1.59 −0.10 51.0 −0.92 0.04 44.6 −2.64 0.10 38.3 −3.74 0.01 31.9 −4.19 −0.09 25.5 −4.00 −0.08 19.1 −3.30 0.01 12.8 −2.28 0.09 6.4 −1.15 0.09 TABLE 15 Pupil function: Image field height Actual value Actual- [mm] [mrad] desired [mrad] 63.6 5.32 0.07 57.3 1.59 −0.10 51.0 −0.92 0.04 44.6 −2.64 0.10 38.3 −3.74 0.01 31.9 −4.20 −0.09 25.5 −4.00 −0.08 19.1 −3.30 0.01 12.8 −2.28 0.09 6.4 −1.15 0.09 TABLE 10 RADIUS THICKNESS 248.3 EPS 248.8 1.0 1.0 1************** 45.143 1.0 1.0 2 −31.6971 28.136 SUPRA1 1.508366 −.055 1.508088 3 −47.9230 39.292 1.0 1.0 4 428.1252 66.494 SUPRA1 1.508366 −.055 1.508088 5 −150.7305 18.557 1.0 1.0 6 195.9789 44.285 SUPRA1 1.508366 −.055 1.508088 7 471.9253 163.776 1.0 1.0 8 −601.7158 22.837 SUPRA1 1.508366 −.055 1.508088 9 −248.8469 22.518 1.0 1.0 STOP .000 10************** 16.000 1.0 1.0 11************** 50.950 1.0 1.0 12 271.7523 46.762 SUPRA1 1.508366 −.055 1.508088 13 −332.7323 16.448 1.0 1.0 14 1632.0761 13.064 SUPRA1 1.508366 −.055 1.508088 15 125.5812 155.737 1.0 1.0 16************** 357.505 1.0 1.0 17 −406.8452 24.422 SUPRA1 1.508366 −.055 1.508088 18 −176.1262 4.072 1.0 1.0 19************** 4.000 SUPRA1 1.508366 −.055 1.508088 20************** 60.000 1.0 1.0 21************** .000 1.0 1.0 22************** 1.0 1.0 TABLE 11 SURFACE ASPHERIC CONSTANTS 5 A .30700259 .36275241E−07 .14555048E−11 −.25367843E−16 .64827842E−21 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 9 A .01609567 .44063917E−07 .16962313E−11 −.81523571E−17 .54237049E−20 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 17 A −.00048398 .45060462E−07 .70280547E−11 .20097185E−14 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 18 A .00009906 .48624218E−07 .27774765E−10 −.49448573E−14 .94856328E−18 −.37136823E−22 .00000000E+00 .00000000E+00 .00000000E+00 TABLE 13 RADIUS THICKNESS 248.3 EPS 248.8 1.0 1.0 1************** 68.629 1.0 1.0 2 −41.3402 37.553 SUPRA1 1.508366 −.055 1.508088 3 −65.1683 1.899 1.0 1.0 4 −1821.9029 52.155 SUPRA1 1.508366 −.055 1.508088 5 −165.0414 20.937 1.0 1.0 6 277.4757 67.266 SUPRA1 1.508366 −.055 1.508088 7 −381.8306 200.731 1.0 1.0 8************** 17.900 1.0 1.0 STOP .000 9************** 19.430 1.0 1.0 10 169.1379 50.513 SUPRA1 1.508366 −.055 1.508088 11 −2197.7333 72.898 1.0 1.0 12 350.2263 11.856 SUPRA1 1.508366 −.055 1.508088 13 103.0750 128.232 1.0 1.0 14************** 339.584 1.0 1.0 15 −183.2474 21.658 SUPRA1 1.508366 −.055 1.508088 16 −114.7171 24.758 1.0 1.0 17************** 4.000 SUPRA1 1.508366 −.055 1.508088 18************** 60.000 1.0 1.0 19************** .000 1.0 1.0 20************** 1.0 1.0 TABLE 14 ASPHERIC SURFACE CONSTANTS 4 A .00088826 .33072665E−08 −.27728125E−12 .66528381E−16 −.27747818E−20 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 7 A .00146323 .23687863E−07 −.73089141E−13 .70178044E−17 −.17741133E−21 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 11 A .00013830 .41436721E−07 −.16796245E−12 .59248839E−17 −.91470033E−22 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 15 A −.02425149 −.95943615E−07 −.10248697E−11 .27847883E−14 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 16 A −.00011652 −.37799825E−07 .24137738E−10 −.59574191E−14 .12288559E−17 −.59577481E−22 .00000000E+00 .00000000E+00 .00000000E+00 TABLE 16 RADIUS THICKNESS 248.3 EPS 248.8 1.0 1.0 1************** 65.935 1.0 1.0 2 −40.6035 38.487 SUPRA1 1.508366 −.055 1.508088 3 −64.3159 5.680 1.0 1.0 4 1995.7246 53.136 SUPRA1 1.508366 −.055 1.508088 5 −189.7903 26.685 1.0 1.0 6 344.0589 66.052 SUPRA1 1.508366 −.055 1.508088 7 −298.0580 198.231 1.0 1.0 8************** 17.900 1.0 1.0 STOP .000 9************** 12.589 1.0 1.0 10 182.3714 55.709 SUPRA1 1.508366 −.055 1.508088 11 −512.3841 47.471 1.0 1.0 12 700.0127 12.241 SUPRA1 1.508366 −.055 1.508088 13 104.1003 149.883 1.0 1.0 14************** 343.316 1.0 1.0 15 −184.4560 20.375 SUPRA1 1.508366 −.055 1.508088 16 −115.3836 22.308 1.0 1.0 17************** 4.000 SUPRA1 1.508366 −.055 1.508088 18************** 60.000 1.0 1.0 19************** .000 1.0 1.0 20************** 1.0 1.0 TABLE 17 ASPHERIC SURFACE CONSTANTS 7 A .00534764 .28361731E−07 −.33416725E−13 −.27596098E−17 .53973409E−22 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 11 A −.00014610 .39915901E−07 −.39110773E−12 .38577737E−17 −.77184166E−22 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 15 A −.03140665 .10763439E−06 .40961531E−11 .26507084E−14 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 .00000000E+00 16 A −.00031061 .48775194E−07 .21584376E−10 .59528473E−14 .12049627E−17 −.59417852E−22 .00000000E+00 .00000000E+00 .00000000E+00 TABLE 18 j124o Sur. No. Radius Thickness/Distance Material Refr. Index Fr. Diam. 0 0 40 1 136 1 0 0 1 162.238 2 0 10 SIO2HL 1.56018811 162.238 3 0 90.00242783 1 166.316 4 0 126.1714501 1 225.352 5 284.819283 88.25879422 SIO2HL 1.56018811 346.704 6 −718.846875 67.94464464 1 344.764 7 332.99532 29.58650607 SIO2HL 1.56018811 277.8 8 229.906571 87.36888257 1 252.304 9 −221.626736 15 SIO2HL 1.56018811 247.846 10 −858.351043 96.28958137 1 258.722 11 −223.041108 15 SIO2HL 1.56018811 272.15 12 −610.039132 43.05996383 1 300.996 13 −221.235303 15 SIO2HL 1.56018811 303.626 14 −496.460616 39.93674981 1 353.65 15 0 0 −1 488.926 REFL 16 261.673247 39.93674981 1 358.9 REFL 17 496.460616 15 SIO2HL 1.56018811 352.086 18 221.235303 43.05996383 1 294.964 19 610.039132 15 SIO2HL 1.56018811 288.496 20 223.041108 96.28958137 1 256.802 21 858.351043 15 SIO2HL 1.56018811 225.826 22 221.626736 87.36888257 1 211.74 23 −229.906571 29.58650607 SIO2HL 1.56018811 209.998 24 −332.99532 67.94464464 1 221.786 25 718.846875 88.25879422 SIO2HL 1.56018811 233.566 26 −284.819283 148.919977 1 231.788 27 0 117.2478983 1 163.64 28 0 24.99733735 1 242.922 29 603.370765 39.04445671 SIO2HL 1.56018811 270.182 30 −636.597636 0.948767519 1 272.294 31 342.176859 50.00126936 SIO2HL 1.56018811 277.832 32 17319.8551 73.84714255 1 272.836 33 −218.591907 8.99910435 SIO2HL 1.56018811 262.016 34 904.679885 54.19491053 1 281.338 35 −680.586753 54.40626463 SIO2HL 1.56018811 299.432 36 −220.41366 5.817238376 1 305.088 37 500.62792 15.60974916 SIO2HL 1.56018811 297.022 38 198.761197 53.16103132 1 282.566 39 814.404669 36.98819327 SIO2HL 1.56018811 289.582 40 −871.120646 0.949164971 1 294.484 41 835.76703 39.91455494 SIO2HL 1.56018811 307.664 42 −726.054716 0.949236893 1 309.074 43 317.363233 57.34718751 SIO2HL 1.56018811 309.176 44 3960.12424 39.5720585 1 301.446 45 −420.71174 9.499467238 SIO2HL 1.56018811 297.386 46 359.94645 56.65260716 1 296.478 47 −2691.51008 44.96770761 SIO2HL 1.56018811 306.182 48 −306.711407 3.572848114 1 310.034 49 742.794849 27.51408106 SIO2HL 1.56018811 310.324 50 −5522.84952 −0.960213691 1 309.836 51 0 1.905954202 1 308.384 52 286.444693 47.52996513 SIO2HL 1.56018811 309.936 53 2180.55421 0.940628914 1 306.14 54 223.755941 47.20113369 SIO2HL 1.56018811 282.118 55 764.2653 0.937188691 1 273.64 56 142.961746 51.14510511 SIO2HL 1.56018811 221.778 57 594.670868 0.91280099 1 207.25 58 120.817932 25.60552721 SIO2HL 1.56018811 154.022 59 234.539697 0.813496277 1 132.74 60 117.536405 41.01820363 SIO2HL 1.56018811 112.148 61 0 2.00024195 H2OV193 1.43667693 40.986 62 0 −0.00024161 1 34.006 TABLE 19 Aspheres Sur. No. K C1 C2 C3 C4 C5 C6 6 0 1.81054E−09 −2.31090E−14 9.96078E−19 −1.12802E−23 7.07088E−29 −6.95390E−34 12 0 −8.90600E−10 −1.51217E−13 4.88272E−21 8.25531E−23 −2.79550E−27 2.35098E−31 14 0 −3.34713E−09 5.94735E−14 −1.82452E−19 −1.16648E−23 7.22990E−28 −2.74308E−32 17 0 3.34713E−09 −5.94735E−14 1.82452E−19 1.16648E−23 −7.22990E−28 2.74308E−32 19 0 8.90600E−10 1.51217E−13 −4.88272E−21 −8.25531E−23 2.79550E−27 −2.35098E−31 25 0 −1.81054E−09 2.31090E−14 −9.96078E−19 1.12802E−23 −7.07088E−29 6.95390E−34 34 0 −2.09777E−09 −5.69167E−14 −2.08879E−19 3.29541E−23 6.66605E−28 −1.96222E−32 45 0 −7.23645E−09 1.09023E−13 −3.10776E−18 3.84103E−22 −9.66600E−27 −8.74269E−32 47 0 −7.61174E−09 2.65544E−13 −7.37805E−18 3.19143E−22 −2.12393E−26 5.21669E−31 53 0 4.28502E−10 4.33345E−13 −2.08439E−17 2.18135E−22 5.73143E−27 −1.02762E−31 57 0 8.39683E−09 8.08208E−13 −6.65945E−17 5.13258E−21 −3.16949E−25 8.16626E−30 59 0 4.78541E−08 6.68577E−12 −1.88747E−16 −1.54458E−20 1.63093E−23 −1.04350E−27 TABLE 20 j127o Sur. No. Radius Thickness/distance Material Refr. Index Fr. Diam. 0 0 40 1 136 1 0 0 1 162.23 2 0 10 SIO2HL 1.56018811 162.23 3 0 90.00136568 1 166.306 4 0 126.9754212 1 225.326 5 287.871657 87.61804518 SIO2HL 1.56018811 346.638 6 −714.813191 72.13214669 1 344.79 7 332.204484 30.00699117 SIO2HL 1.56018811 277.208 8 228.934009 86.52185874 1 251.744 9 −225.793329 15 SIO2HL 1.56018811 247.436 10 −736.477377 88.69950684 1 257.478 11 −223.422523 15 SIO2HL 1.56018811 267.924 12 −670.949887 43.07304995 1 295.618 13 −220.819788 15 SIO2HL 1.56018811 298.228 14 −499.016297 39.4948838 1 345.992 15 0 0 −1 474.852 REFL 16 259.210693 39.4948838 1 351.666 REFL 17 499.016297 15 SIO2HL 1.56018811 344.228 18 220.819788 43.07304995 1 289.47 19 670.949887 15 SIO2HL 1.56018811 283.008 20 223.422523 88.69950684 1 252.278 21 736.477377 15 SIO2HL 1.56018811 225.524 22 225.793329 86.52185874 1 212.25 23 −228.934009 30.00699117 SIO2HL 1.56018811 210.37 24 −332.204484 72.13214669 1 222.306 25 714.813191 87.61804518 SIO2HL 1.56018811 234.366 26 −287.871657 150.4821633 1 232.45 27 0 116.4962314 1 163.22 28 0 24.99582853 1 242.07 29 608.165543 38.78395838 SIO2HL 1.56018811 269.198 30 −633.325408 0.947612575 1 271.334 31 344.637109 45.34004131 SIO2HL 1.56018811 276.98 32 −62952.622 76.39801942 1 273.248 33 −217.488195 8.998996112 SIO2HL 1.56018811 261.15 34 996.855971 54.49706951 1 280.182 35 −688.700451 54.41929128 SIO2HL 1.56018811 298.924 36 −219.471564 1.418978688 1 304.346 37 431.058008 15.20870568 SIO2HL 1.56018811 294.528 38 192.067389 63.01795094 1 278.474 39 987.105089 32.04274664 SIO2HL 1.56018811 290.984 40 −891.544249 0.948742302 1 294.704 41 677.684124 41.63748934 SIO2HL 1.56018811 308.902 42 −818.475719 0.949203181 1 309.902 43 325.99568 57.4047341 SIO2HL 1.56018811 307.608 44 13052.304 36.34195774 1 299.756 45 −390.220688 9.497543304 SIO2HL 1.56018811 297.718 46 350.704764 54.90641556 1 297.02 47 −2978.76559 46.68826821 SIO2HL 1.56018811 306.046 48 −300.028769 0.944451222 1 310.008 49 871.548118 27.20190252 SIO2HL 1.56018811 310.024 50 −2770.02197 −1.193616306 1 309.682 51 0 2.132719511 1 308.032 52 271.299915 46.98951537 SIO2HL 1.56018811 309.962 53 1226.61461 0.930593484 1 305.892 54 234.802856 49.00464753 SIO2HL 1.56018811 284.866 55 1226.61461 0.922464986 1 276.644 56 137.676807 51.75763941 SIO2HL 1.56018811 217.64 57 542.765286 0.899139131 1 202.58 58 118.289771 24.20432254 SIO2HL 1.56018811 149.71 59 209.420984 0.848851855 1 127.784 60 116.984714 40.14644803 SIO2HL 1.56018811 110.648 61 0 2.000071048 H2OV193 1.43667693 40.976 62 0 −0.00007074 1 34.002 TABLE 21 Aspheres Sur. No. K C1 C2 C3 C4 C5 C6 6 0 1.69174E−09 −2.05881E−14 1.03251E−18 −1.12193E−23 3.90449E−29 −5.29045E−34 12 0 −1.41589E−09 −1.57552E−13 1.25094E−18 2.21664E−23 2.23065E−28 1.88935E−31 14 0 −3.46732E−09 6.26464E−14 −3.07498E−19 −8.03587E−24 6.53890E−28 −3.03891E−32 17 0 3.46732E−09 −6.26464E−14 3.07498E−19 8.03587E−24 −6.53890E−28 3.03891E−32 19 0 1.41589E−09 1.57552E−13 −1.25094E−18 −2.21664E−23 −2.23065E−28 −1.88935E−31 25 0 −1.69174E−09 2.05881E−14 −1.03251E−18 1.12193E−23 −3.90449E−29 5.29045E−34 34 0 −2.08973E−09 −3.21415E−14 −4.89621E−19 4.99266E−23 6.37920E−29 −1.16558E−32 45 0 −9.02991E−09 1.92955E−13 −2.66461E−18 2.63723E−22 −8.86762E−27 −3.54012E−32 47 0 −6.06114E−09 1.64132E−13 −4.22802E−18 1.75836E−22 −1.41128E−26 4.02240E−31 53 0 1.24264E−09 2.65702E−13 −1.73022E−17 2.87349E−22 2.96301E−27 −8.89915E−32 55 0 1.24264E−09 2.65702E−13 −1.73022E−17 2.87349E−22 2.96301E−27 −8.89915E−32 57 0 −2.48214E−09 1.65060E−12 −4.57406E−17 4.60607E−22 −6.08631E−26 2.96024E−30 59 0 6.48548E−08 5.64309E−12 −3.20630E−17 −3.28553E−20 2.51656E−23 −1.95410E−27

20070212

20090623

20071108

73318.0

G02B1700

COLLINS, DARRYL J

LITHOGRAPHY LENS SYSTEM AND PROJECTION EXPOSURE SYSTEM PROVIDED WITH AT LEAST ONE LITHOGRAPHY LENS SYSTEM OF THIS TYPE

UNDISCOUNTED

ACCEPTED

G02B

ACCEPTED

TELECOMMUNICATIONS SYSTEM

The present invention relates to a telecommunications system, in particular to a telecommunications system which includes a mobile network having a plurality of portable communication devices, and, a fixed network which includes a signaling agent, a plurality of directory agents, and a plurality of spaced apart attachment points to which the mobile network can attach. In use, each directory agent stores a routing table for routing data to a respective mobile communication device associated with that directory agent. When the point of attachment of the mobile network changes, the mobile network sends a change-of-address message to the signaling agent. In response, the signaling agent is configured to forward the change of address to each directory agent, so that each can update its routing table to take into account the changed point of attachment of the mobile network. Because a signaling agent is provided, each potable device need not itself notify its directory agent when the mobile network moves, and the amount of signaling between the mobile network and the fixed network when the mobile network moves is reduced.

1. A telecommunications system including: a mobile network having a plurality of portable communication devices, and router means arranged in use for routing data to and from the portable communication devices; and, a main network which includes a signalling agent, a plurality of directory agents, and a plurality of spaced apart attachment points to which the mobile network can attach in order to communicate with the main network, wherein in use, each directory agent stores routing information for routing data to a respective mobile communication device associated with that directory agent, and wherein, in response to a signalling message from which it can be inferred that the point of attachment of the mobile network has changed, the signalling agent is configured to send a respective update message to each directory agent, the update messages each including updated routing information such that on receipt of the updated routing information, each directory agent can update the stored routing information thereof so as to take into account the changed point of attachment of the mobile network. 2. A telecommunications system as claimed in claim 1, wherein for each directory agent, the respective routing information stored by a directory agent includes information from which the point of attachment of the or each portable communication device associated with the directory agent can be inferred. 3. A telecommunications system as claimed in claim 1, wherein the signalling message is indicative of the topological position of the changed point of attachment to which the mobile network is attached. 4. A telecommunications system as claimed in claim 1, wherein the mobile network is configured to send the signalling message. 5. A telecommunications system as claimed in claim 1, wherein the attachment points are provided with respective wireless communication means, the mobile network including further wireless communication means such that a wireless link can be formed between an attachment point and the mobile network for communication therebetween. 6. A telecommunications system as claimed in claim 1, wherein the attachment points are stationary. 7. A telecommunications system as claimed in claim 6, wherein the attachment points are provided at respective ground base stations. 8. A telecommunications system as claimed in claim 1, wherein the signalling agent and at least one directory agent are each provided at one or more ground nodes. 9. A telecommunications system as claimed in claim 1, wherein at least some directory agents are located in different geographical locations to one another. 10. A telecommunications system as claimed in any claim 1, wherein a plurality of signalling agents are provided in the main network, each signalling agent being configured to send an update message on behalf of a respective plurality of portable devices in the mobile network, each update message including updated routing information. 11. A telecommunications system as claimed in claim 1, wherein the main network has a predetermined topological structure. 12. A telecommunications system as claimed in claim 11, wherein the main network is formed from a plurality of nodes, and a plurality of links for connecting the nodes, each node in the main network having a respective network address for routing data thereto. 13. A telecommunications system as claimed in claim 12, wherein the respective addresses of the nodes are indicative of their respective topological position within the main network. 14. A telecommunications system as claimed in claim 13, wherein the addresses of the nodes are arranged in a hierarchical structure relatively to one another, each address including an ordered set of components, each node having a hierarchical level associated therewith, each component of an address corresponding to a hierarchical level, and wherein a high level node at one hierarchical level is connected to a plurality of low level nodes which are at a lower hierarchical level, the addresses of the respective lower level nodes being such that the value of the component corresponding to the level of the higher level node is common to each lower level node. 15. A telecommunications system as claimed in claim 12, wherein each directory agent is located at a respective node, differently located directory agents having a different network address associated therewith. 16. A telecommunications system as claimed in claim 12, wherein each portable device has a network address associated therewith, which network address is retained by the portable device as the mobile network moves from one attachment point to another, and wherein the directory agent for each portable device stores a mapping between the network address for that portable device and a temporary address indicative of the current attachment point of the mobile network. 17. A telecommunications system as claimed in claim 16, wherein the mobile network is configured to send a signalling message to the signalling agent when the mobile network changes its point of attachment, the signalling message including at least one address, the address having a prefix portion in indicative of the topological position of the changed point of attachment, and wherein the update message from the signalling agent to each directory agent includes a respective address, the addresses each including the prefix portion indicative of the changed point of attachment. 18. A signalling agent for use in a telecommunications system, the telecommunications system including a main network and a mobile network, the mobile network including a plurality of portable communication devices and router means arranged in use for routing data to and from the portable communication devices, the main network including a plurality of spaced apart attachment points to which the mobile network can attach in order to communicate with the main network, and a plurality of directory agents, wherein the portable communication devices each have a directory agent associated therewith, each directory agent storing routing information for routing data to the or each mobile communication device associated with that directory agent, wherein the signalling agent is configured to send a respective update message to each directory agent in response to a signalling message from which signalling message it can be inferred that the point of attachment of the mobile network has changed, each update message including updated routing information such that on receipt of the updated routing information, each directory agent can update the routing information thereof to take into account the changed point of attachment of the mobile network. 19. A network including: a plurality of directory agents, each directory agent storing routing information for routing data to a respective mobile communication device of a mobile network; a plurality of spaced apart attachment points to which, in use, a mobile network can attach in order to communicate with the main network; and, a signalling agent, the signalling agent being configured to send a respective update message to each directory agent in response to a signalling message from which signalling message it can be inferred that the point of attachment of the mobile network has changed, each update message including updated routing information such that on receipt of the updated routing information, each directory agent can update the routing information thereof to take into account the changed point of attachment of the mobile network. 20. A network as claimed in claim 19, wherein the signalling agent maintains, in respect of each portable device, a mapping between an identifier for that portable device on the one hand and on the other hand address information indicative of the topological position in the network of the directory agent associated with that portable device. 21. A telecommunications system as claimed in claim 1, wherein the mobile network includes support means for supporting the portable devices, the support means being common to each of the portable devices, such that movement of the support means causes a common movement of the portable devices. 22. A telecommunications system as claimed in claim 20, wherein the mobile network includes vehicle means. 23. A telecommunications system as claimed in claim 1, wherein the mobile network is configured to send one or more registration messages to the signalling agent, which registration message(s) includes an indication of the identity of each directory agent to which the signalling agent is to send an update message. 24. A telecommunications system as claimed in claim 1, wherein the mobile network is a personal area network. 25. A method of operating a network which includes a signalling agent, a plurality of directory agents each of which stores routing information for routing data to a respective mobile communication device associated with that directory agent, and a plurality of spaced apart attachment points to which a mobile network having a plurality of portable devices can attach in order to communicate with the main network, the method including the steps of: (i) storing an indication of the identity and/or network location of each directory agent associated with a portable device; (ii) receiving, from the mobile network, temporary address information indicative of the current point of attachment of the mobile network; and, (iii) in response to receiving the temporary address information, using the stored indication of identity and/or network location to send an update message to each directory agent, the update messages each including updated routing information such that on receipt of the updated routing information, each directory agent can update the stored routing information thereof so as to take into account the changed point of attachment of the mobile network.

The present invention relates to a telecommunications system, in particular to a telecommunications system which includes a mobile network. It is known for portable communication devices to attach to different points on a network. Thus, for example, a user can connect a portable computer to one attachment point, move to a new geographical location where there is provided another attachment point and attach the computer to the network at that new attachment point. Where users travel together, for example on a common vehicle such as a train or aeroplane, it can be advantageous for the communication-equipment of each user to be connected to, a local network, such as a Local Area Network (LAN) within the vehicle. As well as being able to communicate amongst each other, the users will normally be able to receive common services from the local network. Furthermore, if the attachment to the main network is through a radio link, and the local network includes a transmitter/receiver, the communication devices may take advantage of the transmitter/receiver provided by the local network. So that the communication devices can be reached at different attachment points on the main network, a directory facility such as a “Home Agent” can be provided in the main network. The directory facility for each communication device normally stores information which can be used to facilitate the routing of data to the current attachment point of the communication device. The directory facility may contain the address corresponding to the current attachment point, or the directory facility may contain another address indicative of a location where further routing information can be found. When the attachment point of a communication device changes, the communication device will normally send a message to the directory facility associated with it, so that the routing information stored in the directory facility can be updated to reflect the change in the attachment point of the communication device. However, in the case where a plurality of communication devices move together as part of a local or mobile network, the amount of signalling required between the communication device's and their respective directory facilities when the point of attachment changes can be undesirable. According to one aspect of the present invention, there is provided a telecommunications system including: a mobile network having a plurality of portable communication devices, and router means arranged in use for routing data to and from the portable communication devices; and, a main network which includes a signalling agent, a plurality of directory agents, and a plurality of spaced apart attachment points to which the mobile network can attach in order to communicate with the main network, wherein in use, each directory agent stores routing information for routing data to a respective mobile communication device associated with that directory agent, and wherein, in response to a signalling message from which it can be inferred that the point of attachment of the mobile network has changed, the signalling agent is configured to send a respective update message to each directory agent, the update messages each including updated routing information such that on receipt of the, updated routing information, each directory agent can update the stored routing information thereof so as to take into account the changed point of attachment of the mobile network. Because the signalling agent is configured to send a respective update message to each directory agent, the need for each communication device to send such a message itself to its respective directory agent is reduced. This will reduce the amount of signalling generated to update the directory facilities when the mobile network changes its attachment point, as compared to the signalling that would be generated if each communications devices were to attempt to contact their respective directory agents. The reduction in traffic will be particularly important in the case of communications devices travelling as part of a mobile network, as such communication devices are likely to each change their point of attachment at the same time. Preferably, the mobile network is configured to (generate and/or) transmit the signalling message, although the signalling message may alternatively be sent by a node at the current point of attachment of the mobile network. The signalling message will preferably include information indicative of the topological position of the changed point of attachment of the mobile network. For example, the signalling message may include a routable network address which corresponds to the current point of attachment. The respective routing information stored by each directory agent will preferably include information from which the point of attachment of the or each portable communication device associated with that directory agent can be ,inferred or from which the location (e.g. the topological location) of a device can be inferred. The point of attachment may be inferred directly, or indirectly: for example, a directory agent may store the address of an intermediate router, the intermediate router itself storing a record of the current point of attachment of the mobile network. To allow the mobile network to be temporarily attached to an attachment point on the main network, the attachment points will preferably be provided with respective wireless communication means, the mobile network including further wireless communication means such that a wireless link can be formed between an attachment point and the mobile for communication therebetween. This will conveniently allow a link between the main network and the mobile network to be formed and broken. Alternatively, the link may be electrical, the attachment points having respective releasable electrical connector means. The attachment points will preferably be stationary, and may be provided by respective ground base stations. However, the attachment points could be formed by satellite nodes, the nodes being either moving with respect to a ground reference point or alternatively stationary, in the manner of a geo-stationary satellite. In a preferred embodiment, the main network is a ground network, the signalling agent and at least one directory agent being provided in one or more ground nodes. This will conveniently allow the signalling agent to be used as part of an existing (modified) network. The nodes of the portable devices will preferably be configured to send a respective or collective registration message indicative of the identity and/or the network location of the respective directory agent of each portable device. The signalling agent may store and then use this identity and/or location information to send updated routing information to each of the directory agents. Thus, the signalling agent will reduce the need for the mobile network to transmit this identity/location information each time the mobile network changes its point of attachment. This will be particularly advantageous if the directory agents each have a different network address, for example if the network agents are located at different geographical locations. The separation between directory agents may be at least 1 km or 10 km or even 100 km. The registration message will preferably also include an indication of any caller node(s) which may wish to contact a portable device, or for example which is/are presently in communication with that portable device. This may be useful if the caller nodes are configured to support route optimisation, in which case an update message may be sent to a caller node, such that the caller node can route data directly to the new location of the portable device with which it communicates. A plurality of signalling agents may be provided, each acting for a plurality of portable devices. A plurality of signalling agents may be useful if for example the mobile network has different classes of portable devices, such as portable “laptop” computers or mobile telephones, where each class of device has different signalling requirements. The main network will preferably have a predetermined topological structure. Normally, the network will be formed by a plurality of nodes, and a plurality of links for connecting the nodes, each node in the main network having a respective network address for routing data thereto. Each node may be a router or other data processing equipment, and need not be located at the intersection of network paths. For example, a node may be formed by terminal equipment, such as a computer terminal, or other communications equipment. Preferably, the signalling agent and each directory agent will be implemented in one or more nodes, the nodes and/or agents each having a network address which is indicative of the respective topological position of each respective node and/or agent. The functionality of a given agent may be distributed between two or more nodes, which nodes need not be co-located. The main network may include two or more sub-networks, the sub-networks for example being administered by different administrators. The directory agents may be located in the same sub-network, or the directory agents may be distributed-between the sub-networks. When the mobile network moves, the portable devices of the mobile network will preferably move together, any relative movement between the portable devices being superposed on the movement of the mobile network. Thus, the movement of the portable devices may be described by the movement of a common reference point, any movement of the devices relative to that common reference point being small in comparison to the movement of the reference point itself. Moveable support means may be provided for supporting the portable devices, such that movement of the support means will cause a common movement of the portable devices. The support means may be a platform, or a vehicle, such as a train. Preferably the topological structure of the mobile network will remain the same as the mobile network moves. The mobile network may be a Local Area Network. Alternatively, the mobile network may be a Personal Area Network (PAN), in which a plurality of portable devices are connected together and mounted on a person. The devices forming a PAN may be connected by a wireless link, and may form connections between themselves on an ad hoc basis (for example one of the devices acting as a mobile router, or alternatively, the devices may need to be connected to one another or to a mobile router by a user). The PAN may include attachment means for releasable attaching the devices to a person. The mobile network may have two or more routing devices for connecting the portable devices, so as to route data within the mobile network. The connections between portable devices and a router may be formed by a respective electrical connection, or a radio link. Although the devices connected within a mobile network may change as devices enter or leave the network, the topological-structure of the mobile-network will preferably remain unchanged as the mobile network moves. In order to route data efficiently through the main network, the addresses of the nodes in the main network will preferably be arranged in a hierarchical structure relative to one another, each address including an ordered set of components, each node having a hierarchical level associated therewith, each component of an address corresponding to a hierarchical level, wherein a high level node at one hierarchical level is connected to a plurality of low level nodes which are at a lower hierarchical level, the addresses of the respective lower level nodes being such that the value of the component corresponding to the level of the high level node is common to each low level node. In such a system, the respective addresses of the high level node and the lower level nodes connected thereto will share the same prefix, the leading components being the same for each address. To distinguish between the different nodes, the address of each node will preferably have different trailing components; that is, the suffixes will be different for each address. Examples of such a system include systems running according to the Internet Protocol, such as IPv6 or IPv4. In such a system, data will preferably be transported as data packets, each packet having a payload portion, and an address portion in which the destination address of the packet is stored. Preferably, each portable device will have an identifier such as a network address, name or other identifier associated therewith, which identifier is retained by the portable device as the mobile network moves from one attachment point to another, the directory agent for each portable device storing a mapping between the identifier for that device and a temporary address indicative of (or routable to or through) the current attachment point of the mobile network. In one embodiment, the identifier of a portable device is a network address. The network addresses of a portable device and its associated directory agent will preferably be topologically related, such that the directory agent can intercept data addressed to its portable device, and forward that data towards the portable device. However, if the identifier of a portable device is a name, for example a DNS name or SIP URI, the network addresses of a portable device and its associated directory agent are unlikely to be topologically related. So that the directory agent for a portable device can more easily route data towards that device and/or so that the directory agent for a portable device can more easily inform a node that wishes to communicate with the portable node of the portable node's current temporary address, the signalling agent will preferably update the directory agents by sending each agent a message, the message for a given directory agent including the current (temporary) address of the or each portable device associated with that agent. Different messages may be addressed to different directory agents, or alternatively the signalling agent may broadcast a collective message to all the directory agents. In a preferred embodiment, the portable devices and the router means of the mobile network will be allocated related temporary addresses, which related addresses have a common prefix portion. The temporary address associated with the current point of attachment will preferably have a prefix portion which is the same as the prefix portion of the addresses allocated to the mobile network. Since the prefix portion will preferably be indicative of the topological position of the attachment point, the allocation of addresses with this same prefix to the mobile network will facilitate the routing of data to the mobile network. In such a situation, the signalling message from the mobile network will preferably include at least one address, the address having the common prefix portion. Likewise, the update message from the signalling agent to each directory agent will preferably include an address having the common prefix portion. The update message for a directory agent may include the temporary address of a portable device itself, or alternatively, the update message may contain the temporary address allocated to the router means of the mobile network, in which case the router means will preferably be configured to open incoming packets and determine which of the portable devices of the mobile network that packet should be addressed to. Further aspects of the invention are specified in the appended claims. The present invention is described in further detail below, by way of example, with reference to the following drawings in which: FIG. 1 shows a network system-according to the invention; FIG. 2 shows in more detail a mobile router shown in FIG. 1; and, FIG. 3 shows a further network system. With reference to FIG. 1, it is known to have a prior art network system 10 in which a mobile network 12 can communicate with a fixed (main) network 14, the fixed network having a plurality of nodes 13 which are generally static. (FIG. 1 shows a system according to the present invention but will be used to describe the prior art, like components in the prior art and in the invention being given like numerals). The mobile network 12 includes a plurality of moveable or otherwise mobile nodes 16 (portable devices), each of which is connected to a mobile network 12 by a respective connection 22. A mobile node may for example be a mobile telephone or computer equipment such as a “laptop” computer, or other portable communications equipment, each respective connection 22 to the mobile router being a wired or wireless connection. When the mobile network 12 moves, the mobile nodes 16 move together with the router 20, such that the mobile nodes retain their respective connections 22 with the router 20. For example, the mobile router 20 may be included in a train or other vehicular system, and the mobile nodes may each be personal communications equipment carried by passengers on the train. Such a mobile network 12 is also known as a vehicular network. Clearly, as the train is moving, the mobile nodes will generally move in common with the mobile router 20, although some relative movement between the nodes may occur as passengers move within the train. The composition of the mobile network 12 will generally be temporary as some mobile nodes will cease their connection 22 with the router 20, and leave the network, (e.g., when a passenger gets off a train), whilst other nodes may join the network and form a new connection 22 (e.g., when a passenger gets onto a train). The mobile router 20 has a wireless transmitter/receiver stage for communicating over a wireless radio link 28 with a base station 30 of the fixed network 14 (in the example of FIG. 1, the mobile network 12 is within range of base station BS-A). When the mobile network 12 moves from a point within range of a first mobile station BS-A, to a point within range of a second base station, BS-B, a handover process occurs, in which the radio link 28 with BS-A is discontinued and a new radio link is formed with BS-B, such that the-mobile network “attaches” to BS-B. In order for a caller node C1 to communicate with one of the mobile node, say MN1, the data between the caller node C1 and the mobile node MN1 must be routed through the fixed network 14, in particular through the correct base station, the correct base station 30 being dependent on the position of the mobile network as the mobile network moves. Several systems/protocols exist for routing data through the correct base station. In the IPv6 (Internet Protocol version v6) system, each node 13 (including the base stations 30) is allocated a permanent IP address by an allocation unit 32. Each address has a plurality of components, 16 in the case of IPv6, each-component belonging to a different hierarchical level. Addresses can be represented in the form a.b.c.d . . . , where each letter corresponds to a component, higher letters of the alphabet corresponding to lower level components. The topology of the fixed network 14 is arranged such that the addresses of lower level nodes, each of which is connected to a common node at the next level above, will share a component. The level of the shared component corresponding to the level of the common node. This allows packets to be routed between nodes in the fixed network solely on the basis of the IP address of the destination node carried by the packet. The mobile router 20 and the mobile nodes 16 each have a permanent address allocated to them (by the address allocation unit 32). However, because these nodes do not have fixed topological positions, within the network system 10, the IP addresses of these nodes will not normally indicate their position with regard to other nodes of the fixed network, and thus the IP address of a mobile node will not normally in itself be sufficient for a packet addressed to it position of that node. To allow a mobile node to “found” in the network system, and to therefore allow packets to be routed to a mobile node, a base station 30 will normally allocate a temporary address to a node connected to it. In IPv6, such an address will normally be a “co-located care of address”, this being allocated to a mobile node from a set of spare v6 addresses which that base station has previously been allocated by the allocation unit 32. The care of address allocated by a base station will have a component in common with the permanent address of the base station itself, the position of that component in the address corresponding to the hierarchical position, of the base station, so that packets whose destination is one of the allocated care of addresses can be routed to the issuing base station. To allow the base station to route packets to the appropriate mobile node, the base station will keep a table which maps the care of address of each mobile node to the radio channel which the mobile router 20 is configured to receive. Each base station BS-A, BS-B will normally be connected to the fixed network via respective access routers AR-A, AR-B, which access routers may store and allocate care, of addresses, the base stations serving merely to transmit messages from the access routers. Each mobile node has associated therewith a home agent (HA) node, the home agent being topologically located such that it can intercept packets being sent to the permanent address of the mobile node with which it is associated (for simplicity, it is assumed that a home agent anode only has one mobile node associated with it). The home agent will store, in a correspondence table, a mapping between the permanent address of its mobile node and the care of address currently allocated to the mobile node. (Thus, each home agent will store a mapping between on the one hand an identifier for the mobile node associated with the home agent, and on the other hand a temporary address for other routing information for routing data to associated mobile node: in the case where a home agent acts for a plurality of mobile nodes, the home agent will store such a mapping for each mobile node). If the home agent intercepts any packets for that mobile node, the home agent is configured to encapsulate each packet it intercepts in a packet whose destination address is the care of address of the mobile node, thereby establishing a “tunnel” between the home agent and the mobile network. The home agent then transmits the encapsulated packet towards the mobile network. Because the care of address is indicative of the topological position of the base station to which the mobile node is connected, the encapsulated packet can be routed to the mobile node in the normal way. In the case of a mobile network where the mobile nodes are routed through another mobile node such as the mobile router MR of FIG. 1, the base station BS-A to which the mobile node is connected will allocate a set of address to the mobile network, one for each node MN1-MN3. The addresses allocated to the mobile network 12 will preferably have a component in common with a correspondingly positioned component in the address of the base station, (that it, the addresses will have the same prefix). The prefix will have a radio channel associated therewith (through a mapping at the base station), the radio channel being received by the mobile router 20, such that packets addressed to any of the mobile nodes MN1-MN3 will inevitably be sent to the mobile router by the base station BS-A. In turn, the mobile router will store a mapping between the connection to each mobile node (identifiable by its permanent address, for example) and the care of address associated with that mobile node. A system in which a home agent HA1 is provided thus allows a caller node C1 to contact a mobile node such as MN1 without the caller node C1 requiring knowledge of the current location of MN1; caller node C1 simply sends packets to the permanent address of the mobile node MN1 with which it is communicating. Although each mobile node may share a common home agent, different mobile nodes will often each have a respective home agent associated with them as indicated in FIG. 1, where home agents HA1, HA2, and HA3 are each provided for mobile nodes MN1, MN2, MN3 respectively. Normally, the home agents will have addresses which are unrelated to one another. Each home agent (and likewise the signalling agent) will normally be implemented in hardware including one or more processors and memory, the hardware preferably being part of the computer apparatus of a node. When a mobile node, say MN1, attaches to the network 14 at a new point, for example through base station BS-B, the mobile node MN1 will register its new care of address with its home agent HA1, and the home agent will update its correspondence table so as to map the mobile nodes permanent address to the new care of address. Likewise, each other mobile node MN2, MN3, which is part of the mobile network 12, will register its new care of address when it attaches to a new point on the network. However, in the case of a mobile network where the mobile nodes MN1-MN3 of the mobile network generally move together, the mobile nodes are likely to connect to a new base station at substantially the same time, in particular where traffic from the mobile nodes is routed through a common mobile router MR as shown in FIG. 1. The mobile nodes are therefore likely to attempt to send registration signals to their respective home agents over the wireless link 28 between the mobile router and the new base station substantially at the same time. Such signalling can be undesirable over the radio link 28 as this link is of relatively low bandwidth as compared to cable links between nodes of the fixed network. To reduce the amount of signalling required between the mobile network 12 and the fixed network 14, in particular the amount of signalling over the wireless link between the two networks when the mobile network 12 attaches to a new point on the fixed network 14, there is provided a signalling agent 34 in the fixed network. The signalling agent is configured to notify the home agent (e.g. HA1) for each mobile node (e.g. MN1) when the mobile nodes attach to a new point on the network, and to provide the home agents with the updated address information required for the home agents to “tunnel” packets to the newly located mobile nodes. Since only a single message is required from the mobile network for the signalling agent 34 to be notified of the new location for the mobile nodes, as opposed to a separate message from each mobile node, the amount of bandwidth used over the radio link between a mobile network and a base station is reduced. The base station can then use the limited bandwidth available to communicate more efficiently with other nodes or mobile networks. The amount of bandwidth saved by the presence of the signalling agents will be particularly important where there are many mobile nodes on the mobile network. Although only three nodes are shown in FIG. 1, a mobile network may have at least 10 mobile nodes, or at least 100 mobile nodes, or even at least 1000 mobile nodes. As shown in FIG. 2, the mobile router 20 has a routing stage 36 for routing packets received from the wireless stage 26 to one or more of the mobile nodes 16, and, for channelling packets from the mobile nodes to the wireless stage 26 for outbound transmission. The routing stage 36, wireless stage 26 and signaling stage 40 need not be co-located in the same node. A mobile network may include more than one instance of any of these stages. For example, there may be a wireless stage that communicates with satellite nodes and another wireless stage that communicates with GPRS base stations. However, the mobile network preferably has a mobile router 20 that includes all three stages; The routing stage 36 stores a routing table 38 mapping, for each mobile node 16 that forms part of the mobile network, the permanent address of that mobile node (or another indication of identity) to (a) the channel or other port over which the mobile router, 20 can communicate to that node and (b) the care of address temporarily allocated to that node. In addition, the mobile router 20 has a signalling stage 40 for generating/forwarding signalling information to the signalling agent 34. The operation of the signalling agent 34 and/or the signalling stage 40 will be described below with reference to the following steps (which need not be carried out in order): a registration step in which the mobile nodes 16 and the signalling stage 40 register with the signalling agent 34; a de-registration step in which mobile nodes 16 and the signalling stage 40 inform the signalling agent 34 that the signalling agent is no longer to send signals on their behalf; a mobility update stage in which the signalling step informs the signalling agent that the mobile network has moved to a point within range of a new base station; and, a signalling step in which the signalling agent sends messages on behalf of the mobile nodes (and possibly the signalling stage). In the registration step, (once communication is possible between the fixed network 14 and the mobile network 12 as in the prior art), the signalling stage 40 will send a message to the signalling agent 34 indicative of the identity of the signalling stage. This information will be useful to the signalling agent as the signalling agent may act for several mobile networks, each mobile network having its own signalling stage. If incoming traffic enters the mobile network via a single router co-located with the signalling stage as shown in FIG. 1, the identity of the signalling stage will simply be the permanent address of the mobile router 20 (that is, the mobile router's “home” address, which home address is topologically located to the mobile router's home agent). Alternatively, if the signalling stage is not co-located with the mobile router but located on another node, then the signalling stage may be identified, for example by that node's IP address or MAC address, depending on the configuration of the mobile network. Each mobile node 16 within the mobile network 12 will register with the signalling agent 34 by sending a message to the signalling agent, which message includes an identifier for the mobile node, such as its permanent address. The mobile router will also indicate to the signalling agent 34 the address of the signalling stage associated with that router. Although the signalling stage may be separate from the mobile router, for simplicity, it will be assumed that the signalling stage 40 is co-located with the routing stage, such that the functionality of the routing stage 36 and the signalling stage 40 is combined within the mobile router 20. In this case, the identity of the signalling stage will be the permanent address of the mobile router 20. Each mobile node will also indicate to the signalling agent 34 which protocol is to be used for communication between the signalling agent 34 and the home agents (that is, the protocol which the mobile node is configured to normally use), since there may be situations where a mobile node is not IPv6 is enabled (in which case translation means may be required). Each mobile node will send to the signalling agent 34 a list indicating the respective addresses of the nodes which should be updated with the mobile node's care of address when the mobile network attaches to a new base station. For each mobile node, the “receiving nodes” which should be informed of the mobile node's new care of address include that mobile node's home agent, so that the home agent can update its correspondence table when necessary with the mobile node's current care of address. This list of receiving nodes for a mobile node will preferably also include the addresses of other nodes such as “calling nodes” which are or will be in communication with that mobile node. Such calling nodes could include news providers which send news items at intervals to nodes on their membership list. Alternatively, a calling node may be a mobile telephone in communication with a mobile node. In either case, it would be useful for the signalling agent to be able to update these calling nodes with the mobile node's new care of address. If route optimisation is taking place, and a tunnel has been established between a calling node and a mobile node, then if a calling, node is informed of the mobile node's new care of address, a new tunnel can be established directly, without first contacting the home agent of that mobile node. As an alternative to the registration method described above, the mobile router 20 may register with the signalling agent 34, (after the mobile nodes have registered with the mobile router), and the mobile router may send to the signalling agent a message indicating the permanent address of each mobile node registered with the mobile router (as opposed to simply routing the registration messages of each mobile node). As a further alternative, the mobile router may intercept the registration messages of the mobile nodes, and send a registration message itself on behalf of the mobile nodes. In this way, the signalling agent 34 will be able to store information indicative of the identity of each mobile node 16 for which it is to act. In order for mobile nodes to discover the existence of the signalling agent 34, the signalling agent may send each mobile node which enters the mobile network 12 a message. This message will indicate the address of the signalling agent 34 and preferably indicate the type of mobility management messages which the signalling agent 34 can send, as well as other indications of the capabilities of the signaling agent. Alternatively, the signalling agent 34 may be reachable at a “well-known” address which has been previously been entered into the memory of each mobile node. In either case, when the mobile node enters the mobile network 12, for example by connecting to the mobile router 20, the mobile node can attempt to register with the signalling agent. The mobility update step takes place when the mobile network 12 changes its point of attachment on the fixed network 14, for example when the mobile router 20 ceases to communicate with BS-A and instead communicates with BS-B. When this occurs, the mobile router 20 and the mobile nodes 16 will lose the care of addresses previously allocated to them by the base station BS-A, which care of addresses will each be replaced by a new set of addresses issued by the base station BS-B. The message(s) sent by the mobile router 20 to the signalling agent 34 when the mobility update takes place will depend on the way in which the mobile nodes are allocated care of addresses by the base station. In one embodiment where a base station delivers a set of addresses to the mobile router, which addresses are related by a common prefix, the following steps are carried out: (i) each mobile node is issued with a care of address (for example at a base station) which care of address includes the common prefix, the suffix of the address being related to a unique identifier for the mobile node, (such as the mobile node's MAC address) in order to reduce the risk of address duplication; (ii) at the registration stage, the mobile router informs the signalling agent 34 that upon a change of point of attachment, each mobile node will retain its suffix, the new care of address of each mobile node having the new prefix for the new location, followed by the existing suffix; (iii) when the point of attachment of the mobile network changes, a signalling message with the new prefix for the new location is sent to the signalling agent; and, (iv) the signalling agent (which has stored a mapping between an indication of each mobile node and the suffix for that mobile node received at the registration stage) then combines the new prefix and the existing suffix for each mobile node so as to form the care of address for each mobile node, and the signalling agent then sends respective update messages with the new care of address to each home agent. This will reduce the amount of signalling required over the radio link 28 when carrying out the update step, since only the prefix of each new care of addresses needs be transmitted, as opposed to each entire care of address each time the mobile router attaches to a new point in the fixed network 14. In another embodiment, the mobile router will not request specified suffixes for the care of addresses it receives from a base station. In the mobility update step, the mobile router will then inform the signalling agent of the entire new care of addresses allocated to itself and to the mobile nodes 16. Once the signalling agent 34 has received information from the mobile router indicative of the new care of address of at least some of the mobile nodes, the signalling agent 34 can carry out a signalling step in which the signalling agent informs the respective home agent of each mobile node of the mobile node's new care of address. To do that, the signalling agent will retrieve from a memory location the addresses of the home agents previously received at the registration stage, and will send “binding agent” information to each home agent indicating to that home agent the new care of address of its mobile nodes. If a home agent is acting for more than mobile node in the mobile network 12, the signalling agent will send an update message to the home agent which update message will include: an identifier which identifies the list of mobile nodes (identified by their respective permanent addresses) which the signalling agent is acting for (the permanent addresses in the list having previously been sent to the signalling agent at a registration stage); the new care of address for each mobile node; and, an indication that the update is for the aforementioned list. An update message will preferably also be sent by the signalling stage 34 to one or more correspondence or “calling” nodes, such as node C1 or C2. Although the home agent of a portable device will allow the calling node to reach that portable device without the calling node being aware of any changes in the attachment point of the mobile network, a calling node may be configured to carry out route optimisation, such that the calling node sends messages to the portable device directly rather than through the home agent. In such a situation, an update message from the signalling agent containing the new care of address of a portable device can be used by the caller node to carry out fresh route optimisation and send packets directly to the new location of the portable device. Clearly, once a mobile node has successful registered with a signaling agent, it may be advantageous that, when the mobile node receives a new care of address because the mobile network has changed its point of attachment on the fixed network, the mobile node ceases to send update messages to its respective home agent, since the signaling agent will send update messages to its directory agent(s) as required on its behalf. The main network may include more than one signaling agent 34. The mobile router 20 currently registered with a signaling agent may register with another signaling agent. Such re-registration could be carried out following for example a request from the first signaling agent. Alternatively the mobile router may decide to re-register, for example because it is significantly nearer to the second signaling agent, or the second signaling agent has better capabilities or it is cheaper to use. Preferably the second signaling agent would obtain the information from the first signaling agent about the mobile node's 16 currently registered with it. Re-registration would preferably be accompanied by de-registration from the first signaling agent, but this is not required. It is possible for some mobile nodes 16 to be registered on one signaling agent and other mobile nodes 16 within the same mobile network 12 to be registered on another signaling agent. For example, the signaling agents may be able to support different kinds of update messaging to a directory agent; for example, mobile IPv4 and mobile IPv6. In this case, the mobile router will be registered with each signaling agent and send each message(s) when the mobile network changes its point of attachment on the fixed network 14. When a mobile network 12 is about to leave the fixed network 14, the manner in which de-registration takes place will depend on how registration was previously achieved. For example, if each mobile node registered directly (through the mobile router), then each mobile node will de-register directly by sending a message to the signalling agent indicating to the signalling agent that it will no longer be required to send update messages to the mobile node's home agent. A mobile node will also send a de-registration message if the mobile node is about to leave the mobile network, even when the mobile network remains attached to the fixed network 14. A de-registration message. when a mobile node is about to leave the mobile network will be important, since without such de-registration, the signalling agent may continue to send to the home agent updated addresses which are no longer indicative of the mobile node's location. FIG. 3 shows a further network system. The fixed network 14 may include one or more sub networks. For example, as shown in FIG. 3, the fixed network may include a ground network 141 and a transport network 142, the transport and ground networks each having respective border routers 151, 152, a link 153 being provided between the border routers to allow for communication between the ground network and the transport network. The home agents may not all be in the same sub network. For example HA1 may be in a ground network 141 and HA2 may be in a transport network 142. In the case where the mobile network is a Personal Area Network (PAN), the network being formed by a group of nodes that is very localised and closely associated with a single person, travelling together as a single unit, a node may wish to communicate with another node within the PAN. It may also wish to communicate with a node in the main network. Such communication would be through one of the nodes within the PAN that acts as a gateway with the main network. In another embodiment a mobile node (MN) does not obtain a temporary address from the Base Station. Instead the MN obtains an address from the mobile router 20 which is a “private address”, that is to say the address is only meaningful, and should be used, within the mobile network 24. The mobile router includes “Network Address, Translator” (NAT) functionality whereby it stores a mapping between a MN's private address used within the mobile network and a public address, such that the mobile router has sufficient public addresses to allocate one to each MN. The public address is the address by which the MN is known within the main network. A packet sent to this address reaches the mobile router 20, which looks up this address in its mapping table and alters the address to the private address at which the MN can be reached within the mobile network 24. The opposite mapping process occurs in the reverse direction (that is, when a MN sends a packet to a node in the main network). When the mobile network moves to a new base station, it obtains a new set of public addresses. The MN's private address does not change, however the mobile router updates its mapping table by selecting a new one of its public addresses to map to a MN's private address. The mobile router sends a message to the signalling agent 34 informing it about each MN's new public address. The signalling agent 34 updates each of the MN's Home agents. In the case where the mobile router does not have sufficient public addresses to allocate one to each MN, then the mobile router includes “Network Address Port Translator” (NAPT) functionality whereby it stores a mapping between a MN's private address used within the mobile network and a public address combined with a port number. For example, in one embodiment the same public address is used for all the MNs. When the mobile network moves to a new base station, it obtains a new public address. The mobile router sends a message to the signalling agent 34 informing it of this new public address. The signalling agent 34 updates each of the MN's HAs with this new public address. Alternatively, a MN's permanent home address can be used within the mobile network 24, as though it were a “private address”. In such a situation, the mobile router 20 will have NAT or NAPT functionality. The mobile network 12 or some or all of the fixed network 14 may operate according to the IPv4 protocol. When the mobile network 12 is attached to those portions of the fixed network which operates using IPv4, the mobile nodes will preferably be allocated care of addresses which are not co-located, such that a base station attached to the mobile network will not store a mapping between the care of address of a mobile node and a radio channel, but will instead decapsulate the packet, and forward it to the correct mobile node using a mapping between the care of address of the mobile node and its permanent address (a mapping being provided between the permanent address and the correct radio channel). In an another possible embodiment, when each mobile node is informed that it has a new care of address (because the mobile network has changed its point of attachment on the fixed network 14), then it sends an update message to its directory agent(s), for example to its home agent, and also the “calling nodes” C1,C2 if route optimisation is used. (In some others embodiments, the mobile nodes does not send such update messages). The mobile router has an additional interception stage 99, associated with its routing stage 36, which: (i) recognises such an update message, (ii) stores it temporarily, along with other similar update messages, (iii) creates a new message which contains several or all of the update messages that have been temporarily stored, (iv) sends the new message to the signaling agent. On receiving this message the signaling agent extracts the original update messages, which it then routes as normal i.e. to the directory agent(s). Preferably, the interception, stage 99 will recognise that a packet is an update message (rather than for instance an ordinary data packet) by examining the protocol number in the packet; the interception stage 99 is either pre-configured with the protocol numbers to look out for, or else a mobile node could inform it. Alternatively, the interception stage 99 will recognise that a packet is an update message (rather than for instance an ordinary data packet,) by examining the destination address in the packet, a mobile node having earlier informed the interception stage of the address of its home agent. This will reduce the need for mobile nodes to register with the signaling agent 34, but may increase the amount of traffic over the wireless link in comparison to the bandwidth needed in the case where the signaling stage 40 simply provides the signaling agent with a new location identifier each time the point of attachment changes. In another embodiment a similar inception stage 101 is included within the Signalling Agent, which stage (i) recognises a response to a mobility update message (eg an Acknowledgement), (ii) stores it temporarily, along with other similar responses to update messages, (iii) creates a new message which contains several or all of the responses messages that have been temporarily stored, (iv) sends the new message to the mobile router. On receiving this message the mobile router extracts the original responses, which it then sends as normal to the mobile node(s). The interception may stage recognise that a packet is a response (rather than for instance an ordinary data packet) through the protocol number (and which mobile router it should send it to through the destination address). In order to be able to intercept a response message, the Signalling Agent will normally be on the forwarding path the response follows, for example it is located at the Base Station. To allow for secure communication between nodes, a security relationship will normally be established prior to messages being sent. For example, a security relationship may be established between a mobile node and the signalling agent by the use of a shared secret or key. Likewise, a security relationship may be established between the mobile router and the signalling agent. The shared key may be in the form of a token, which token is sent to the signalling agent by a mobile node, such that the signalling agent can provide the token for the related home agent. Normally, each mobile node will provide to its respective home agent details of the token that the signalling agent will send to the home agent, so that the home agent can authenticate the signalling agent.

20060314

20110621

20060928

90633.0

H04Q700

AJIBADE AKONAI, OLUMIDE

TELECOMMUNICATIONS SYSTEM

UNDISCOUNTED

ACCEPTED

H04Q

ACCEPTED

Power saving operation of an apparatus with a cache memory

An apparatus that contains an instruction processing circuit (14), a main memory (18) addressable by the instruction processing circuit (14) and a cache memory (16). In a normal mode the cache memory (16) is used to cache a part of data and /or instructions that the instruction processing circuit (14) addresses in the main memory (18) during execution, and to substitute cached data and/or instructions when the instruction processing circuit (14) addresses the data and/or instructions in the main memory (18). The circuit is able to switch to a low power operating mode. Upon the switch an interrupt program for executing a function during operation in the low power operating mode is loaded into the cache memory (16) from the main memory (18). Power supply to the main memory (18) is then switched off, but keeping at least a part of the cache memory (16) continuous to receive power supply. This part ensures that the program of instructions for executing the function is available to the instruction processing circuit. The program is executed from said at least part of the cache memory (16) in the low power operating mode.

1. An apparatus that is switchable to a low power operating mode and to a normal operating mode, the apparatus comprising: an instruction processing circuit (14); a main memory (18) for providing instructions for the instruction processing circuit (14) during execution by the instruction processing circuit (14); a cache memory (16) coupled between the instruction processing circuit (14) and the main memory (18), operable in the normal operating mode to cache a part of data and/or instructions that the instruction processing circuit (14) addresses in the main memory (18) during execution, and to substitute cached data and/or instructions when the instruction processing circuit (14) addresses the data and/or instructions in the main memory (18); low power operating mode activating circuit (10, 12, 14), arranged to keep part of the apparatus deactivated during operation in the low power operating mode, said part of the apparatus including the main memory (18), but excluding at least part of the cache memory (16), the low power mode activating circuit (10, 12, 14) being arranged to load a program of instructions for executing a function during operation in the low power operating mode into said at least part of the cache memory (16) before switching to the low power operating mode. 2. An apparatus according to claim 1, wherein the cache memory (16) is switchable to a locked state, wherein the cache memory (16) is disabled from discarding locked information, the low power operating mode activating circuit (10, 12, 14) being arranged to switch the cache memory (16) to the locked state so as to lock the program of instructions for executing the function in the cache memory (16). 3. An apparatus according to claim 1, wherein the low power operating mode activating circuit (10, 12, 14) is arranged to load, upon switching to the low power operating mode, all data into the cache memory (16) that will be addressed with addresses in main memory (18) by the program of instructions for executing the function. 4. An apparatus according to claim 1, wherein said program of instructions for executing a function in the low power operating mode is an interrupt program, the apparatus comprising an interrupt circuit (19) for triggering the instruction processing circuit to execute the interrupt program at selected times during operation in the low power operating mode. 5. A method of operating an apparatus that contains an instruction processing circuit (14), a main memory (18) addressable by the instruction processing circuit (14) and a cache memory (16), the method comprising: using the cache memory (16) and the main memory (18) in a normal operating mode, to cache in cache memory (16) a part of data and/or instructions that the instruction processing circuit (14) addresses in the main memory (18) during execution, and to substitute cached data and/or instructions when the instruction processing circuit (14) addresses the data and/or instructions in the main memory (18); switching to a low power operating mode, by loading a program of instructions for executing a function during operation in the low power operating mode into the cache memory deactivating the main memory (18) to reduce power consumption, but keeping active at least a part of the cache memory (16), that is needed for retrieving the program of instructions for executing the function; executing the program of instructions in the low power operating mode from said at least part of the cache memory (16).

The invention relates to an apparatus that supports a low power operating mode. U.S. Pat. No. 5,784,628 describes a method of reducing power consumption by a data processing apparatus. The apparatus switches to a low power mode in which most parts of the apparatus are powered down. Critical data is saved in a memory that is not powered down so that the apparatus can easily resume operation when it leaves the low power mode. Thus, next to a normal operating mode (and next to an “off” mode in which the apparatus does not operate or consume power at all), a low power mode is realized from which the apparatus can resume operation faster than from the off mode. In many apparatuses it is desirable that the apparatus can perform certain basic functions in the low power mode without switching to the normal operating mode. Typical examples of such functions include processing interrupts caused by user activation of control switches, inspecting possible received messages etc. Switching back the apparatus to a normal operating mode to perform such basic functions would considerably increase power consumption if they have to be performed frequently while the apparatus does not have to return to full operation for other reasons. In practice the apparatus will be in the low power mode for long periods of time. Therefore it is desirable that power consumption in this low power mode is minimized. This is critical for battery operated apparatuses, but it is also important for other apparatuses, such as mains operated television sets that are switched to standby, in view of the extended period of times that such apparatuses remain in the standby mode. Known apparatuses that contain a computer processor and a main memory with data and/or instructions for use by the processor are often provided with a cache memory in order to speed up execution. The cache memory temporarily stores copies of part of the data and/or instructions that the processor has addressed in main memory, so that it can be retrieved given its main memory address. When the processor addresses such data and/or instructions again, the cache memory substitutes the cached data and/or instructions for the data and/or instructions from main memory. Thus, the delay before the data and/or instructions becomes available is considerably reduced. Of course, the cache memory is conventionally one of the circuits that are deactivated when the apparatus is switched to the low power mode, because it merely stores redundant copies of part of the data and/or instructions that were used during previous processing. Among others it is an object of the invention to provide a reduction of power consumption by an apparatus with a low power operating mode. The apparatus according to the invention is set forth in Claim 1. According to the invention, at least part of a cache memory is selectively kept active in the low power mode while the main memory is deactivated (deactivation typically comprising cutting power supply to the main memory, or at least significantly reducing power supply consumption, so that the main memory is not or not fully operational). Prior to switching to the low power mode a program of instructions that are needed to perform a function while the apparatus is in the low power mode is loaded into the cache memory for later use. When an instruction processing circuit performs the function in the low power mode, it loads the instructions from the cache memory, without activating (supplying full power) the main memory. Because the main memory generally is much larger than the cache memory it generally consumes more power than the relatively small cache memory. On the other hand, the function performed during the low power mode usually requires only modest programs that fit in the cache memory. Hence, power consumption is reduced by using the cache memory as only memory in the low power operating mode. These and other objects and advantageous aspects of the invention will be described in a non-limitative way using the following figures. FIG. 1 shows an apparatus that supports a low power operating mode FIG. 2 shows illustrates operation of the apparatus FIG. 1 shows an apparatus with a main power supply circuit 10, a low power mode power supply circuit 12, a processor 14, a cache memory 16, a main memory 18 and an interrupt circuit 19. It should be realized that FIG. 1 merely provides a simplified schematic drawing, from which many details have been omitted. Main power supply circuit 10 supplies power to main memory 18 and other circuits not shown. Low power mode supply circuit 12 supplies power to processor 14, cache memory 16 and interrupt circuit 19. Processor 14 has an address/data interface coupled to cache memory 16, which in turn has an address/data interface coupled to main memory 18. Interrupt circuit 19 is coupled to processor 14. In operation the apparatus supports at least a normal operating mode and a low power mode. In the normal operating mode both power supply circuits 10, 12 are active, so that interrupt circuit 19, processor 14, cache memory 16, main memory 18 and any further circuits connected to main power supply circuit 10 are fully operational. In this normal mode processor 14 executes programs of instructions that are retrieved from main memory 18 and/or use data from main memory 18. In the normal operating mode cache memory 16 functions as a conventional cache memory 16. When processor 14 needs an instruction and/or data, processor 14 outputs the address with which the instruction and/or data is addressed in main memory on its address/data interface. Cache memory 16 receives the address and tests whether an instruction and/or data corresponding to the address is stored in cache memory 16. Techniques for this type of testing are known per se. If the addressed instruction and/or data is available in cache memory 16, cache memory 16 returns the instruction and/or data from cache memory 16. If the addressed instruction and/or data is not available in cache memory 16, cache memory forwards the address to main memory 18, which returns the instruction and/or data to cache memory 16. Cache memory 16 then supplies the instruction and/or data from main memory 18 to processor 14. Preferably, cache memory 16 also stores a copy of this instruction and/or data, for later use, when processor 14 uses the address again. (Generally, without deviating from the invention, main memory 18 will return a line of data, including neighboring instructions and/or data in addition to the addressed instruction and or data, and the whole line will be stored in cache memory 16). Although cache memory 16 is shown as a single unit for the sake of simplicity, it will be appreciated that cache memory may comprise for example a separate instruction cache memory and a data cache memory, as well as a cache management unit for selecting data and/or instructions that should be retained in cache etc. Similarly, the address/data interface of processor 14 may be connected directly to main memory 18, cache memory 16 intervening only if it detects an address of data that is stored in cache memory 16. Similarly, although main memory 18 is shown as a single block, it should be appreciated that this main memory 18 may comprise different units, such as RAMs or flash memory for data, flash memory or ROM for instructions etc. The words “main memory” should not be taken to imply the absence of any other memory that is distinguished from cache memory 16: “main memory” does not exclude the existence of other, possibly larger memory in the apparatus. FIG. 2 illustrates an embodiment of switchover to a low power operating mode and operation in that mode. Initially in a first execution block 21 processor 14 operates in a normal mode. When processor 14 detects in block 22 that it is no longer necessary to operate in the normal mode, processor 14 starts executing a switchover program to switch over to the low power mode. A first step 23 of the switchover program optionally causes data to be saved for later return to the normal operating mode. In a second step 24 the switchover program causes processor 14 to signal to cache memory 16 to load all instructions of an interrupt program from main memory 18 into cache memory 16. The interrupt program is stored at addresses in main memory that have been selected so that all instructions of the interrupt program can be stored together in cache memory 16. Various solutions exist for loading the interrupt program. In one example the switchover program is provided with the start address and the end address of the interrupt program, so that the switchover program can address all memory locations from the start address to the end address, forcing them to be loaded into cache memory 16. If it is known that main memory 18-retums lines of instruction and/or data, only one address from each line needs to be addressed. This assumes that it is guaranteed that cache memory 16 will retain all addressed data. Cache memory 16 may also be provided with a conventional locking mechanism, which enables processor 14 to signal that (and optionally from which addresses) instructions and/or data must be kept in cache. In this case the switchover program preferably makes processor 14 signal to cache memory 16 that the instructions of the interrupt program must be kept. As an alternative the interrupt program (and optionally the switchover program) may be stored at addresses that are selected so that it is ensured in advance that the switchover program can load the entire interrupt program into cache memory 16 without being subsequently discarded. As a further alternative the circuit may be arranged so that the instruction set of processor 14 contains an instruction to cause specified instructions, or specifically the interrupt routine, to be loaded into cache memory 16. Once the interrupt program has been loaded into cache memory 16, the switchover program executes a third step 25 to cause processor 14 to signal to main power supply circuit 10 to deactivate itself. Next the switchover program may cause processor 14 to switch to a pause mode, or to enter a wait state. The apparatus is now said to have entered the low power operating mode. During operation in the low power operating mode, in response to some event, such as for example actuation of a user interface button or the like, or reception of a possible message via a bus or a wireless interface, or a periodic timing signal, interrupt circuit 19 may trigger processor 14 to execute the interrupt program. During execution of the interrupt program main memory 18 remains deactivated. A first step 26 of the interrupt program is indicated in FIG. 2 as the target of dashed lines to indicate activation by interrupt. In first step 26 of the interrupt program processor 14 addresses the instructions of the interrupt program that are stored in cache memory 16 and therefore is able to execute the interrupt program without recourse to main memory 18. If in a second step 27 of the interrupt program the execution of the interrupt program results in a need to return to the normal operating mode, processor 14 will execute a third step 28 of the interrupt program to cause main power supply circuit 10 to reactivate. However, when this is not necessary processor 14 will execute further steps 29, if any, of the interrupt program and main memory 10 will remain deactivated during the entire execution of the interrupt program, the processor 14 eventually returning to a pause more or a wait state. The apparatus remains in the low power operating mode for example if the interrupt program determines that the possible message that triggered the interrupt was irrelevant, or no valid button was actuated, or no state was the detected that necessitated return to the normal operating mode. It should be appreciated that additional measures may be taken. For example, in addition to the interrupt program, the switchover program may be arranged to load data relevant for interrupt processing into cache memory 16 from main memory before switching to the low power operating mode. However, this is not necessary, for example if no data is needed, or if a dedicated data memory is provided for data that is needed in the low power operating mode. Cache memory 16 may be arranged to be switchable between a normal mode and a stand alone mode for use in the low power operating mode. In this case the switchover program makes processor 14 signal to cache memory to enter the stand alone mode before entering the low power operating mode. In the stand alone mode cache memory 16 is arranged to refrain from addressing main memory, either for writing back data or for other purposes. However it should be appreciated that it may not be necessary to support a stand alone mode if execution of the interrupt program does not cause cache memory 16 to access main memory 18. It should be realized that part of cache memory 16 may be deactivated in the low power operating mode in order to reduce power supply consumption. This may be realized by supplying power to these parts from main power supply circuit 10, or by including an instruction in the switchover program to make processor 14 signal to cache memory 16 to deactivate these parts. Thus, for example, the cache management unit (not shown) that manages replacement of data in cache memory 16 may be switched off. The same may holds for address comparison circuits that are used to detect whether instructions from the interrupt program are in cache memory 16, since it is known that these instructions are in cache memory 16 in the low power operating mode. Similarly, excess storage capacity of cache memory 16, which is not needed during operation in the low power operating mode may be deactivated. Although a single processor 14 has been shown, it should be realized that in practice an instruction processing circuit may used that contains more than one processor coupled to cache memory 16, of which part may be deactivated in the low power operating mode, for example because they receive power supply from main power supply circuit 10. In this case, for example, a processor with limited performance and low energy consumption may be included in the instruction processing circuit for executing the interrupt program. Although the invention has been illustrated for execution of an interrupt program during the low power operating mode, it will be appreciated that the invention also applies to other types of program, such as a program that loops during the low power operating mode, without be triggered by interrupt circuit 19, which may be omitted in this case. Similarly, a plurality of interrupt programs, for servicing different types of interrupt may be kept in cache memory 16 in the low power operating mode. Similarly, other measures may be taken to reduce power consumption in the low power operating mode, such as lowering the supply voltage, reducing the instruction cycle frequency etc. For this purpose, circuits such as cache memory 16 that are active in both the normal operating mode and the low power operating mode may be switched to receive power from main power supply circuit 10 in the normal operating mode and from a dedicated power supply circuit in the low power operating mode. Although switching to the low power operating mode has been described in terms of deactivating main power supply circuit 10, e.g. by making a switch between a source of power and the circuit non-conductive, it will be realized that other ways of deactivation to reduce power consumption can be used, such as disabling clock signals or other signals. Cache memory 16 and processor 14 may even be deactivated in this sense during part of the time in the low power operating mode, when it is not operating in the sense of executing the interrupt program, as long as this deactivation does not cause a loss of data or instructions. Although an embodiment of the invention has been described wherein a switchover program executed by processor 14 controls switching to the low power operating mode, it should be appreciated that alternatively the steps involved switchover may be executed under control of a dedicated (not-programmed) circuit for this purpose, which is activated when the apparatus signals that it should switch to the low power operating mode, or by any other processor, which may have its own access to cache memory 16 and/or main memory for this purpose. Nor does the switchover have to be controlled by a single circuit such as processor 14. For example, part of the switchover, such as loading the interrupt program could be. executed by one circuit, while another part, such as deactivating the main power supply could be executed by another circuit.

20060313

20090421

20070308

80813.0

G06F132

BAE, JI H

POWER SAVING OPERATION OF AN APPARATUS WITH A CACHE MEMORY

UNDISCOUNTED

ACCEPTED

G06F

ACCEPTED

High intensity discharge lamp

A metal halide lamp is disclosed comprising an elongated discharge vessel, preferably made of a ceramic material, surrounded by an outer envelope and having a wall which encloses a discharge space containing an inert gas, such as xenon, and an ionizable filling, wherein at both ends in said discharge space an electrode is arranged between which a discharge arc can be maintained along a discharge path, wherein one end of the discharge vessel is mounted in a mounting base, said lamp comprising a band-shaped light-shielding strip extending laterally of the discharge path, and a lead-back conductor supplying current from the mounting base to the electrode at the other end of the discharge vessel, wherein, seen in cross section, the lead-back conductor is positioned within the sector defined by the two lines through the center of the discharge vessel and the edges of said strip. Also a metalhalide lamp is disclosed wherein the light-shielding strip is a conductive strip, and the antenna or the lead-back conductor is integrated with said strip. Furthermore a metal-halide lamp is disclosed wherein the lead-back wire is provided inside the wall of the outer envelope.

1. A high-intensity discharge lamp comprising an elongated discharge vessel, preferably made of a ceramic material, surrounded by an outer envelope and having a wall which encloses a discharge space comprising an ionizable filling including an inert gas, such as xenon, wherein at both ends in said discharge space an electrode is arranged between which a discharge arc can be maintained along a discharge path, wherein one end of the discharge vessel is mounted in a mounting base, said lamp comprising a substantially band-shaped light-shielding strip extending laterally from the discharge path, and a lead-back conductor supplying current from the mounting base to the electrode at the other end of the discharge vessel, characterized in that, seen in cross section, the lead-back conductor is positioned within the sector defined by the two lines through the center of the discharge vessel and the edges of said strip. 2. A lamp according to claim 1, seen in cross section, the lead-back conductor is positioned within the sector defined by the two tangent lines touching the circumference of the half-value maximum luminance distribution area of the discharge arc during operation and running through the respective nearest edges of said strip. 3. A lamp according to claim 1, wherein said strip and the lead-back conductor are positioned substantially on one radial line through the center of the lamp, seen in cross section. 4. A lamp according to claim 1, further comprising a conductive antenna extending laterally from the discharge path and, seen in cross section, positioned within said sector or on said radial line. 5. A lamp according to claim 1, wherein said strip and the lead-back conductor are positioned substantially on one radial line through the center of the lamp, seen in cross section. 6. A lamp according to claim 1, wherein the light-shielding strip is a conductive strip, and the antenna or the lead-back conductor is integrated with said strip. 7. A lamp according to claim 6, wherein said strip is integrated with the antenna and is provided on the outer side of the discharge vessel. 8. A lamp according to claim 6, wherein said strip is integrated with the antenna and is provided on the inner side of the outer envelope. 9. A lamp according to claim 6, wherein said strip is integrated with the lead-back conductor and is provided inside the wall of the outer envelope. 10. A lamp according to claim 6, wherein said strip is integrated with the lead-back conductor and is provided on the outer side of the outer envelope. 11. A vehicle head lamp comprising a reflector and a lamp according to claim 1 mounted therein.

The invention relates to a high intensity discharge lamp comprising an elongated discharge vessel, preferably made of a ceramic material, surrounded by an outer envelope and having a wall which encloses a discharge space comprising an ionizable filling including an inert gas, such as xenon, wherein at both ends in said discharge space an electrode is arranged between which a discharge arc can be maintained along a discharge path, wherein one end of the discharge vessel is mounted in a mounting base, said lamp comprising a substantially band-shaped light-shielding strip extending laterally from the discharge path, and a lead-back conductor supplying current from the mounting base to the electrode at the other end of the discharge vessel. Such lamps are known, and are mainly used in the automotive field, more specifically for use in headlights. The band-shaped light-shielding strip usually extends along the length of the discharge vessel as a light absorbing coating on the wall of either the discharge vessel or the outer envelope. The light-shield achieves a light/dark boundary, which is projected many times by the multi-facet lens of the headlight assembly or by a so called “free form reflector” such that a sufficiently sharp beam delineation in the beam pattern of the headlight is provided in order to avoid radiation of light giving rise to dazzle, for example. Just below the light/dark-boundary in a dimmed beam pattern there must be a very high light intensity to lighten a road at a distance, whereas just above said light/dark boundary a very low light intensity must be present to avoid said dazzle. This is called the cut-off, which must be sharp, and in many countries must comply with prescribed standards. The lead-back conductor is usually a wire running at some distance from the outer envelope, positioned below the horizontally extending lamp when it is fitted in a reflector. This lead-back conductor is usually shielded from the light source by an additional shield. Some lamp types also comprise a conductive antenna extending laterally from the discharge path. The conductive antenna in such lamps usually extends along the length of the discharge vessel between electrodes and serves as a so-called ignition strip or starting antenna. The antenna capacitively couples the high voltage pulse from an electrode, through the gas filling and the wall, to the antenna, and finally to the other electrode. This reduces the apparent distance between electrodes and therefore increases the applied electric field which accelerates primary electrons and initiates the so- called Townsend avalanche. This occurs when at least one secondary electron is emitted in the gas filling for each primary electron, and the discharge current becomes self-sustaining. The drawbacks of the known lamps are that the lead-back wire and its external shield, and if present also the antenna, is partially blocking the light way and thus absorbs a lot of light, which is then not available for the beam pattern. Another drawback of the known lamps is that they may have disadvantageous effects on the light pattern which is projected by the lamp as explained above, and in particular may lead to a less sharp cut-off. The object of the invention is to provide a lamp which is simple, compact, has a better efficiency and/or produces a better beam pattern. In order to accomplish said object, seen in cross section, the lead-back conductor, and if present preferably also the antenna, is positioned within the sector defined by the two lines through the center of the discharge vessel and the edges of said strip. Preferably, seen in cross section, the lead-back conductor is positioned within the sector defined by the two tangent lines touching the circumference of the half-value maximum luminance distribution area of the discharge arc during operation and running through the respective nearest edges of said strip. Furthermore, the middle of the arc will not be positioned in the center of the tube, but slightly above, which is caused by convection inside the discharge vessel. The projection lines that touch the circle where the luminance is about 50% of the maximum luminance and which run through the nearest edges of the strip define the boundaries between which the lead-back conductor and the antenna should be, so that they have almost no negative impact on the projection of the strip, and the light is blocked substantially by the light shielding strip only. In an alternative definition of the preferred embodiment of the invention, said strip, the lead-back conductor and if present the antenna, are positioned roughly or substantially on one radial line through the center of the lamp, seen in cross section. In a particular preferred embodiment the light-shielding strip is a conductive strip, preferably made of tungsten, and the antenna or the lead-back conductor is integrated with said strip. This feature can be considered as an invention on its own, and can be applied also when the remaining separate antenna or the lead-back conductor is not positioned within the sector mentioned. Not only the previously mentioned advantages are achieved hereby, but also a cost reduction and a more compact lamp can be achieved by combining two different parts to one part. In a first preferred embodiment said strip is integrated with the antenna and is provided on the outer side of the discharge vessel. In a second preferred embodiment said strip is integrated with the antenna and is provided on the inner side of the outer envelope. In a third preferred embodiment said strip is integrated with the lead-back conductor and is provided on the outer side of the outer envelope. In a fourth preferred embodiment said strip is integrated with the lead-back conductor and is provided inside the wall of the outer envelope. In a special preferred embodiment also the antenna is integrated therein, such that all three functions are integrated with one conducting strip inside said wall. In that case the conducting strip should be positioned as close as possible to the discharge vessel, in order to have a properly functioning antenna. In this fourth embodiment the lead-back conductor is surrounded by the wall material, preferably quartz glass, of the outer envelope, which has the further advantage that it is electrically insulated thereby. Preferably the lead back conductor, the light-absorbing strip and/or the antenna are provided with a dark or black light absorbing coating, in order to prevent light scattering. Other combinations and positions of the strip and the antenna or the lead-back conductor as defined herein are of course possible, each having its own advantages, and those will be obvious to the man skilled in the art. The invention also relates to a vehicle head lamp comprising a reflector and a lamp as described above mounted therein. The above and further aspects of the lamp in accordance with the invention will now be explained with reference to lamp embodiments shown in the figures, wherein: FIG. 1 shows a lamp in side elevation; FIG. 2 shows a perspective view of a discharge vessel in the lamp; FIGS. 3-9 show cross sections of a lamp; and FIG. 10 shows a lamp in side elevation. In FIG. 1 the electric discharge lamp has a tubular, light transmissive ceramic discharge vessel 3 of polycrystalline aluminum oxide, and a first and a second current conductor 40, 50 which enter the discharge vessel 3 opposite each other, and each conductor 40, 50 supports an electrode 4, 5 in the vessel 3. Said electrodes are made of tungsten and are welded to the current conductors 40, 50. Ceramic seals 34, 35 seal the discharge vessel 3 around the current conductors 40, 50 in a gas tight manner. The discharge vessel 3 has an ionizable filling comprising xenon as a rare gas and a metal halide mixture comprising sodium and rare earth iodides. The discharge vessel 3 is surrounded by a substantial cylindrical transparent outer envelope 1. The outer ends of current conductors 40, 50 are connected to connecting wires 8, 9 which extend outside the seals 34, 35 and through the end walls of outer envelope 1. One connecting wire 8 is connected directly to a first electric pole in mounting base 2, the other connecting wire 9 is connected to a lead back wire 19, which extends alongside the outer envelope 1 and is connected to a second electric pole in the mounting base 2. The lead back wire 19 is surrounded by a ceramic isolation shield 10. In FIG. 2 the discharge vessel 3 is provided with a conductive antenna 51 extending along the length of the vessel 3 and connecting rings 52, 53 surrounding the electrode tips, as known from U.S. Pat. No. 5,541,480. The optional rings 52, 53 are part of the antenna The antenna reduces the breakdown voltage at which the gas filling ionizes. The cross section of the lamp in FIG. 3 shows the discharge vessel 3 surrounded by the outer envelope 1. Outside the outer envelope extends the lead back wire 19, which may be isolated by the ceramic shield 110 (not shown). In the outer side of the discharge vessel 3 is shown the antenna 51. A band-shaped light-shielding strip 11 extends along the length of the discharge vessel as a light absorbing coating as explained in the introduction. FIG. 4 shows the circumference of the half-value maximum luminance distribution area 64 of the discharge arc during operation. A sector 61 is defined by the two tangent lines 62, 63 touching the circumference of the area 64 and running through the respective nearest edges of the light-shielding strip 11. The antenna 51 and the lead back wire 19 are preferably positioned inside the sector 61, as shown for example in FIG. 5. FIGS. 6 to 9 show particular embodiments of the lamp, wherein the tasks of the antenna 51, the light-shielding strip 11 and/or the lead back wire 19 are combined. Also in these embodiments the remaining antenna 51 and/or the lead back wire 19 are positioned inside the sector 61 shown in FIG. 4, as is preferred. According to FIG. 6 the strip 11 is integrated with the antenna 51 and is provided on the outer side of the discharge vessel 3. According to FIG. 7 the strip 11 is integrated with the antenna 51 and is provided on the inner side of the outer envelope 1. According to FIG. 8 the strip 11 is integrated with the lead-back wire 19 and is provided on the outer side of the outer envelope 1. According to FIG. 9 the strip 11 is integrated with the lead-back wire 19 and is provided in the wall of the outer envelope 1. In FIG. 10, the electric discharge lamp has a tubular, light transmissive ceramic discharge vessel 3 of polycrystalline aluminum oxide, and a first and a second current conductor 40, 50 which enter the discharge vessel 3 opposite each other, and each conductor 40, 50 supports an electrode 4, 5 in the vessel 3. Said electrodes are made of tungsten and are welded to the current conductors 40, 50. Ceramic seals 34, 35 seal the discharge vessel 3 around the current conductors 40, 50 in a gas tight manner. The discharge vessel 3 has an ionizable filling comprising xenon as a rare gas and a metal halide mixture comprising sodium and rare earth iodides. The discharge vessel 3 is surrounded by a substantial cylindrical transparent outer envelope 1. The outer ends of current conductors 40, 50 are connected to connecting wires 8, 9 which extend outside the seals 34, 35 and through the end walls of outer envelope 1. One connecting wire 8 is connected directly to a first electric pole in mounting base 2, the other connecting wire 9 is connected to a lead back wire 19, which extends through the cylindrical side wall 22 of the outer envelope I and is connected to a second electric pole in the mounting base 2. During manufacturing of the lamp according to FIG. 10 the envelope 1 is left open at the side of end wall 20. A recess 21 is made in the wall 22 and a bore hole is provided over the length of the wall 22. If the lead back 19 wire must act as an antenna, the bore hole should preferably located as close as possible to the inner side of the outer envelope. Lead back wire is welded to connecting wire 9, and the discharge vessel 3 is then inserted in the envelope 1, while at the same time the lead back wire 19 is inserted in the bore hole in the wall 22. Finally the end wall 20 is closed by locally melting the outer envelope.

20060315

20090915

20070208

98570.0

H01J162

HOLLWEG, THOMAS A

HIGH INTENSITY DISCHARGE LAMP

UNDISCOUNTED

ACCEPTED

H01J

ACCEPTED

Fabric display

The present invention provides a fabric display using the action of electrostatic charges to manipulate visual displays. The fabric display comprises areas of furry fabrics (16) that can serve as visual effects or display of information and can be usable in a wearable garment, furniture, or other suitable locations where it c be incorporated to close a circuit. Through activation by the user, the surface of furry fabrics (16) is electrostatically charged causing the furs to repel from the surface and each other in a substantially vertical orientation with portions of the furs extending cut of the surface, thus revealing the color of the fabric surface.

1. A display fabric (10) comprising: a fabric layer (14) having at least one conductive layer (12) therein for passing an electrostatic field, said fabric layer (14) having a plurality of furs (16) on the surface thereof responsive to said electrostatic field to extend out of said fabric layer (14) in a substantially vertical orientation, thereby revealing the surface color of said fabric. 2. The display fabric of claim 1, wherein the surface of said fabric layer (14) includes a plurality of predetermined color pattern surfaces. 3. The display fabric of claim 1, wherein said conductive layer(12) carries a positive or negative charge on its outwardly facing surface so that said electrostatic field that exists within the surface of said fabric layer (14) forces said furs to repel and extend in a substantially vertical orientation. 4. The display fabric of claim 1, wherein said conductive layer (12) serves as a coupling to a power source. 5. The display fabric of claim 1, wherein said fabric layer (14) is coupled to a fabric circuit integrated in a garment 6. The display fabric of claim 5, wherein said garment is a shirt. 7. The display fabric of claim 5, wherein said garment is a vest. 8. The display fabric of claim 5, wherein said garment is a jacket. 9. The display fabric of claim 5, wherein said garment is a hat. 10. The display fabric of claim 1, wherein said fabric layer (14) is coupled to a fabric circuit integrated in furniture. method for providing a visual display with a wearable comprising the steps of: providing a fabric layer (14) having at least one conductive layer (12) therein for passing an electrostatic field and a plurality of furs (16) on the surface thereof; dressing a person in said garment provided with said fabric layer (14); and, selectively providing an electrostatic force to a selective region of said conductive layer (12) to force the corresponding said furs (16) to extend out of said fabric layer (14) in a substantially vertical orientation, thereby revealing the surface color of said fabric. 12. The method of claim 11, further comprising the step of providing a plurality of predetermined color pattern surfaces on the surface of said fabric layer (14). 13. The method of claim 11, further comprising the step of coupling a power source to said conductive layer (12) to generate an electric field thereon by an activation of said person. 14. The method of claim 11, wherein said garment is a shirt. 15. The method of claim 11, wherein said garment is a vest. 16. The method of claim 11, wherein said garment is a jacket. 17. The method of claim 11, wherein said garment is a hat. 18. A method for providing a visual display with a wearable garment, said method comprising the steps of: providing a fabric layer (14) having at least one conductive layer (12) therein for passing an electrostatic field and a plurality of furs (16) on the surface thereof; integrating said fabric layer (194) in furniture; and, selectively providing an electrostatic force to a selective region of said conductive layer (12) to force the corresponding said furs (16) to extend out of said fabric layer (14) in a substantially vertical orientation, thereby revealing the surface color of said fabric. 19. The method of claim 18, further comprising the step of providing a plurality of predetermined color pattern surfaces on the surface of said fabric layer (14).

The present invention relates to visual fabric articles intended to permit the display of a certain pattern or design. More specifically, the present invention relates to a visual fabric display system that may be implemented in an article of clothing, furniture, or in other location to provide communication and informational or decorative display by the action of electrostatic charges. The idea of dynamically changing the appearance of the fabric of a garment, for example, is highly desirable and certainly attractive for designers and the fashion industry. There are a number of display devices that utilize informational and decorative manipulatives. Attempts so far include embedded LEDs, thermochromic liquid crystal, and electroluminescent materials applied to the fabrics. However, these techniques employ additional manufacturing efforts and costs. As described in detail below, it has been found efficacious to use electrostatic charges applied to an area of fabric to realize visual display, and unlike prior art they do not involve the use of additional devices. The present invention discloses a display fabric system, which includes a fabric layer having at least one conductive layer therein for passing an electrostatic field and a plurality of surfaces having a plurality of furs on the surface thereof, so that selective regions covered by the furs can selectively extend out of the fabric layer in a substantially vertical orientation in response to the electrostatic field, thereby revealing the surface color of the fabric layer. In operation, an electric field is generated by the activation of a user via a conductive layer, so that the selected regions covered by the furs can repel each other and extend out of the fabric layer in a substantially vertical direction. The fabric surface may comprise a plurality of different color surfaces. According to one aspect of the invention, a garment or furniture of desired form and function can be constructed in a conventional manner using readily available fabrics and materials, and the fabrics serving as a visual display system can be positioned advantageously within a wearable garment or furniture that permits easy manual activation by a person. According to another aspect of the invention, the garment comprises a shirt, a hat, a jacket, a vest, a fashion accessory or the like. FIG. 1 illustrates an embodiment of a fabric display system in accordance with this invention. FIG. 2 illustrates a side view of the fabric layer of FIG. 1 in accordance with the embodiment of this invention. In the following description, for purposes of explanation rather than limitation, specific details are set forth such as the particular architecture, interfaces, techniques, etc., in order to provide a thorough understanding of the present invention. For purposes of simplicity and clarity, detailed descriptions of well-known devices, circuits, and methods are omitted so as not to obscure the description of the present invention with unnecessary detail. Referring now to FIG. 1 of the drawings, a fabric display system 10 in accordance with this invention includes a fabric layer 14 having a flexible layer 12 of conductive material mounted thereunder. On the top surface of the fabric 14, a fur-like or hair-like 16 is formed thereof (hereinafter referred to as “fur”). The conductive layer 12 may be coupled to a power source in the form of loops to transmit the desired voltage level in conjunction with a user activation switch in any well-known manner, so that a fur-like surface coupled to an electrical power source is able to electrostatically charge the area of the fur-like surface causing a local change in the orientation of the fur. The embodiment illustrated in FIG. 1 may be incorporated in the form of a conventional sleeveless top shirt, hat, or a short or long-sleeved vest or jacket, for example. In an alternate embodiment, the embodiment of FIG. 1 may be implemented in furniture or in other locations where the layers of electrically conductive layer 12 can be used as a coupling of electrical power for visual display purposes. Referring to FIG. 2, the furs 16(b) are resting nearly flat and covering most of the surface of the fabric 14 in the normal state. When a given surface of the fabric 14 is electrostatically charged through the activation by the user, then the furs 16(b) repel each other and also are repelled by the surface, therefore standing nearly vertical to the surface and revealing the color of the surface. Discharging of an area causes the fur to rest back in their initial position. The charged layer 12 can carry either a positive or negative charge on its outwardly-facing surface in such a way that electrostatic forces that exist in the surface force the furs 16 to repel and extend out of the surface in a substantially vertical orientation, thereby revealing the color of the surface. The surface of fabric 14 may be divided into a number of predetermined patterns and different colors. Hence, the pattern is determined by the fabric surfaces of different colors as well as the orientation of pieces of fabric that make up the pattern. For example, each area can be considered as a pixel and therefore charging/discharging different areas, a change in the contrast can be achieved which can form a binary image or pattern. The material of the fabric layer 14 can be either natural or synthetic, and the fabric created from such materials can be either woven or sheet-formed in any well-known manner. For example, the fabric layer 14 can be formed of a material such as cotton, polyester, spandex, a combination thereof, or the like. Alternatively, the fabric layer 14 can be constructed from non-woven (felted) or knitted fabrics or a composite structure. However, in each alternative case, electrically conductive layer 12 is included in the production of the fabric, thus providing electrically conductive layers. The conductive layer 12 may be produced by printing them onto the fabric layer 14 or it may be mounted as adhesive tape. Alternatively, the conductive layer 12 may be produced by printing a material containing conductive particles onto the fabric layer 14. All of the alternatively described methods provide a suitable bond, forming a reliable electrical connection. While the preferred embodiments of the present invention have been illustrated and described, it will be understood by those skilled in the art that various changes and modifications can be made, and equivalents can be substituted for elements thereof without departing from the true scope of the present invention. Thus, the shape of an interconnect system in the drawings should not impose limitations on the scope of the invention. Therefore, it is intended that the present invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out the present invention, but that the present invention include all embodiments falling within the scope of the appended claims.

20060313

20090512

20070405

67833.0

F21V2108

JUSKA, CHERYL ANN

FABRIC DISPLAY

UNDISCOUNTED

ACCEPTED

F21V

ACCEPTED

Device for the sorting of flat mailings

The invention relates to a device for the sorting of flat mailings comprising pouches for individual mailings, circulating on a conveyor belt on two levels, the emptying of which may be controlled corresponding to the read target address and the sorting plan. The total circulation in the pouch loop (5) is carried out in several partial loops. The level transitions for each partial loop are adjacent within the total circulation, whereby on each level transition the conveyor belt is diverted inwards. The pouch loading stations (10) are arranged adjacently for each partial loop in the lower level.

1. A device for the sorting of flat mailings comprising pouches (6) for individual mailings (4), circulating on a conveyor belt on two levels, the emptying of which may be controlled corresponding to the read target address and the sorting plan, with the total circulation in the pouch loop (5) being carried out in several partial loops, and with the level transitions for each partial loop being positioned adjacent to one another within the total circulation, characterized in that at each level transition the conveyor belt is diverted inwards and that pouch loading stations (10) are arranged adjacently for each partial loop on the lower level. 2. The device according to claim 1, characterized in that a buffer device (2) with circulating buffer pouches (3) is provided between the two levels of the circulating pouches (6) and which may be fed by one or more feeder stations with separating devices (1) and subsequent reading devices and whose buffer pouches (3), which may be controllably emptied, transfer the mailings to the pouch loading stations (10). 3. The device according to claim 1, characterized in that unloading stations (11), for the additional removal of mailings (4) are arranged before the pouch loading stations (10) in transport stations in the planar extension of the pouch loop (10).

The invention relates to a device for the sorting of flat mailings, comprising pouches for individual mailings, circulating on a conveyor belt on two levels, the emptying of which may be controlled corresponding to the read target address and the sorting plan. According to the prior art for sorting machines with circulating pouches (EP 0 708 693 B1, EP 0 820 818 A1), the mailings are loaded into the pouches at one position. The circulating pouches are opened as soon as the mailing has reached a predetermined end position. The pouches then move forward empty until they have reached the loading point, where they are once again loaded with a new mailing. Thus the pouches cover long distances empty, which reduces the throughput of the sorting machine. It would be more advantageous, therefore, to provide a loading point after each half circulation, for example, resulting in a reduction of the distances covered by the empty pouches. This is known per se when sorting parcels with tilting tray sorting machines but has not been used when sorting flat mailings, as loading the mailings at different points from a single feeder is too costly, or an operator would be necessary at each loading point (feeder area). Even with circulations on two levels, a loading point is only provided at one point (EP 0 708 693 B1). In the abstract, EP-A-0 638 501 discloses a device for the sorting of flat mailings comprising pouches for individual mailings, circulating on a conveyor belt on two levels, the emptying of which may be controlled corresponding to the read target address and the sorting plan, whereby the total circulation in the pouch loop is carried out in several partial loops and whereby the level transitions for each partial loop are adjacent within the total circulation. The object of the invention is to provide a device for sorting flat mailings with pouches circulating on a conveyor belt on two levels, with which either the throughput can be increased at the same circulating speed or, with the same throughput, either the circulating speed and/or the number of pouches can be reduced, without increased staff costs and with reduced additional equipment costs. In this connection, it is possible to carry out loading from a buffer with buffer pouches which circulate on one level. The object is achieved according to the invention by the features of claim 1. This particular layout of the conveyor belt allows a plurality of loading stations to be arranged adjacently on the lower level, although they feed into the circulation at a distance from one another around a circulation loop. This allows the loading stations and/or feeder areas to be operated with minimal use of operators. Advantageous embodiments of the invention are shown in the sub-claims. A buffer with circulating buffer pouches is advantageously provided between the two levels of the circulating pouches and which may be fed by one or more feeder stations with separating devices and subsequent reading devices and whose buffer pouches, which may be controllably emptied, transfer the mailings to the pouch loading stations. As a result, it is possible to feed in the mailings from one or more separating devices, independently from emptying the pouches for sorting. It is moreover advantageous to provide unloading stations, for the additional removal of mailings, which are located before the pouch loading stations in the direction of transportation in the planar extension of the pouch loop, so that there is the possibility of further pouches being empty at the pouch loading stations. The invention is described in more detail hereinafter in an embodiment with reference to the drawings, in which: FIG. 1 is a diagrammatic side view of a device for sorting according to the order of distribution, with the loading of a collector belt subdivided into sections, FIG. 2 is a perspective view of the sorting device with two levels and one bend, FIG. 3 is a perspective view of the sorting device with two levels and two bends. In this example, the mailings are sorted in a plurality of end positions assigned to the target addresses which are arranged along the straight sections below the circulations. The mailings 4 are firstly separated from a stack in the known manner in a separating device 1. The receiver addresses of the mailings 4 are then recorded and identified in a reading device, not shown. The read mailings 4 are then conveyed to a buffer device 2. At this point each mailing 4 is conveyed into a circulating buffer pouch 3 via a loading station, whereby these buffer pouches 3 may be controllably coupled to a circulating conveying means and may be controllably uncoupled from the conveying means and the transfer is carried out in the coupled state. If, for throughput reasons, a plurality of separating devices 1 are provided, the mailings 4 are transported from each separating device 1 into the buffer pouches 3 via a separate loading station. Due to the capacity of the buffer, it is possible to process further both an irregular incoming flow from the separating devices 1 and an outgoing flow which is not synchronized with the incoming flow and/or is irregular. The buffer pouches 3 can be controllably opened downwards in order to deposit the mailings 4 into empty pouches 6 of a further pouch loop 5 circulating below. In this connection, the pouches 6 are fixedly connected to the circulating conveying device. The pouch loop 5 and the buffer pouches 3 circulate in the same direction. The mailings 4 are sorted according to the current sorting plan, with the mailings 4 falling downwards in a controlled manner into the sorting end positions 7 by opening the bottoms of the pouches 6. In order to accommodate the sorting device on the smallest possible floor area, the pouch loop 5 passes through two levels. Parts of the pouch loop 5 are bent back over one another about horizontal axes: in principle, the pouch loop 5 has the path of horizontal figures of eight which have been bent where they cross and are surrounded at that point by the buffer device 2. The actuators for opening the pouches 6 of the pouch loop 5 can be fixedly arranged. According to FIG. 2, two adjacent level transitions are respectively diverted by 540° over the interior of the installation. Visible outside the sorting end positions, not shown for reasons of clarity, are two adjacent pouch loading stations 10 with outlets of the buffer device 2 for loading the pouches 6 on the lower level, unloading stations 11 for additionally removing mailings 4 from the pouches 6 according to specific sorting criteria and which are arranged before the loading stations 10, so that there is the possibility of further pouches 6 being empty at the loading stations 10, a loading station 12 for loading the buffer pouches with the mailings from the separating device 1 and an outlet 13 of the buffer device 2 for removing mailings which have been separated off. In FIG. 3 a sorting device is shown with two sets of bends. The diversions, together with the level transitions, are also arranged adjacent to one another inside the circulation, whereby the outer diversions are 540° due to the changeover to the other side and the inner diversions, where the mailings move forward on the same side, are 360°. In this connection, after respectively ¼ of the total circulation, a pouch loading station 10 is provided on the lower level, whereby the four loading stations are adjacent to one another (two on each side). In these examples the mailings circulate in the diversions in the same direction, which is not imperative, however.

20060314

20080708

20070201

59847.0

B65B122

RODRIGUEZ, JOSEPH C

DEVICE FOR THE SORTING OF FLAT MAILINGS

UNDISCOUNTED

ACCEPTED

B65B

ACCEPTED

Powder Container and Image Forming Apparatus

A powder container that is detachably installed in a container housing unit of an image forming apparatus includes a container body including an opening located at a head of the container body, and an engaging part located at a bottom of the container body, the engaging part being engaged with an engagement receiving part of the container housing unit; a drive transferring member that rotates integrally with the container body; and a lid including a discharge outlet that further discharges powder discharged from the opening of the container body, and a shutter that opens and closes the discharge outlet. A position of the powder container in the container housing unit is determined by engaging the engaging part with the engagement receiving part, and operating the lid such that the shutter opens the discharge outlet.

1. A powder container that is detachably installed in a container housing unit of an image forming apparatus, the powder container comprising: a container body including an opening located at a head of the container body; and an engaging part located at a bottom of the container body, the engaging part being engaged with an engagement receiving part of the container housing unit; a drive transferring member that rotates integrally with the container body; and a lid including a discharge outlet that further discharges powder discharged from the opening of the container body; and a shutter that opens and closes the discharge outlet, wherein a position of the powder container in the container housing unit is determined by engaging the engaging part with the engagement receiving part, and operating the lid such that the shutter opens the discharge outlet. 2. The powder container according to claim 1, wherein the engaging part is formed in a concave and circular shape. 3. The powder container according to claim 1, wherein the engagement receiving part is formed in a convex shape. 4. The powder container according to claim 1, wherein the lid includes a fitting part that fits to a counterpart of the container housing unit in conjunction with opening of the discharge outlet. 5. The powder container according to claim 1, wherein the drive transferring member is a gear located on a circumferential surface of the container body and on a side of the opening. 6. The powder container according to claim 1, wherein the container body includes a spiral protrusion on an inner circumferential surface. 7. The powder container according to claim 1, wherein the container body stores toner. 8. The powder container according to claim 7, wherein the container body further stores a carrier. 9. An image forming apparatus comprising a powder container that includes a container body including an opening located at a head of the container body; and an engaging part located at a bottom of the container body, the engaging part being engaged with an engagement receiving part of the container housing unit; a drive transferring member that rotates integrally with the container body; and a lid including a discharge outlet that further discharges powder discharged from the opening of the container body; and a shutter that opens and closes the discharge outlet, wherein a position of the powder container in the container housing unit is determined by engaging the engaging part with the engagement receiving part, and operating the lid such that the shutter opens the discharge outlet, the powder container is detachably installed in the container housing unit, and the container housing unit includes the engagement receiving part with which the engaging part of the powder container is engaged. 10. The image forming apparatus according to claim 9, wherein the container housing unit includes a counterpart to which a fitting part of the lid fits in conjunction with opening of the discharge outlet. 11. The image forming apparatus according to claim 9, wherein the image forming apparatus includes a driving unit that transfers a drive to the drive transferring member. 12. A powder container comprising: a container body including a conveying part that conveys powder stored in the container body towards an opening of the container body; and a lid that supports the container body such that the container body is rotatable, and discharges the powder discharged from the opening through a discharge outlet, wherein the lid includes a contacting part that makes a contact with the opening; and a preventing part that prevents a gap from forming between the opening and the contacting part, and the powder container is installed in an image forming apparatus by fixing the lid to the image forming apparatus. 13. The powder container according to claim 12, wherein the lid is rotated to be engaged with an engaging part of the image forming apparatus after being set in a predetermined position of the image forming apparatus to install the powder container in the image forming apparatus, and the preventing part prevents the gap from forming between the opening and the contacting part by restricting a rotational central axis of the container body from being deviated from a predetermined position when the lid is rotated by more than a predetermined amount. 14. The powder container according to claim 13, wherein the lid includes a handle for a user to grasp, and the preventing member is a rib that is parallel to an axial direction of the powder container, and is positioned opposite to the handle with respect to the rotational central axis. 15. The powder container according to claim 13, wherein the lid includes a handle for a user to grasp, and the preventing member is hemispherical, and is positioned opposite to the handle with respect to the rotational central axis on an edge of the lid near the container body. 16. The powder container according to claim 14, wherein a plurality of preventing members is provided. 17. An image forming apparatus comprising a powder container that includes a container body including a conveying part that conveys powder stored in the container body towards an opening of the container body; and a lid that supports the container body such that the container body is rotatable, and discharges the powder discharged from the opening through a discharge outlet, wherein the lid includes a contacting part that makes a contact with the opening, and a preventing part that prevents a gap from forming between the opening and the contacting part, the powder container in which toner is contained can be installed the image forming apparatus, and the powder container is installed in an image forming apparatus by fixing the lid to the image forming apparatus.

TECHNICAL FIELD The present invention relates to a powder container that is detachably attached to a body of an image forming apparatus to replenish powder such as toner consumed during an image forming process, and an image forming apparatus including the powder container. BACKGROUND ART An image forming apparatus such as a composite machine has at least two functions of a printer, a copier, or a fax machine. Toner is consumed when the image forming apparatus is used; thus, the toner needs to be successively replenished into a developing unit according to the amount of consumption. The toner is typically replenished into the developing unit from a toner container such as a toner cartridge or a toner bottle. When the toner container is empty, it is replaced with a new one. There is known a cylindrical toner bottle for replenishing toner into the developing unit of the conventional image forming apparatus, such as that disclosed in Japanese Patent Application Laid Open No. 2000-338758 (hereinafter referred to as “first document”). In the first document, the toner bottle is set in the body of the image forming apparatus (hereinafter, “apparatus body”) as follows. First, a user pulls out a holding stand of a toner replenishing unit of the apparatus body, and takes out the empty bottle existing on the holding stand. The user then sets a new toner bottle sideways in the holding stand. The user pushes the holding stand with the new toner bottle into the back of the toner replenishing unit. Accordingly, a convex part provided on the bottom of the toner bottle engages with a joint part at the back of the toner replenishing unit. This fixes the position of the toner bottle in the toner replenishing unit. Spiral protrusions are provided on the inner circumferential surface of the toner bottle. Thus, when the joint part is rotatably driven and the toner bottle is rotated, toner contained in the toner bottle is discharged from an opening. The toner discharged from the toner bottle is replenished to the developing unit. The toner bottle constructed as above is relatively low-cost in that fewer components are used as compared to a toner container with a conveying member such as an agitator inside. Moreover, the above toner bottle is useful for recycling purposes, because it has a higher level of mechanical strength as compared to a bag-shaped toner container. Because a user exchanges the toner container, the toner container should be easy to exchange, and toner scattering should be prevented so as not to soil hands and clothes of the user. Moreover, toner density becomes uneven if a stable amount of toner is not constantly discharged from the toner container and replenished into the developing unit. This can cause deterioration in image quality, such as blurring or uneven colors. Therefore, a stable amount of toner needs to be discharged from the toner container to the toner replenishing unit. Various toner containers have been proposed and implemented to meet such demands. A well known example is a cylindrical toner bottle that has a spiral toner conveying part as disclosed in, for example, Japanese Patent Application Laid Open No. 2004-139031 (hereinafter referred to as “second document”). On one end of this toner bottle is a mouth (opening) that has a smaller diameter than the spiral-shaped bottle body. This toner bottle is set in the apparatus body so that the bottle axis is substantially horizontal. Moreover, this type of toner bottle discharges toner from the mouth (opening) by being rotated. Furthermore, the toner bottle can be set from above the apparatus, and a grasping part (handle) is provided on the toner bottle. Thus, a user can easily set the toner bottle only by using his fingers. FIG. 20 is a diagram of the toner container with the grasping part (handle) and the spiral toner conveying part. As shown in FIG. 20, a toner container 101 includes a cylindrical container body 102, a cylindrical discharge member (lid) 110 that is attached to a mouth (opening) 103 of the container body 102, and a grasping part (handle) 111 is provided on the discharge member (lid) 110. The container body 102 is connected to the discharge member (lid) 110 by engagement of a projecting part 104 along the outer circumference of the container body 102 near the mouth (opening) 103 with a claw part 112 formed on the discharge member (lid) 110. Accordingly, the discharge member (lid) 110 and the container body 102 can be rotated integrally. The projecting part 104 and the claw part 112 are to be engaged with a gap within a fit tolerance (about 0.01 mm to 0.2 mm) used in machine designing, so that the discharge member (lid) 110 and the container body 102 can be rotated. An elastic member 113 such as foamed polyurethane with a thickness of 3 mm is attached to the discharge member (lid) 110. Therefore, as the side surface of the mouth (opening) 103 of the container body 102 is pressed against the elastic member 113, toner is prevented from leaking from where the container body 102 and the discharge member (lid) 110 contact each other. The container body 102 of the toner container 101 is rotatably driven by a gear 106. Accordingly, toner stored inside is conveyed towards the mouth (opening) 103 by force of a spiral toner conveying part 105, and the toner is discharged out of a replenishing opening (not shown) provided on the circumferential surface of the discharge member (lid) 110. To rotate the container body 102, a predetermined gap is provided in the cylindrical direction of the toner container 101 where the discharge member (lid) 110 overlaps with the container body 102 (in the example in FIG. 2, a 2 mm gap is provided in a radial direction). In other words, the toner container 101 is provided with a gap ΔL of substantially 2 mm in the radial direction where the discharge member (lid) 110 overlaps with the container body 102. However, in the conventional technology disclosed in the first document, a user cannot clearly feel a mechanical click when attaching the toner bottle to the apparatus body. Thus, there is a possibility that the toner bottle is not set properly. Specifically, when the user sets the toner bottle on the holding stand pulled out from the toner replenishing unit, the user cannot feel safe and sure that the toner bottle is set properly. Only after the user pushes the holding stand with the toner bottle into the toner replenishing unit, the user can feel safe and sure that the toner bottle is set properly. This means that there is a possibility that the toner bottle is not set properly when the toner bottle is being set on the holding stand. If the holding stand is pushed into the toner replenishing unit with the toner bottle not properly set, components of the toner replenishing unit or the toner bottle can break. Moreover, if the toner bottle does not engage with the joint, toner might not be replenished properly. The toner container with the grasping part (handle) and the spiral toner conveying part disclosed in the second document has the following problem. When a user sets the toner container 101 shown in FIGS. 20, 21 into the image forming apparatus, the user holds it with the grasping part (handle) 111 to hold the whole toner container. The grasping part (handle) 111 is located on the discharge member (lid) 110 at one end of the toner container 101, and there is the gap within a fit tolerance between the toner container 101 and the discharge member (lid) 110. Thus, the toner container 101 is only held at one end, and the container body 102 tilts downward. In other words, because of the weight of the container body 102 including the toner stored, the bottom side opposite to the discharge member (lid) 110 tilts downward. As a result, a rotational central axis C1 of the container body 102 deviates from a central axis C2 of the discharge member (lid) 110, as shown in FIG. 21. In this state, the container body 102 can loosen from the discharge member (lid) 110, and a gap can be formed in between. If the toner container 101 is attached to the apparatus body in such state, toner leaks out and scatters from the loose part or the gap, by a shock caused by the attachment. In some cases, the toner might be saved from leaking from the loose part. However, if the rotational central axis of the container body 102 is tilted when the toner container 101 is attached to the apparatus body, the gear 106 deviates from the rotational central axis. This creates a fluctuation and increases a rotational torque of driving the apparatus body. The present invention is made in view of the above. An object of the present invention is to provide a powder container and an image forming apparatus with which a user can clearly feel a mechanical click when attaching the container to the body of the image forming apparatus. Moreover, the object of the present invention is to ensure that the powder container is set properly, so that the rotational central axis of the container body is prevented from deviating from the central axis of the discharge member (lid part), to prevent powder scattering and a torque increase, with a simple construction. In other words, the object of the present invention is to provide a powder container and an image forming apparatus, such that the powder container is surely attached to the body of the image forming apparatus. DISCLOSURE OF INVENTION It is an object of the present invention to at least solve the problems in the conventional technology. A powder container according to one aspect of the present invention, which is detachably installed in a container housing unit of an image forming apparatus, includes an opening located at a head of the container body, and an engaging part located at a bottom of the container body, the engaging part being engaged with an engagement receiving part of the container housing unit; a drive transferring member that rotates integrally with the container body; and a lid including a discharge outlet that further discharges powder discharged from the opening of the container body, and a shutter that opens and closes the discharge outlet. A position of the powder container in the container housing unit is determined by engaging the engaging part with the engagement receiving part, and operating the lid such that the shutter opens the discharge outlet. An image forming apparatus according to another aspect of the present invention includes a powder container that includes a container body including an opening located at a head of the container body, and an engaging part located at a bottom of the container body, the engaging part being engaged with an engagement receiving part of the container housing unit; a drive transferring member that rotates integrally with the container body; and a lid including a discharge outlet that further discharges powder discharged from the opening of the container body, and a shutter that opens and closes the discharge outlet. A position of the powder container in the container housing unit is determined by engaging the engaging part with the engagement receiving part, and operating the lid such that the shutter opens the discharge outlet. The powder container is detachably installed in the container housing unit. The container housing unit includes the engagement receiving part with which the engaging part of the powder container is engaged. A powder container according to still another aspect of the present invention includes a container body including a conveying part that conveys powder stored in the container body towards an opening of the container body; and a lid that supports the container body such that the container body is rotatable, and discharges the powder discharged from the opening through a discharge outlet. The lid includes a contacting part that makes a contact with the opening; and a preventing part that prevents a gap from forming between the opening and the contacting part. The powder container is installed in an image forming apparatus by fixing the lid to the image forming apparatus. An image forming apparatus according to still another aspect of the present invention includes a powder container that includes a container body including a conveying part that conveys powder stored in the container body towards an opening of the container body; and a lid that supports the container body such that the container body is rotatable, and discharges the powder discharged from the opening through a discharge outlet. The lid includes a contacting part that makes a contact with the opening, and a preventing part that prevents a gap from forming between the opening and the contacting part. The powder container in which toner is contained can be installed the image forming apparatus. The powder container is installed in an image forming apparatus by fixing the lid to the image forming apparatus. The other objects, features, and advantages of the present invention are specifically set forth in or will become apparent from the following detailed description of the invention when read in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is an overall diagram of an image forming apparatus according to a first embodiment and a second embodiment; FIG. 2 is a cross-sectional view of an image forming unit in the image forming apparatus shown in FIG. 1; FIG. 3 is a perspective view of a toner bottle set in the image forming apparatus according to the first embodiment shown in FIG. 1; FIG. 4 is a perspective view from below of the toner bottle according to the first embodiment shown in FIG. 3; FIG. 5 is a cross-sectional view of a head side of the toner bottle according to the first embodiment shown in FIG. 3; FIG. 6 is a perspective view of the toner bottle according to the first embodiment and the second embodiment, loaded onto a bottle housing unit; FIG. 7 is a cross-sectional view of the toner bottle according to the first embodiment being loaded onto the bottle housing unit; FIG. 8A is a cross-sectional view of the toner bottle according to the first embodiment loaded onto another example of the bottle housing unit; FIG. 8B is a cross-sectional view of the toner bottle according to the first embodiment loaded onto still another example of the bottle housing unit; FIG. 9 is a front view of a case of the toner bottle according to the first embodiment being loaded onto the bottle housing unit; FIG. 10 is a front view of the case of the toner bottle according to the first embodiment shown in FIG. 9 being rotated on the bottle housing unit; FIG. 11 is a front view of the case of the toner bottle according to the first embodiment shown in FIG. 10 after being rotated; FIG. 12 is a perspective view of the toner bottles according to the first embodiment connected to toner conveying units; FIG. 13 is another perspective view of the toner bottles according to the first embodiment connected to the toner conveying units; FIG. 14 is an enlarged cross-sectional view of a side of an opening of the toner bottle according to the second embodiment; FIG. 15 is a perspective view inside a case (bottle cap) of the toner bottle according to the second embodiment; FIG. 16 is a cross-sectional explanatory diagram of a part where a bottle body of the toner bottle and the case overlap, when held, according to another embodiment of the second embodiment; FIG. 17 is a cross-sectional explanatory diagram of the part where the bottle body of the toner bottle and the case overlap, when set, according to the other embodiment of the second embodiment; FIG. 18 is a perspective view inside a case of the toner bottle according to still another embodiment of the second embodiment; FIG. 19 is a cross-sectional explanatory diagram of the part where the bottle body of the toner bottle and the case overlap, when set, according to the still another embodiment of the second embodiment; FIG. 20 is a cross-sectional block diagram of a conventional toner bottle in a separated state; and FIG. 21 is a cross-sectional block diagram of the conventional toner bottle in an assembled state. BEST MODE(S) FOR CARRYING OUT THE INVENTION A powder container and an image forming apparatus that are best modes for carrying out the present invention will be described below in detail with reference to accompanying drawings. Common or corresponding components are denoted by the same reference numerals and overlapping descriptions are simplified or omitted. The present invention is not limited to these embodiments. An image forming apparatus according to a first embodiment is described below. FIG. 1 and FIG. 2 are diagrams for describing the overall construction and operations of the image forming apparatus. FIG. 1 is a diagram of a printer as the image forming apparatus and FIG. 2 is an enlarged diagram of an image forming unit in the printer. As shown in FIG. 1, four toner bottles 32Y, 32M, 32C, and 32K corresponding to yellow, magenta, cyan, and black, respectively, are detachably set in a bottle housing unit 31 located at the top part in a body of the image forming apparatus (hereinafter, “apparatus body”) 100. An intermediate transfer unit 15 is provided below the bottle housing unit 31. Image forming units 6Y, 6M, 6C, and 6K corresponding to yellow, magenta, cyan, and black, respectively, are aligned facing an intermediate transfer belt 8 of the intermediate transfer unit 15. As shown in FIG. 2, the image forming unit 6Y corresponding to yellow includes a photoconductive drum 1Y, and a charging unit 4Y, a developing unit 5Y, a cleaning unit 2Y, a destaticizing unit (not shown), and so forth, arranged around the photoconductive drum 1Y. An image forming process (charging step, exposing step, developing step, transferring step, cleaning step) is performed on the photoconductive drum 1Y, and a yellow image is formed on the photoconductive drum 1Y. The three other image forming units 6M, 6C, and 6K have substantially the same construction as the image forming unit 6Y corresponding to yellow, except that each uses a different color toner and forms an different color image. Thus, descriptions of the three other image forming units 6M, 6C, and 6K are omitted, and only the image forming unit 6Y corresponding to yellow is described below. As shown in FIG. 2, the photoconductive drum 1Y is rotatably driven by a driving motor (not shown) in a direction indicated by an arrow R1 in FIG. 2. The surface of the photoconductive drum 1Y is uniformly charged at the position of the charging unit 4Y (charging step). Subsequently, at a position where a laser beam L is irradiated from an exposing unit 7 to the surface of the photoconductive drum 1Y, an electrostatic latent image for yellow is formed on the surface of the photoconductive drum 1Y by exposing/scanning (exposing step). Subsequently, at a position where the surface of the photoconductive drum 1Y faces the developing unit 5Y, the electrostatic latent image is developed, and a yellow toner image is formed (developing step). Subsequently, at a position where the surface of the photoconductive drum 1Y faces the intermediate transfer belt 8 and a first transfer-bias-roller 9Y, the toner image is transferred from the photoconductive drum 1Y to the intermediate transfer belt 8 (first transferring step). At this step, a marginal amount of toner is not transferred and remains on the photoconductive drum 1Y. Subsequently, at a position where the surface of the photoconductive drum 1Y faces the cleaning unit 2Y, a blade 2a collects the toner remaining on the photoconductive drum 1Y (cleaning step). Finally, at a position where the surface of the photoconductive drum 1Y faces the destaticizing unit (not shown), electric potential remaining on the photoconductive drum 1Y is removed. Accordingly, the image forming process performed on the photoconductive drum 1Y ends. The three other image forming units 6M, 6C, and 6K perform the same image forming process performed by the yellow image forming unit 6Y as described above. Specifically, in each of the image forming units 6M, 6C, and 6K, the laser beam L based on image information is irradiated from the exposing unit 7 provided below the image forming unit to the photoconductive drum. More specifically, the exposing unit 7 emits the laser beam L from a light source, reflects the laser beam L by rotating a polygon mirror, and irradiates the laser beam L onto the photoconductive drum through a plurality of optical elements. Subsequently, each toner image formed on each photoconductive drum at the developing step is transferred on the intermediate transfer belt 8 so as to be superposed on each other. As a result, a full-color toner image is formed on the intermediate transfer belt 8. As shown in FIG. 1, the intermediate transfer unit 15 includes the intermediate transfer belt 8, four first transfer-bias-rollers 9Y, 9M, 9C, and 9K, a second transfer back-up roller 12, a cleaning back-up roller 13, a tension roller 14, an intermediate-transfer cleaning-unit 10, and so forth. The intermediate transfer belt 8 is stretched across and supported by three rollers 12 to 14. Moreover, rotation of the second transfer back-up roller 12 causes the intermediate transfer belt 8 to rotate endlessly in a direction indicated by an arrow in FIG. 1. Each of the four first transfer-bias-rollers 9Y, 9M, 9C, and 9K sandwiches the intermediate transfer belt 8 with each of the photoconductive drums 1Y, 1M, 1C, and 1K, respectively, forming first transfer nips. As a result, a transfer bias of a polarity opposite to that of toner is applied to each of the first transfer-bias-rollers 9Y, 9M, 9C, and 9K. The intermediate transfer belt 8 rotates in the direction indicated by the arrow, and sequentially passes each of the first transfer nips of the first transfer-bias-rollers 9Y, 9M, 9C, and 9K. As a result, each toner image of the corresponding color on each photoconductive drum 1Y, 1M, 1C, and 1K is transferred (first transfer) and superposed onto the intermediate transfer belt 8. Subsequently, at a position where the intermediate transfer belt 8 with the superposed toner images faces a second transfer roller 19, the second transfer back-up roller 12 sandwiches the intermediate transfer belt 8 with the second transfer roller 19, forming a second transfer nip. The full-color toner image formed on the intermediate transfer belt 8 is then transferred onto a transfer material P such as transfer paper that is conveyed to the second transfer nip. At this step, a marginal amount of toner is not transferred to the transfer material P and remains on the intermediate transfer belt 8. Subsequently, at the intermediate-transfer cleaning-unit 10, the toner remaining on the intermediate transfer belt 8 is collected. Accordingly, a transfer process performed on the intermediate transfer belt 8 ends. The transfer material P conveyed to the second transfer nip is conveyed from a paper feed unit 26 located at the bottom part in the apparatus body 100, through a paper feeding roller 27 and a pair of registration rollers 28. Specifically, a plurality of transfer materials P such as transfer paper is stacked in the paper feed unit 26. When the paper feeding roller 27 is rotatably driven in a direction indicated by an arrow R2 (anti-clockwise) in FIG. 1, the top transfer material P is fed from a paper feed port 26a towards the pair of registration rollers 28. The pair of registration rollers 28 stops rotating so that the transfer material P stops in a roller nip of the pair of registration rollers 28. As the full-color image on the intermediate transfer belt 8 approaches the second transfer nip, the pair of registration rollers 28 starts rotating to convey the transfer material P into the second transfer nip in synchronization with the full-color toner image. At this time, a transfer bias (voltage) of a polarity opposite to that of the toner of the full-color toner image on the surface of the intermediate transfer belt 8 is applied to the second transfer roller 19. As a result, the full-color toner image on the surface of the intermediate transfer belt 8 is transferred at once onto the transfer material P. Accordingly, the intended color image is transferred onto the transfer material P. After the color image is transferred onto the transfer material P at the second transfer nip, the transfer material P is conveyed to a fixing unit 20. In the fixing unit 20, a fixing roller and a pressurizing roller apply heat and pressure to the transfer material P to fix the transferred color image onto the transfer material P. Subsequently, the transfer material P is conveyed outside the apparatus through a pair of paper ejecting rollers 29. A plurality of the transfer materials P ejected outside the apparatus by the pair of paper ejecting rollers 29 is sequentially stacked on a cover 30 as output images. Accordingly, an image forming process performed by the image forming apparatus ends. The above description is an image forming operation for forming a full-color image on the transfer material P. However, the image forming operation can be performed by using only one, two, or three of the image forming units 6Y, 6M, 6C, and 6K, to form a monochrome image, a 2-color image or a 3-color image. Next, constructions and operations of the developing unit 5Y in the image forming unit 6Y is described in detail with reference to FIG. 2. The developing unit 5Y includes a developing roller 51Y facing the photoconductive drum 1Y, a doctor blade 52Y facing the developing roller 51Y, two conveying screws 55Y provided inside developer containers 53Y, 54Y, a toner replenishing unit 58Y that communicates to the developer container 54Y through an opening, a density detecting sensor 56Y that detects a toner density in a developer, and so forth. The developing roller 51Y includes a magnet fixed inside, and a sleeve that rotates around the magnet, etc. A two-component developer including carriers and toner is stored in the developer containers 53Y, 54Y. The developing unit 5Y with the above construction operates as follows. The sleeve in the developing roller 51Y rotates in a direction indicated by an arrow in FIG. 2. The magnet in the developing roller 51Y forms a magnetic field. As the sleeve rotates, the magnetic field causes a developer carried on the developing roller 51Y to move on the developing roller 51Y. In the developing unit 5Y, a proportion of toner included in the developer (toner density) is adjusted to be within a predetermined range. Specifically, as toner is consumed in the developing unit 5Y, the toner in the toner bottle 32Y is replenished into the developer container 54Y, through a toner conveying pipe 43Y of a toner conveying unit (see FIG. 12) and the toner replenishing unit 58Y. The constructions and operations of the toner bottle 32Y are described later in detail. Subsequently, the toner replenished in the developer container 54Y is stirred and mixed with the developer by the two conveying screws 55Y, and is circulated to and fro the two developer containers 53Y, 54Y (movement in a horizontal direction as viewed in FIG. 2). The toner in the developer is friction-charged with the carriers so as to adhere to the carries. The toner adhering to the carriers is then carried on the developing roller 51Y by magnetic force on the developing roller 51Y. The developer carried on the developing roller 51Y is conveyed in the direction indicated by the arrow in FIG. 2, and reaches a position facing the doctor blade 52Y. The amount of the developer carried on the developing roller 51Y is adjusted appropriately by the doctor blade 52Y. The appropriate amount of developer is then conveyed to a position facing the photoconductive drum 1Y (developing area). An electric field formed in the developing area causes toner to adhere to a latent image formed on the photoconductive drum 1Y. As the sleeve continues rotating, the developer remaining on the developing roller 51Y reaches the top part of the developer container 53Y, where the developer comes off the developing roller 51Y. Next, the toner bottle that supplies toner to the developing device is described with reference to FIGS. 3 to 13. As was described with FIG. 1, the four toner bottles 32Y, 32M, 32C, and 32K are detachably set in the bottle housing unit 31. At the end of a life of each toner bottle 32Y, 32M, 32C, and 32K (when almost all of the toner stored is consumed and the bottle is empty), the toner bottle is exchanged with a new toner bottle. Accordingly, toner of a color corresponding to each toner bottle 32Y, 32M, 32C, and 32K is replenished into the developing unit of each image forming unit 6Y, 6M, 6C, and 6K. First, a construction of the toner bottle is described with reference to FIGS. 3 to 5. FIG. 3 is a perspective view of the toner bottle 32Y. FIG. 4 is a perspective view of the toner bottle 32Y viewed from below. FIG. 5 is a cross-sectional view of the head side of the toner bottle 32Y. The three other toner bottles 32M, 32C, and 32K have substantially the same construction as the toner bottle 32Y containing yellow toner, except that each contains a different color toner. Thus, descriptions of the three other toner bottles 32M, 32C, and 32K are omitted, and only the toner bottle 32Y containing yellow toner is described below. As shown in FIG. 3, the main components of the toner bottle 32Y are a bottle body 33Y and a case 34Y (bottle cap) functioning as a lid provided on the head of the bottle body 33Y. The head of the bottle body 33Y has a gear 37Y, as a drive transferring member, that rotates integrally with the bottle body 33Y, and an opening C (refer to FIG. 5). The gear 37Y meshes with a driving gear of the apparatus body 100 to rotate the bottle body 33Y in a direction indicated by an arrow, around a rotational axis A as shown in FIG. 3. Toner stored in the bottle body 33Y is discharged through the opening C to a space in the case 34Y. As shown in FIG. 4, a concaving, circular engaging part 63Y is formed at a bottom part 62Y of the bottle body 33Y. The engaging part 63Y engages with a convex part 61Y formed on a side wall of the bottle housing unit 31. As shown in FIG. 5, spiral protrusions 33a protrude from the outer circumferential surface into the inner circumferential surface of the bottle body 33Y. The spiral protrusions 33a are provided to rotate the bottle body 33Y to discharge toner out of the opening C. The bottle body 33Y and the gear 37Y constructed as above can be manufactured by blow molding. As shown in FIG. 3, a handle 35Y for manually rotating the case 34Y, a toner outlet D (refer to FIG. 5) for discharging toner from the toner bottle 32Y, and a shutter 36Y for opening and closing the toner outlet D, are provided on the circumferential surface of the case 34Y. As shown in FIG. 5, the shutter 36Y engages with a guide part 34b on the case 34Y, and moves along the guide part 34b on the circumferential surface of the case 34Y, so as to open and close the toner outlet D. A spring 44 is provided on one end of the shutter 36Y. The urging force of the spring 44 causes the shutter 36Y to close the toner outlet D. As shown in FIG. 3, on a side of the case 34Y is provided a fitting part 38Y, formed of long and short straight walls and a curved wall. The fitting part 38Y fits onto a convex part 39Y formed on another side wall of the bottle housing unit 31. As shown in FIG. 5, a projection 34a of the case 34Y constructed as above is pushed in between the gear 37Y and a rim part 33b of the bottle body 33Y. In other words, the case 34Y and the bottle body 33Y are assembled to be relatively rotated with respect to each other in a circumferential direction. Accordingly, the case 34Y can be manually rotated when setting the bottle and the bottle body 33Y can be rotatably driven when replenishing toner, which will be described later. Next, an operation for attaching/detaching the toner bottle 32Y to/from the bottle housing unit 31 is described with reference to FIGS. 6 to 11. FIG. 6 is a perspective view of the yellow toner bottle 32Y loaded onto the bottle housing unit 31 (in a direction indicated by an arrow E). FIG. 7 is a cross-sectional view of FIG. 6 cut along a line Z-Z. FIGS. 9 to 11 are front views of motions of the case 34Y for setting the bottle. As shown in FIG. 6, the bottle housing unit 31 has four bottle housing parts 31Y, 31M, 31C, and 31K corresponding to the four toner bottles 32Y, 32M, 32C, and 32K. Each of the four bottle housing parts 31Y, 31M, 31C, and 31K has the part 61 that engages with the engaging part of the bottle body, and the part (not shown) that fits with the fitting part of the case. When attaching the toner bottle 32Y to the bottle housing unit 31 of the apparatus body 100, the cover 30 shown in FIG. 1 is firstly opened upwards to expose the bottle housing unit 31. Subsequently, as shown in FIGS. 6 and 7, the toner bottle 32Y is mounted on the bottle housing part 31Y (in the direction indicated by the arrows). The toner bottle 32Y is set so that the engaging part 63Y on the bottom part 62Y of the bottle body 33Y engages with the part 61Y of the bottle housing part 31Y. At the same time, the toner bottle 32Y is set so that the straight wall of the fitting part 38Y provided on the side of the case 34Y slides along the part 39Y of the bottle housing part 31Y (refer to FIGS. 9 and 10). Accordingly, the toner bottle 32Y is fit in between the part 61Y and the part 39Y. This can restrict, to some extent, the toner bottle 32Y from trembling in a longitudinal direction. Because the engaging part 63Y is concaved, the toner bottle 32Y can stand up with the bottom part 62Y at the bottom. This facilitates the process of filling toner into the toner bottle 32Y at a factory, and increases the degree of freedom in storing stock of toner bottles at a user's location, a factory, or a sales subsidiary. In the present embodiment, the part 61Y that is a cylindrical shape and the engaging part 63Y that is a concave circular shape are engaged, so that the bottom of the toner bottle 32Y does not lift from the wall of the bottle housing unit 31. However, the shapes of the part 61Y and the engaging part 63Y are not limited to these examples; for example, they can be shaped as shown in FIGS. 8A, 8B. In FIG. 8A, the part 61Y has a tapering shape that is engaged with the concave engaging part 63Y. In FIG. 8B, the part 61Y includes a plate 61Ya that is a circular disk or a cross-shaped disk that is engaged with the concave engaging part 63Y. Moreover, the engaging part 63Y can be a concave and tapering shape (not shown). After the toner bottle 32Y is set as shown in FIG. 7, a user grasps the handle 35Y of the toner bottle 32Y, and rotates the case 34Y. Accordingly, the position of the toner bottle 32Y is finally set in the bottle housing part 31Y. Motions of the case 34Y for setting the toner bottle 32Y are described below. As shown in FIG. 9, the case 34Y is mounted so that the straight wall of the fitting part 38Y slides along the part 39Y of the bottle housing part 31Y (in a direction indicated by an arrow E). As described with FIGS. 6 and 7, the engaging part 63Y of the bottle body 33Y engages with the part 61Y of the bottle housing part 31Y. When the toner bottle 32Y is set on the bottle housing part 31Y, the straight wall of the fitting part 38Y is in contact with the part 39Y of the bottle housing part 31Y, as shown in FIG. 10. The shutter 36Y of the case 34Y is urged by the spring 44 to a position that blocks the toner outlet D (locked at a position of a first stopper 45a). From the position shown in FIG. 10, the handle 35Y is moved in a direction indicated by an arrow F. Accordingly, the case 34Y rotates in the direction indicated by the arrow F. The case 34Y stops rotating when a part of the wall of the fitting part 38Y is blocked by the part 39Y (as shown in FIG. 11). The toner outlet D is rotated as the case 34Y is rotated, and finally stops at the bottom position (as shown in FIG. 11). Moreover, rotation of the shutter 36Y is blocked by a stopping part 31a of the bottle housing part 31Y. Thus, an edge of the shutter 36Y presses against the spring 44 that is held by a second stopper 45b at one end, so that the shutter 36Y opens the toner outlet D. As the shutter 36Y opens the toner outlet D when the case 34Y is rotated, the fitting part 38Y fits to the part 39Y, so that the position of the toner bottle 32Y is fixed in the bottle housing part 31Y. Therefore, a user clearly feels a mechanical click when attaching the toner bottle 32Y, so that he knows that the toner bottle 32Y has been set. This prevents the user from failing to properly set the toner bottle 32Y. This prevents toner from not being replenished properly, and prevents components of the toner bottle 32Y and the bottle housing part 31Y from breaking. Particularly, because the engaging part 63Y engages with the part 61Y at the bottom part 62Y of the toner bottle 32Y, the bottom part 62Y is prevented from lifting when the bottle body 33Y is rotatably driven. When the bottle body 33Y is rotatably driven, the engaging part 63Y and the part 61Y are rubbed against each other; therefore, the engaging part 63Y and the part 61Y are preferably made of a material with a low friction coefficient. When the toner bottle 32Y is removed from the bottle housing part 31Y, a user performs a procedure opposite to the procedure of attaching the toner bottle 32Y. Specifically, the user rotates the handle 35Y of the toner bottle 32Y in the opposite direction (opposite to the direction indicated by the arrow F in FIG. 11). Accordingly, the fitting part 38Y of the case 34Y is released from the part 39Y of the bottle housing part 31Y. At the same time, the shutter 36Y moves relatively and closes the toner outlet D. The user holds the handle 35Y while he releases the engaging part 63Y from the part 61Y, and pulls out the toner bottle 32Y upwards. Next, the toner conveying unit that conveys toner from inside the toner bottle 32Y set in the bottle housing unit 31 to the developing unit 5Y is described with reference to FIGS. 12 and 13. FIG. 12 is a front perspective view of the toner bottles 32Y, 32M, 32C, and 32K set in the bottle housing unit 31 and connected to toner conveying units 40Y, 40M, 40C, and 40K, respectively. FIG. 13 is a side perspective view of the toner bottles 32Y, 32M, 32C, and 32K connected to the toner conveying units 40Y, 40M, 40C, and 40K, respectively. The bottle housing unit 31 is omitted from FIGS. 12 and 13. The toner conveying units 40Y, 40M, 40C, and 40K are fixed next to the intermediate transfer unit 15 (at the back of the apparatus body 100). The toner outlets of toner bottles 32Y, 32M, 32C, and 32K and the toner replenishing unit 58Y of the developing unit 5Y are positioned next to the intermediate transfer unit 15. The four toner conveying units 40Y, 40M, 40C, and 40K have the same construction except that each conveys a different color toner. Thus, only the toner conveying unit 40Y for conveying yellow toner is described. As shown in FIG. 12, the toner conveying unit 40Y mainly includes a driving motor 41Y and a driving gear 42Y functioning as a driving unit, and the toner conveying pipe 43Y. Inside the toner conveying pipe 43Y is a flexible conveying coil (not shown). The driving gear 42Y meshes with the gear 37Y (drive transferring member) of the toner bottle 32Y. Thus, when the driving gear 42Y is driven, the bottle body 33Y of the toner bottle 32Y is rotated. The bottle body 33Y is rotated to discharge toner in accordance with consumption of toner in the developing unit 5Y. Specifically, when the density detecting sensor 56Y in the developing unit 5Y shown in FIG. 2 detects a shortage in toner density in the developer container 54Y, the driving motor 41Y is activated by signals from a control unit. As described earlier, the spiral protrusions 33a are formed on the inner surface of the bottle body 33Y of the toner bottle 32Y. Accordingly, as the bottle body 33Y rotates, the toner is conveyed from the bottom part 62Y of the bottle body 33Y to the case 34Y at the head of the bottle body 33Y. Then the toner is discharged from the opening C of the bottle body 33Y, passes through the space in the case 34Y, and is discharged outside the bottle from the toner outlet D. The toner discharged from the toner bottle 32Y drops to a toner receiving part (not shown) in the toner conveying unit 40Y. The toner receiving part communicates to the toner conveying pipe 43Y. By activating the driving motor 41Y, the bottle body 33Y rotates, and the conveying coil in the toner conveying pipe 43Y rotates. Accordingly the toner that dropped to the toner receiving part is conveyed in the toner conveying pipe 43Y, and is replenished into the toner replenishing unit 58Y in the developing unit 5Y. As described above, in the image forming apparatus according to the first embodiment, the engaging part 63Y formed at the bottom part 62Y engages with the part 61Y of the bottle housing part 31Y. Moreover, the position of the toner bottle 32Y is fixed in the bottle housing part 31Y by rotating the case 34Y so that the shutter 36Y opens the toner outlet D. Accordingly, a user clearly feels a mechanical click when attaching each toner bottle 32Y, 32M, 32C, and 32K to the apparatus body 100. This prevents the user from failing to properly set the toner bottles 32Y, 32M, 32C, and 32K. In the present embodiment, only toner is stored in the toner bottles 32Y, 32M, 32C, and 32K. However, in another type of an image forming apparatus in which a two-component developer containing toner and carriers is provided to the developing unit 5, the two-component developer can be stored in the toner bottles 32Y, 32M, 32C, and 32K. Next an image forming apparatus according to a second embodiment is described below. In the first embodiment, the engaging part formed at the bottom part of the bottle body engages with the part on the bottle housing part. Moreover, the position of the toner bottle is fixed in the bottle housing part by rotating the case so that the shutter opens the toner outlet. In the second embodiment, ribs are provided in the case of the toner bottle. The ribs prevent gaps from forming between a holder part of the case and the opening of the bottle body that are in close contact with each other. Moreover, the ribs prevent a gap from forming between the holder part of the case and the opening of the bottle body when the case is attached to the apparatus body. The overall construction of the image forming apparatus according to the present invention is the same as that of the first embodiment as shown in FIG. 1. Moreover, the construction of the image forming unit is the same as that of the first embodiment as shown in FIG. 2. Furthermore, the state of the toner bottle mounted on the bottle housing unit in the image forming apparatus according to the present embodiment is the same that of the first embodiment as shown in FIG. 6. FIG. 14 is a cross-sectional view of the top end of the toner bottle 32Y according to the present embodiment. The three other toner bottles 32M, 32C, and 32K have substantially the same construction as the toner bottle 32Y containing yellow toner, except that each contains a different color toner. Thus, only the toner bottle 32Y containing yellow toner is described below; however, the present embodiment is also applicable to the three other toner bottles 32M, 32C, and 32K. In FIG. 14, the toner bottle 32Y includes a cylindrical bottle body 133 as a container body. A cylindrical case 140 (bottle cap) functioning as a lid is provided on an opening 135 at the top end of the bottle body 133. The case 140 rotates in relation with the bottle body 133. The bottle body 133 includes spiral protrusions (spiral conveying part) 136 that convey toner towards the opening 135, when the bottle body 133 rotates. The case 140 includes a cap part 141 that has a toner outlet (toner replenishing opening) 144 provided at the bottom of the circumferential surface. A holder part 142 is fixed to the cap part 141, and attaches the cap part 141 to the bottle body 133. A claw part 143 provided on the holder part 142 engages with a gap of the bottle body 133, so that the case 140 and the bottle body 133 are relatively rotated with respect to each other. A seal 145 is provided where the bottle body 133 and the cap part 141 join, to prevent toner from leaking from this part. The holder part 142 of the case 140 includes a handle 146 and a shutter 147. Moreover, a bottle gear 134 is provided near where the case 140 is attached to the bottle body 133. The bottle gear 134 is an input gear used as an input part, and is formed integrally with the bottle body 133. When attaching the toner bottle 32Y to the apparatus body 100, the cover 30 shown in FIG. 1 is firstly opened upwards to expose the bottle housing unit 31. As shown in FIG. 6, after the toner bottle 32Y is mounted on the bottle housing part 31Y, a user rotates the handle 146. This rotates the case 140 that is formed integrally with the handle 146, and moves the shutter 147 along a circumferential direction on the case 140 so as to open the toner outlet (toner replenishing opening) 144. At the same time, the case 140 and the bottle housing part 31Y are connected and fixed to each other. This mechanism is not the main point of the present invention; thus, a detailed description is omitted. The bottle gear 134 of the toner bottle 32Y set in the bottle housing part 31Y meshes with, and is driven by, the driving gear (not shown) of the apparatus body 100. On the other hand, when the toner bottle 32Y is detached from the apparatus body 100, a user rotates the handle 146 in an opposite direction. Accordingly, the case 140 is released from the bottle housing part 31Y. At the same time, the shutter 147 closes so as to close the toner outlet (toner replenishing opening) 144. The user holds the handle 146 while he detaches the toner bottle 32Y from the apparatus body 100′. Because the toner bottle 32Y can be attached to/detached from the apparatus body 100 from above, the process of replacing the toner bottle 32Y is easy to understand, and easy to carry out. Moreover, because the case 140 has the handle 146, the toner bottle 32Y can be easily fixed to the bottle housing unit 31 by rotating the case 140. When the toner bottle 32Y is detached from the apparatus body 100, the shutter 147 does not open even if the handle 146 of the case 140 is rotated. Thus, when replacing the toner bottle 32Y, the toner is prevented from spilling out by accident, because the shutter 147 is kept shut. As described above, the handle 146 is held when attaching/detaching the toner bottles 32Y, 32M, 32C, and 32K. Thus, because only one end of the toner bottle 32Y is held, the central rotational axis of the bottle body 133 deviates from that of the case 140. This causes problems such as toner scattering and an increase in driving torque. Accordingly, in the present invention, ribs 148 are provided on the inner circumferential surface as preventing members, so as to narrow a gap where the bottle body 133 of the toner bottle 32Y overlaps with the case 140. As shown in FIGS. 14 and 15, the ribs 148 are located at a side opposing the handle 146 with respect to the central axis of the case 140. As described above, the case 140 has ribs 148 provided on the side opposing the handle 146. Accordingly, even when a user holds the handle 146 while rotating the toner bottle 32Y while setting it into the apparatus, and only one end of the toner bottle 32Y is held, the ribs 148 prevent the bottle body 133 from loosening from the case 140. This prevents a gap from being formed between the case 140 and the bottle body 133, so as to prevent toner scattering. Moreover, the case 140 is prevented from falling off, or nearly falling off, from the bottle body 133. This prevents toner scattering and a torque increase. Furthermore, when the bottle body 133 is rotated, the ribs 148 restrict the central rotational axis of the bottle body 133 from deviating too far from a predetermined position, such that a gap is not formed between the opening 135 and the holder part 142. Accordingly, the central rotational axis of the bottle body 133 is kept from deviating largely from the predetermined position, thus preventing a torque increase. Moreover, because the preventing members are ribs 148, an area of the preventing members contacting the rotating bottle body 133 is small. This reduces torque caused by contacting the bottle body 133. Furthermore, according to the present embodiment, there are three ribs 148 extending in parallel to the central axis of the case 140, as shown in FIG. 15 to 17. A rib 148a is located opposite to the handle 146, and ribs 148b are located on both sides of the rib 148a. The rib 148a prevents the bottle body 133 from falling off, or nearly falling off, from the case 140, by its own weight. When the toner bottle 32Y is being set in the apparatus, the rib 148a and the ribs 148b prevent the bottle body 133 from falling off, or nearly falling off, from the case 140, due to a load applied from the handle 146. This prevents toner scattering and a torque increase. The number of ribs 148 is not limited to three; any number of ribs 148 can be provided. However, too many ribs 148 can possibly increase a sliding load when the bottle body 133 rotates; thus, it is preferable to have only a few ribs 148. FIG. 18 is a perspective view of the case 140 according to another embodiment of the present invention. In the present embodiment, a hemispherical projection 149 is provided as the preventing member at a position opposite to the handle 146, similarly to the rib 148. Because the preventing member is the hemispherical projection 149 provided at the edge of the case 140, an area of the preventing member contacting the rotating bottle body 133 is considerably small. This reduces torque caused by contacting the bottle body 133. Still another embodiment is shown in FIG. 19. To prevent the bottle body 133 from tilting downward by gravity after being set in the apparatus, another rib 148c or the projection 149 is preferably provided at a position corresponding to the bottom of the case 140. With this construction, the rib 148a and the ribs 148b prevent, at three locations, the bottle body 133 from tilting downward when a user holds the handle 146. Moreover, the rib 148c prevents the toner bottle body 133 from tilting downward when the bottle is set and driven in the apparatus. An optimal height of the rib 148 was examined, using ribs of different heights. Results are shown in table 1. The ribs used for this experiment satisfies the following condition: as shown in FIGS. 16 and 17, when the central axis of the bottle body 133 and that of the case 140 are aligned, a gap ΔL where the bottle body 133 overlaps with the case 140 is 2 mm. Based on this condition, four ribs each forming a gap β between the bottle body 133 of 0 mm, 0.5 mm, 1.0 mm, and 1.5 mm, were used. TABLE 1 Rotatability of toner Gapβ (mn) Toner scattering bottle 0 ◯(Does not X(Rib rubs toner bottle and scatter) increases load) 0.5 ◯(Does not ◯(Good) scatter) 1 ◯(Does not ◯(Good) scatter) 1.5 X(Scatters) X(Axis shifts and increases load) As shown in Table 1, the ribs that form a gap β of 1 mm and 0.5 mm did not cause toner scattering, and rotatability of the container was good. The rib that forms a gap β of 0 mm did not cause toner scattering but deteriorated the rotatability of the container due to a large load caused by the rib 148 rubbing against the toner bottle. Moreover, the rib that forms a gap β of 1.5 mm caused toner scattering and deteriorated the rotatability of the container because the central axis shifted and increased the rotating load. The results say that when the gap ΔL is 2 mm, the height of the rib 148 is preferably about 1 mm to 1.5 mm. Favorable embodiments of the present invention are described above. However, the present invention is not limited to these embodiments, and various changes can be made. For example, in the second embodiment, the toner bottle was taken as an example of the powder container. However, the powder container is not limited to the toner bottle; the powder container can be a container for storing a developer that is a mixture of toner and carriers, or just carriers. As described above, in the image forming apparatus according to the second embodiment, the case 140 includes ribs 148 that prevent a gap from forming between the holder part 142 and the opening 135 that are in close contact with each other. Moreover, the ribs 148 prevent a gap from forming between the holder part 142 and the opening 135 when the case 140 is attached to the apparatus body 100. Accordingly, even when a user holds the handle 146 while setting the toner bottle into the apparatus, and only one end of the toner bottle is held, the ribs 148 prevent the bottle body 133 from loosening from the case 140. This prevents a gap from being formed between the case 140 and the bottle body 133, so that toner scattering is prevented. Moreover, after the case 140 is set in the predetermined position of the apparatus body 100, the case 140 is rotated to be engaged with the engaging part of the apparatus body 100. Furthermore, when the bottle body 133 is rotated, the ribs 148 restrict the central rotational axis of the bottle body 133 from deviating too far from a predetermined position, such that a gap is not formed between the opening 135 and the holder part 142. Accordingly, the central rotational axis of the bottle body 133 is kept from deviating largely from the predetermined position, thus preventing a torque increase. The present invention is not limited to these embodiments. It is clear that various changes may be made without departing from the scope of the present invention. Moreover, the numbers of components, positions, shapes are not limited to these embodiments, and may be changed to preferable numbers of components, positions, shapes to carry out the present invention. Although the invention has been described with respect to a specific embodiment for a complete and clear disclosure, the appended claims are not to be thus limited but are to be construed as embodying all modifications and alternative constructions that may occur to one skilled in the art that fairly fall within the basic teaching herein set forth.

<SOH> BACKGROUND ART <EOH>An image forming apparatus such as a composite machine has at least two functions of a printer, a copier, or a fax machine. Toner is consumed when the image forming apparatus is used; thus, the toner needs to be successively replenished into a developing unit according to the amount of consumption. The toner is typically replenished into the developing unit from a toner container such as a toner cartridge or a toner bottle. When the toner container is empty, it is replaced with a new one. There is known a cylindrical toner bottle for replenishing toner into the developing unit of the conventional image forming apparatus, such as that disclosed in Japanese Patent Application Laid Open No. 2000-338758 (hereinafter referred to as “first document”). In the first document, the toner bottle is set in the body of the image forming apparatus (hereinafter, “apparatus body”) as follows. First, a user pulls out a holding stand of a toner replenishing unit of the apparatus body, and takes out the empty bottle existing on the holding stand. The user then sets a new toner bottle sideways in the holding stand. The user pushes the holding stand with the new toner bottle into the back of the toner replenishing unit. Accordingly, a convex part provided on the bottom of the toner bottle engages with a joint part at the back of the toner replenishing unit. This fixes the position of the toner bottle in the toner replenishing unit. Spiral protrusions are provided on the inner circumferential surface of the toner bottle. Thus, when the joint part is rotatably driven and the toner bottle is rotated, toner contained in the toner bottle is discharged from an opening. The toner discharged from the toner bottle is replenished to the developing unit. The toner bottle constructed as above is relatively low-cost in that fewer components are used as compared to a toner container with a conveying member such as an agitator inside. Moreover, the above toner bottle is useful for recycling purposes, because it has a higher level of mechanical strength as compared to a bag-shaped toner container. Because a user exchanges the toner container, the toner container should be easy to exchange, and toner scattering should be prevented so as not to soil hands and clothes of the user. Moreover, toner density becomes uneven if a stable amount of toner is not constantly discharged from the toner container and replenished into the developing unit. This can cause deterioration in image quality, such as blurring or uneven colors. Therefore, a stable amount of toner needs to be discharged from the toner container to the toner replenishing unit. Various toner containers have been proposed and implemented to meet such demands. A well known example is a cylindrical toner bottle that has a spiral toner conveying part as disclosed in, for example, Japanese Patent Application Laid Open No. 2004-139031 (hereinafter referred to as “second document”). On one end of this toner bottle is a mouth (opening) that has a smaller diameter than the spiral-shaped bottle body. This toner bottle is set in the apparatus body so that the bottle axis is substantially horizontal. Moreover, this type of toner bottle discharges toner from the mouth (opening) by being rotated. Furthermore, the toner bottle can be set from above the apparatus, and a grasping part (handle) is provided on the toner bottle. Thus, a user can easily set the toner bottle only by using his fingers. FIG. 20 is a diagram of the toner container with the grasping part (handle) and the spiral toner conveying part. As shown in FIG. 20 , a toner container 101 includes a cylindrical container body 102 , a cylindrical discharge member (lid) 110 that is attached to a mouth (opening) 103 of the container body 102 , and a grasping part (handle) 111 is provided on the discharge member (lid) 110 . The container body 102 is connected to the discharge member (lid) 110 by engagement of a projecting part 104 along the outer circumference of the container body 102 near the mouth (opening) 103 with a claw part 112 formed on the discharge member (lid) 110 . Accordingly, the discharge member (lid) 110 and the container body 102 can be rotated integrally. The projecting part 104 and the claw part 112 are to be engaged with a gap within a fit tolerance (about 0.01 mm to 0.2 mm) used in machine designing, so that the discharge member (lid) 110 and the container body 102 can be rotated. An elastic member 113 such as foamed polyurethane with a thickness of 3 mm is attached to the discharge member (lid) 110 . Therefore, as the side surface of the mouth (opening) 103 of the container body 102 is pressed against the elastic member 113 , toner is prevented from leaking from where the container body 102 and the discharge member (lid) 110 contact each other. The container body 102 of the toner container 101 is rotatably driven by a gear 106 . Accordingly, toner stored inside is conveyed towards the mouth (opening) 103 by force of a spiral toner conveying part 105 , and the toner is discharged out of a replenishing opening (not shown) provided on the circumferential surface of the discharge member (lid) 110 . To rotate the container body 102 , a predetermined gap is provided in the cylindrical direction of the toner container 101 where the discharge member (lid) 110 overlaps with the container body 102 (in the example in FIG. 2 , a 2 mm gap is provided in a radial direction). In other words, the toner container 101 is provided with a gap ΔL of substantially 2 mm in the radial direction where the discharge member (lid) 110 overlaps with the container body 102 . However, in the conventional technology disclosed in the first document, a user cannot clearly feel a mechanical click when attaching the toner bottle to the apparatus body. Thus, there is a possibility that the toner bottle is not set properly. Specifically, when the user sets the toner bottle on the holding stand pulled out from the toner replenishing unit, the user cannot feel safe and sure that the toner bottle is set properly. Only after the user pushes the holding stand with the toner bottle into the toner replenishing unit, the user can feel safe and sure that the toner bottle is set properly. This means that there is a possibility that the toner bottle is not set properly when the toner bottle is being set on the holding stand. If the holding stand is pushed into the toner replenishing unit with the toner bottle not properly set, components of the toner replenishing unit or the toner bottle can break. Moreover, if the toner bottle does not engage with the joint, toner might not be replenished properly. The toner container with the grasping part (handle) and the spiral toner conveying part disclosed in the second document has the following problem. When a user sets the toner container 101 shown in FIGS. 20 , 21 into the image forming apparatus, the user holds it with the grasping part (handle) 111 to hold the whole toner container. The grasping part (handle) 111 is located on the discharge member (lid) 110 at one end of the toner container 101 , and there is the gap within a fit tolerance between the toner container 101 and the discharge member (lid) 110 . Thus, the toner container 101 is only held at one end, and the container body 102 tilts downward. In other words, because of the weight of the container body 102 including the toner stored, the bottom side opposite to the discharge member (lid) 110 tilts downward. As a result, a rotational central axis C 1 of the container body 102 deviates from a central axis C 2 of the discharge member (lid) 110 , as shown in FIG. 21 . In this state, the container body 102 can loosen from the discharge member (lid) 110 , and a gap can be formed in between. If the toner container 101 is attached to the apparatus body in such state, toner leaks out and scatters from the loose part or the gap, by a shock caused by the attachment. In some cases, the toner might be saved from leaking from the loose part. However, if the rotational central axis of the container body 102 is tilted when the toner container 101 is attached to the apparatus body, the gear 106 deviates from the rotational central axis. This creates a fluctuation and increases a rotational torque of driving the apparatus body. The present invention is made in view of the above. An object of the present invention is to provide a powder container and an image forming apparatus with which a user can clearly feel a mechanical click when attaching the container to the body of the image forming apparatus. Moreover, the object of the present invention is to ensure that the powder container is set properly, so that the rotational central axis of the container body is prevented from deviating from the central axis of the discharge member (lid part), to prevent powder scattering and a torque increase, with a simple construction. In other words, the object of the present invention is to provide a powder container and an image forming apparatus, such that the powder container is surely attached to the body of the image forming apparatus.

<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is an overall diagram of an image forming apparatus according to a first embodiment and a second embodiment; FIG. 2 is a cross-sectional view of an image forming unit in the image forming apparatus shown in FIG. 1 ; FIG. 3 is a perspective view of a toner bottle set in the image forming apparatus according to the first embodiment shown in FIG. 1 ; FIG. 4 is a perspective view from below of the toner bottle according to the first embodiment shown in FIG. 3 ; FIG. 5 is a cross-sectional view of a head side of the toner bottle according to the first embodiment shown in FIG. 3 ; FIG. 6 is a perspective view of the toner bottle according to the first embodiment and the second embodiment, loaded onto a bottle housing unit; FIG. 7 is a cross-sectional view of the toner bottle according to the first embodiment being loaded onto the bottle housing unit; FIG. 8A is a cross-sectional view of the toner bottle according to the first embodiment loaded onto another example of the bottle housing unit; FIG. 8B is a cross-sectional view of the toner bottle according to the first embodiment loaded onto still another example of the bottle housing unit; FIG. 9 is a front view of a case of the toner bottle according to the first embodiment being loaded onto the bottle housing unit; FIG. 10 is a front view of the case of the toner bottle according to the first embodiment shown in FIG. 9 being rotated on the bottle housing unit; FIG. 11 is a front view of the case of the toner bottle according to the first embodiment shown in FIG. 10 after being rotated; FIG. 12 is a perspective view of the toner bottles according to the first embodiment connected to toner conveying units; FIG. 13 is another perspective view of the toner bottles according to the first embodiment connected to the toner conveying units; FIG. 14 is an enlarged cross-sectional view of a side of an opening of the toner bottle according to the second embodiment; FIG. 15 is a perspective view inside a case (bottle cap) of the toner bottle according to the second embodiment; FIG. 16 is a cross-sectional explanatory diagram of a part where a bottle body of the toner bottle and the case overlap, when held, according to another embodiment of the second embodiment; FIG. 17 is a cross-sectional explanatory diagram of the part where the bottle body of the toner bottle and the case overlap, when set, according to the other embodiment of the second embodiment; FIG. 18 is a perspective view inside a case of the toner bottle according to still another embodiment of the second embodiment; FIG. 19 is a cross-sectional explanatory diagram of the part where the bottle body of the toner bottle and the case overlap, when set, according to the still another embodiment of the second embodiment; FIG. 20 is a cross-sectional block diagram of a conventional toner bottle in a separated state; and FIG. 21 is a cross-sectional block diagram of the conventional toner bottle in an assembled state. detailed-description description="Detailed Description" end="lead"?

20060314

20090707

20081002

63227.0

G03G1508

LEE, SUSAN SHUK YIN

POWDER CONTAINER AND IMAGE FORMING APPARATUS

UNDISCOUNTED

ACCEPTED

G03G

ACCEPTED

Modular approach to the tcp/ipv6 hardware implementation

A method for processing a packet comprising an ordered sequence of packet parts is disclosed. The method uses a set of hardware processing modules, and the method comprises the steps of broadcasting, in a step the next header field of a received packet part to the set of processing modules, and processing, in a step the received packet part by a sub-set of the modules dependent upon the broadcast next header field.

1. A method for processing a packet comprising an ordered sequence of packet parts using a set of hardware processing modules, the method comprising the steps of: broadcasting the next header field of a received packet part to the set of processing modules; and processing the received packet part by a sub-set of the modules dependent upon the broadcast next header field. 2. A method according to claim 1, wherein the packet is an IPv6 packet. 3. A method according to claim 2, wherein prior to the processing step, the method comprises the steps of: identifying options fields expected to be present in received packets; incorporating in the set of hardware processing modules, hardware processing modules corresponding to the identified options fields; and omitting from the set of hardware processing modules hardware processing modules not corresponding to the identified options fields. 4. A method according to claim 3, wherein: the method is performed using an Application Specific Integrated Circuit (ASIC); and the incorporating and omitting steps are performed at least during one of: a system block level synthesis stage; a Register Transfer Level (RTL) description level synthesis stage; and a net-list level synthesis stage, for the ASIC. 5. A method according to claim 4 further comprising, prior to the processing step, a step of: seizing control, by one of the sub-set of modules, dependent upon the broadcast next header field. 6. A method according to claim 5 further comprising, after the processing step, a step of: broadcasting, by one of the sub-set of modules, the next header field of the subsequent packet part to the set of processing modules. 7. A method according to claim 6 further comprising, following the broadcasting of the next header field of the subsequent packet part, a step of: repeating the broadcasting, seizing and processing steps until the packet is completely processed. 8. A method according to claim 7, wherein: the set of hardware processing modules is associated with a corresponding set of logical indices; and wherein in regard to a current packet: the repeated broadcasting, seizing and processing steps are performed in a linearly progressive manner in regard to the sub-sets of logical indices, whereby once a current said sub-set of hardware processing modules has performed an associated processing operation on an associated packet part of the current packet, the said current sub-set of hardware modules is no longer needed to process the packet in question. 9. A method for processing an IPv6 packet for sending, the packet comprising an ordered sequence of packet parts, using a set of processing modules, the method comprising the steps of: (a) handing control to a current one of the set of modules, wherein said current module: (i) processes a corresponding packet part; (ii) appends, to the packet part, a next header field referencing said current module; (iii) concatenates, if a received packet part has been obtained, the packet part with the received packet part to form a composite packet part; and (iv) sends the composite packet part to a subsequent one of the set of processing modules; (b) handing control to the subsequent one of the set of processing modules which is thereby designated; and (c) repeating the steps (a)-(b) until the packet is completely processed. 10. A modular apparatus for processing a packet comprising an ordered sequence of packet parts, the apparatus comprising: a set of hardware processing modules; means for broadcasting the next header field of a received packet part to the set of processing modules; and means for processing the received packet part by a sub-set of the modules dependent upon the broadcast next header field. 11. An apparatus according to claim 10, wherein the hardware processing modules communicate using a common communication medium. 12. An apparatus according to claim 11, wherein the hardware processing modules are connected to the common communication medium by common interfaces. 13. A modular apparatus for processing, using a notionally indexed sequence of processing modules, a packet comprising a correspondingly notionally indexed sequence of packet parts, said apparatus comprising: the indexed sequence of processing modules; and means for repeatedly assigning a sub-set of said modules for processing a corresponding sub-set of said packet parts until all the packet parts have been processed; wherein: a lowest index of each successive said sub-set of modules is greater than a lowest index of a previous said sub-set of modules; and a lowest index of each successive said sub-set of packet parts is greater than a lowest index of a previous said sub-set of packet parts.

FIELD OF THE INVENTION The present invention relates generally to hardware architectures for TCP/IP, and in particular, to an architecture supporting implementation of modular TCP/IPv6 devices. BACKGROUND FIG. 1 shows a communication packet 100 based on Version 4 of the Internet Protocol (hereinafter referred to as IPv4). The packet 100 has packet parts 101-108. When considering how such packets are processed in hardware, the OPTIONS packet parts 106-107 are of particular importance as will be explained in regard to FIGS. 2 and 3. FIG. 2 shows an example of how the packet 100 of FIG. 1 can be processed in an IPv4 environment. The process 200 comprises process steps 201-206. A dashed arrow 207 on the right-hand side of the process step 201 indicates that the process step 201 makes use of information in the packet parts 101-105 of the packet 100 of FIG. 1. Similar dashed arrows are associated with the process steps 202 and 204-206 and in each case relate to the packet parts that are required by the corresponding process step. The first step 201 reads the header of the packet 100. The header comprises the packet parts 101-105. The step 201 checks the DESTINATION ADDRESS at 105, and calculates the header checksum. In order to determine the header checksum all the packet parts 101-105 and 106-107 are required. Accordingly, the checksum is determined over the entire header, including the options. Thereafter, a step 202 processes OPTIONS fields in the packet parts 106-107. In the present packet example 100, the OPTION relates to the IPv4 ROUTING option. The subsequent step 203 discards the packet 100 if the header checksum calculated in the step 201 is incorrect. A following step 204 performs operations concerned with fragment handling. This relates to the situation in which the packet 100 is one of a number of packets associated with a source data packet (not shown) that has been fragmented. The step 204 thus involves consideration of the PACKET IDENTIFICATION field and the FRAGMENT OFFSET field at 102 to check that fragmentation integrity has been maintained. Thereafter, a step 205 adds data from the DATA packet part 108 to a fragment buffer (not shown), provided that the check carried out in the step 204 is valid. A following step 206 establishes whether the data fragment carried in the packet 100 is the final fragment from the source data packet. If this is the case, then the data payload in the packet part 108, plus other information from the packet header is sent to the transport layer for sending to the next destination. The process 200 can be realized using one or more processing modules implemented as state machines. It is apparent that the process 200 accesses and operates upon the packet parts 101-108 of the packet 100 in a non-linear fashion. Thus, for example, even though the packet parts 101-105 are processed in the step 201, the packet part 102 is again processed by the step 204. Because of the non-linear packet part access that is required for IPv4 processing, practical implementations of processors for IPv4 packets typically include a control module as well as other modules. The control module is generally responsible, among other things, for scheduling the flow of packet data among the other processing modules. A multiplicity of communication paths are required for the aforementioned non-linear packet part access and processing between the control module and the other processing modules. Processing and communication also takes place between the other processing modules themselves. The arrangement of the communication paths and the data and control flows are dependent upon the type of packets being processed, and in particular, dependent upon the OPTIONS included in the packets. Thus, it is difficult to customise the structure of an IPv4 processing machine to specific circumstances. FIG. 3 shows a representative prior art process flow for processing an IPv4 packet, using hardware processing modules in the IPv4 environment. FIG. 3 depicts an architecture having a control module 308, an IPv4 module 309, a routing module 310 and a fragmentation module 312. In a first step 301 the control module 308 receives the packet (such as 100 in FIG. 1) from a data bus that is depicted a “B” in a circle. In a following step 302 the control module 308 sends IP header data onto the data bus “B”. The IPv4 module 309 reads the header data from the bus “B” and processes the header data in a step 313. The aforementioned steps 301-302 and 313 correspond to the step 201 in FIG. 2. In a next step 303 the control module 308 checks the OPTION field in the packet 100, and then a step 304 sends routing option data to the routing module 310 over the bus “B”. The routing module 310 processes the received routing data in a step 314. The steps 303-304 and 314 correspond to the step 202 in FIG. 2. The next step 305 again checks the OPTION field in the packet 100 after which a step 306 send fragmentation option data to the fragmentation module 312. The fragmentation module 312 processes the fragmentation data in a step 315. The steps 305-306 and 315 correspond to the steps 204-206 in FIG. 2. A re-entrant arrow 311 indicates that the processing of fragmentation data (ie adding data to the fragment buffer referred to in relation to FIG. 2) is associated with a corresponding process step for the next packet if not all fragments have yet been received. A final step 307 sends data to the transport module (not shown). It is apparent from FIG. 3 that the packet process 300 involves repeated communication between the control module 308 and the other modules 309, 310 and 312. Furthermore, the accesses to the packet parts 101-108 of the packet 100 are non-linear. SUMMARY OF THE INVENTION This specification describes a hardware architecture that facilitates customisation of IP processing machines to specific circumstances. The architecture can be decomposed into “essential” and “selectable” processing modules. Typically the “essential” modules in any system, (having regard to the receive side 504 of the system 500 in FIG. 5 for example), are the IPv6 receive module 501, and at least one transport module such as the TCP receive module 517. Having regard to the transmit side 505 of the system 500, the “essential” modules are the IPv6 send module 526, and at least one transport layer module such as the TPC send module 522, as well as the IPv6 scheduler with neighbour discovery 519 (see FIG. 5). Essential modules are required in every IPv6 processing machine, while selectable modules may be included or omitted depending upon the particular application. The selectable modules are often, but not always, associated with the presence or absence of various OPTIONS fields in the packets being considered (IPv6 packets will be described in more detail in regard to FIG. 4). Selectable processing modules may be included or omitted from the disclosed arrangements without requiring extensive reworking of inter-module communication and data flows. In some cases selectable modules can be added or omitted with only minor changes to “glue” logic in order to accommodate the change to the architecture. In many cases, even these minor logic changes are not required. This architecture is referred to as the “modular architecture” in this description. According to one arrangement, the modular functionality is provided by broadcasting NEXT HEADER fields to a set of processing modules, one of which seizes control according to the specifics of the broadcast NEXT HEADER field. According to another arrangement, an a-priori sequence of processing modules is established according to the order of the packet parts of an incoming packet. In the modular architecture, the flow of packet data (see 410 in FIG. 4) and the direction of inter-module hand-over of processing control generally takes place in one direction along a logical processing path. However, in some cases, control information may also flow in the opposite direction along the logical processing path. OPTION packet parts (such as 405-407 and 408-409 in FIG. 4) in each packet (such as 400 in FIG. 4) can be ordered differently within the packet 400. Furthermore, not all packets 400 in a packet stream need have the same options. However, the modular architecture provides, in regard to each packet, a packet-specific logical processing path in which the uni-directional processing and hand-over of processing control described above is performed. The NEXT HEADER fields (at 405 and 408 in FIG. 4) that are present for each IPv6 OPTION, facilitate provision of the packet-specific linear logical processing path. Once a “current” processing hardware module has performed an associated processing operation on an associated packet part of the current IPv6 packet, that current hardware module is no longer needed to process the packet in question. The current module then “hands over” the processing and control role, and any data that is required, to the relevant “next” processing module. Similarly, once the next processing hardware module has performed an associated processing operation on the associated next packet part, the next module then hands over the processing and control role, and any data that is required, to the relevant subsequent processing module and so on. A common communication medium and uniform module interfaces are used to implement the modular architecture. The modular architecture enables IPv6 packets with any one of a variety of upper layer protocols (such as TCP, ICMP, UDP and so on) and one or more IPv6 OPTIONS to be processed. If a particular application needs a specific IPv6 stack, the architecture can be realised in a modular fashion, incorporating only those processing modules which are needed for the particular processing stack. Modules which are not required for the application in question can be easily and transparently omitted from the implemented system, without impairing the function of the overall system and without requiring extensive reworking of the communication and control paths in the system. This approach allows, for example, an optimised Application Specific Integrated Circuit (ASIC) to be implemented for a specific application without incorporating unnecessary processing modules. According to a first aspect of the present disclosure, there is provided a method for processing a packet comprising an ordered sequence of packet parts using a set of hardware processing modules, the method comprising the steps of: broadcasting the next header field of a received packet part to the set of processing modules; and processing the received packet part by a sub-set of the modules dependent upon the broadcast next header field. According to another aspect of the present disclosure, there is provided a method for processing an IPv6 packet for sending, the packet comprising an ordered sequence of packet parts, using a set of processing modules, the method comprising the steps of: (a) handing control to a current one of the set of modules, wherein said current module: (i) processes a corresponding packet part; (ii) appends, to the packet part, a next header field referencing said current module; (iii) concatenates, if a received packet part has been obtained, the packet part with the received packet part to form a composite packet part; and (iv) sends the composite packet part to a subsequent one of the set of processing modules; (b) handing control to the subsequent one of the set of processing modules which is thereby designated ; and (c) repeating the steps (a)-(b) until the packet is completely processed. According to another aspect of the present disclosure, there is provided a modular apparatus for processing a packet comprising an ordered sequence of packet parts, the apparatus comprising: a set of hardware processing modules; means for broadcasting the next header field of a received packet part to the set of processing modules; and means for processing the received packet part by a sub-set of the modules dependent upon the broadcast next header field. According to another aspect of the present disclosure, there is provided a modular apparatus for processing, using a notionally indexed sequence of processing modules, a packet comprising a correspondingly notionally indexed sequence of packet parts, said apparatus comprising: the indexed sequence of processing modules; and means for repeatedly assigning a sub-set of said modules for processing a corresponding sub-set of said packet parts until all the packet parts have been processed; wherein: a lowest index of each successive said sub-set of modules is greater than a lowest index of a previous said sub-set of modules; and a lowest index of each successive said sub-set of packet parts is greater than a lowest index of a previous said sub-set of packet parts. Other aspects of the invention are also disclosed. BRIEF DESCRIPTION OF THE DRAWINGS Some aspects of the prior art and one or more embodiments of the present invention will now be described with reference to the drawings and appendices, in which: FIG. 1 shows an IPv4 communication packet; FIG. 2 shows a logical process flow diagram for the Ipv4 packet of FIG. 1; FIG. 3 shows distribution of the process flow of FIG. 2 among processing modules; FIG. 4 shows an IPv6 communication packet; FIG. 5 shows an example of a hardware IPv6 processing system using the disclosed modular architecture; FIG. 6 shows IPv6 hardware modules communicating over a common communication bus medium; FIG. 7 shows IPv6 hardware modules communicating over a common communication chain medium; FIG. 8 shows a process flow diagram for an IPv6 packet using the disclosed modular architecture; FIG. 9 shows an example of distribution of the process flow of FIG. 8 among processing modules; FIG. 10 shows another example of distribution of the process flow among processing modules; and FIG. 11 shows a top level process for processing packet parts according to the disclosed modular architecture. DETAILED DESCRIPTION INCLUDING BEST MODE Where reference is made in any one or more of the accompanying drawings to steps and/or features, which have the same reference numerals, those steps and/or features have for the purposes of this description the same function(s) or operation(s), unless the contrary intention appears. It is to be noted that the discussions contained in the “Background” section and that above relating to prior art arrangements relate to discussions of documents or devices which form public knowledge through their respective publication and/or use. Such should not be interpreted as a representation by the present inventor(s) or patent applicant that such documents or devices in any way form part of the common general knowledge in the art. IP version 6 (IPv6) is the successor to IP version 4 (IPv4). The changes from IPv4 to IPv6 include header format simplification, and improved support for extensions and options. FIG. 4 shows an IPv6 communication packet 400. The packet 400 has packet parts 401-410. Of particular importance, when considering how such IPv6 packets are processed in hardware, are the OPTIONS packet parts 405-407 and 408-409. The packet parts 405-407 relate to a ROUTING option, and the packet parts 408-409 relate to a FRAGMENTATION option. It is noted that only the NEXT HEADER fields at the packet parts 402, 405 and 408 are placed onto the address bus (see “AB” in FIGS. 9 and 10). FIG. 5 shows one example of a hardware IPv6 processing system 500 implemented using the disclosed modular architecture. Rounded boxes such as 501 (which refers to an IPv6 Receive Module) indicate modules or groups of state machines that implement a protocol or an OPTION. Rectangular boxes such as 502 (which depicts a ‘Neighbour Cache’) indicate memory elements. Triangles such as 503 indicate tri-state driving units. The system 500 is split into two sides 504 and 505 for respectively receiving and sending data over a bus 525. Layers 506-509 correspond respectively to the Ethernet layer, the IPv6 (also referred to as the Network or Inter-network) layer, the transport layer and the application layer. Each of these layers 506-509 has its own communication mechanism with other layers. In order to increase the speed and throughput of the system 500 on the receive side 504, all protocols are designed to avoid buffering of packets between layers. Data is operated on in parallel as much as possible, and is operated on while a packet is still arriving. Accordingly, after each packet arrives at the Ethernet interface 510, the packet is passed to the IPv6 Receive Unit 501 that places the packet onto a receive bus 511. As will be described in relation to FIGS. 9 and 10 the bus 511 includes a data bus (referred to as “DB” in FIGS. 9 and 10) and an address bus (referred to as “AB” in FIGS. 9 and 10). This bus 511 carries broadcast packet data, making it available to other modules connected to the bus 511. Thus, for example, the transport layer 508 can operate on the broadcast packet data by, for example, storing the packet data in RAM (not shown), as soon as the data is presented on the bus 511. No memory units are used in the network layer 507 except possibly for small registers (not shown) in the various modules. This minimises the packet processing delay in the network layer 507. A similar arrangement is used when sending a packet using the send side 505. The bus 511 constitutes the common communication medium for the receive side, and the processing modules (such as 515) typically have uniform interfaces to communicate over the bus 511. Modules which have interfaces that are uniform (ie perfectly compatible with the bus 511) can be added or removed without requiring glue logic patches. When module interfaces are only substantially uniform (ie somewhat less compatible), then some glue logic patches will be required when modules are added or removed. The receive side 504 of the system 500 uses mainly the one bus 511 for inter-module communications. OPTIONS in IPv6 are identified by an associated NEXT HEADER field such as 405 for each option. This contrasts with the monolithic PROTOCOL field at 103 in the IPv4 packet 100. Each OPTION in the IPv6 packet 400 has an associated NEXT HEADER value. In this way, the IPv6 protocol enables substantially any number of OPTIONS to be present in an IPv6 packet. The final OPTION in the packet has a NEXT HEADER value referencing the destination protocol for the packet. This destination protocol may, for example, be ICMP (which is processed by a corresponding module 515), UDP (which is processed by a corresponding module 516), TCP (which is processed by a corresponding module 517) and so on. The disclosed implementation of the system 500 can handle any order of IPv6 OPTIONS in a packet. On the receive side 504, this flexibility is achieved by implementing the single bus 511 with all OPTION modules 512-514, and all protocol modules 515-517, listening to the bus 511. This provides the broadcast communication capability needed to support the semi-transparent addition and removal of processing modules at the network layer 507 and the transport layer 508. Any OPTION module (eg 512) or protocol module (eg 517) can process the information associated with their own NEXT HEADER. When appropriate, an aforementioned module can let the next OPTION module (ie the OPTION module referenced by the subsequent NEXT HEADER field of the packet) know when its NEXT HEADER is about to start being streamed on the bus 511. Still considering the receive side 504 the packets are processed in real time at line speed or greater as the packets are passed from the network layer 507 through the required OPTION modules 514-512 and on to the transport layer 508. All the IPv6 option processing modules 514-512 and the transport layer protocol modules 515-517 communicate via the receive bus 511. A current module processes the data in the packet part with which the current module is associated. When the current module has completed its processing, it signals, by sending the subsequent NEXT HEADER over the address bus AB which forms part of the bus 511, all other modules that the next module is to commence processing. The packet data is, in the mean time, being passed blindly on the bus 511 and is thus available to all modules. According to this modular arrangement, the ‘Bus Master’, which for the receive side 504 is the Receive Module 501, does not need to know which processing modules are present in the system 500. The modular arrangement also enables a packet to be dropped cleanly if the required processing module is not present. In this event, an error message can be generated if desired. More particularly, even if the NEXT HEADER that is placed onto the address bus is not recognised by any processing module that has been realised in the particular system being considered, this does not cause a communication failure since the OPTION associated with the aforementioned NEXT HEADER is merely not acted upon. Furthermore, it is possible to incorporate a function, either in a separate module or as an additional capability in an existing module, which recognises that no other module has reacted to the NEXT HEADER in question and emits an error message. In contrast, in IPv4 if a particular processing module is not implemented then the central controller (such as 308 in FIG. 3) needs to be made aware that the module in question is absent. When the ASIC is implemented, this modular arrangement enables modules to be added to, or removed from, the network and transport layers 507, 508 with little or no impact on other modules which are to be included. The addition and/or removal of modules can be implemented at various stages in the ASIC design/fabrication process. Thus, for example, modules can be added and/or removed at the system block level stage, the Register Transfer Level (RTL) description level stage, and/or the net-list level stage. These aforementioned design/fabrication stages will be referred to generally as the ASIC ‘synthesis stage’. The system 500 that is implemented using the modular approach enables a typical received IPv6 packet to be processed without buffering until the packet reaches the transport layer 508, thus reducing costly memory access operations. Packet reconstruction options however, such as IPv6 fragmentation, and IPSec, do require limited amounts of buffering at the network layer 507. Turning to the send side 505 of the system 500, it is noted that in order to send an IPv6 packet, OPTIONS may also be required. A chain of OPTION modules 518 is incorporated into the system 500 so that OPTION modules in the chain 518 can add appropriate NEXT HEADER fields (which may be in the order recommended by RFC 2460) to an outgoing packet. Each required NEXT HEADER is thus created by an associated processing module. The order in which NEXT HEADER fields are created is controlled by extra logic in the chain 518, thereby allowing the sending bus masters (ie the packet Scheduler 519 and the transmit IPSec unit which forms part of the chain 518) to determine which OPTIONS are to be incorporated into which packet parts. This arrangement allows for fast creation of packet headers (often faster than line speed) while requiring no extra memory to buffer the created IPv6 OPTION headers before they are incorporated into the packets for sending. This arrangement also allows the modules that create and handle IPv6 OPTIONS on outgoing packets on the transmit side 505 to be added or removed when the ASIC design is synthesised (ie at one or more of the system block, RTL or net-list description stages). Since the transmit side 505 predetermines which OPTION fields are to be added to outgoing packets, modularity can be achieved without needing the handover of control and broadcast of information to all modules as is needed on the receive side. Provision of a common communication medium and uniform module interfaces are sufficient to provide the modular architecture on the transmit side 505. According to this arrangement, since each OPTION is known ahead of time, the OPTIONS can be set up via logic ahead of time. According to one example, the chain 518 of OPTION modules on the transmit side 505 is implemented by cascading the option modules as described in regard to FIG. 7. According to this chain arrangement, the output of one OPTION module feeds into the input of a following OPTION module, whose output in turn feeds into the input of a succeeding module. Each OPTION module thus outputs its own NEXT HEADER field to the lower downstream OPTION modules, (ie those modules towards the Ethernet layer 506), and then allows the higher upstream OPTION modules (ie those modules upstream towards the application layer 509) to output their header and data. At the bottom of this chain is the data link layer 510, which operates on the same basis as the OPTION module chain 518. As noted, the receive side 504 of the system 500 uses the common bus 511 for communication between the receive OPTION modules 512-514, while the transmit side 505 of the system 500 uses a chain arrangement depicted by 518. Both these arrangements are examples of inter-module communication using (a) a Common Communication Medium, and (b) a Uniform Module Interface as will be described in regard to FIGS. 6 and 7. FIG. 6 shows an arrangement 600 having modules 601, . . . , 605 that communicate over a common communication medium 609 which is depicted as a bus in FIG. 6. This arrangement is similar to the communication bus arrangement 511 used in FIG. 5. The bus 609 is depicted as being bi-directional, but unidirectional media may also be used. The module 601 receives, as depicted by an arrow 602, data off the bus 609, via a uniform module interface 604. The module 601 sends, as depicted by an arrow 603, data onto the bus 609, via the uniform module interface 604. The module 605 receives, as depicted by an arrow 606, data off the bus 609, via a uniform module interface 608. The module 605 sends, as depicted by an arrow 607, data onto the bus 609, via the uniform module interface 608. FIG. 7 shows an arrangement 700 having modules 701 and 705 that communicate over a common communication medium 709 which is depicted as a cascaded chain. This arrangement is similar to the communication chain arrangement 518 used in FIG. 5. The chain 709 is depicted as being bi-directional in FIG. 7, but uni-directional media may also be used. The module 705 receives, as depicted by an arrow 703, data from the module 701, via a uniform module interface 704. The module 705 sends, as depicted by an arrow 707, data to the next module (not shown) on the chain 709, via a uniform module interface 708. The module 701 receives, as depicted by an arrow 702, data from the module 705, via a uniform module interface 704. The module 705 receives, as depicted by an arrow 706, data from modules further down the chain (not shown) via a uniform module interface 708. The module 701 sends, as depicted by an arrow 703, data to the module 705, via the uniform module interface 704. Returning to FIG. 5, it is noted that the transport layer protocol modules 521-523 are connected to the packet scheduler 519 by a simple bus 520. Outgoing packets are output by the IP Scheduler 519 before the packets are sent down the chain 518 on the transmit side 505. The Scheduler 519 uses Neighbour Discovery to determine the link layer address of the next hop node (not shown). The scheduler 519 receives packets to be sent from the transport layer 508 (using a pointer to the RAM memory where the packet is stored), and the scheduler 519 also receives information such as the destination of the outgoing packet and so on. The Scheduler 519 uses next hop determination and the neighbour cache 502 to determine whether the Scheduler 519 already knows what the link layer address is for the next hop device. If this address is not known, the Scheduler 519 performs the required Neighbour Solicitation operations. Multiple packets can be buffered while waiting for neighbour advertisements to arrive. There is, accordingly, very little delay to any protocols that wish to send packets. The above arrangement allows the transport option modules 521-523 on the send side 505 to be plugged blindly into the system 500 above the packet scheduler 519 in a modular fashion at the ASIC synthesis stage. The IP scheduler 519 is not “aware” of the protocols above it. In other words, the scheduler 519 does not differentiate between different transport layer protocols such as the TCP module 522, and the UDP module 523. Consequently, the scheduler 519 is not affected by which protocols may or may not be present. An application interface 524 controls communication between the system 500 and the software application (not shown). This interface 524 can be implemented as a programming or communication interface for the ASIC. This interface is adapted to support communication with the software application via a peripheral or system bus (not shown) such as Advanced Microprocessor Bus Architecture (AMBA). FIG. 8 shows an example of how the packet 400 of FIG. 4 can be processed in an IPv6 environment. The process 800 comprises process steps 801-805. A dashed arrow 806 on the right-hand side of the process step 801 indicates that the process step 801 makes use of information in the packet parts 401-404 of the packet 400 of FIG. 4. Similar dashed arrows are associated with the process steps 802-804 and in each case relate to the packet parts that are required by the corresponding process step. A first step 801 (implemented by the IPv6 receive module 501 in FIG. 5) reads the base IPv6 header of the packet 400 of FIG. 4. The header comprises the packet parts 401-404. The step 801 checks the DESTINATION ADDRESS (at 404) and writes the subsequent NEXT HEADER value (at 402) onto the bus 511. The step 801 also passes all further packet data (from 405 onwards) onto the bus 511. These actions make the NEXT HEADER associated with the ROUTING OPTION, the ROUTING OPTION, and the FRAGMENT OPTION, as well as the packet data at 410, available to all processing 10 modules that are listening to the bus 511. It is note that the initial NEXT HEADER resides at 402. The NEXT HEADER at 402 relates to the packet parts 405-407. The NEXT HEADER at 405 relates to the packet parts 408-409. A following step 802 (implemented by the ROUTING OPTION module which is not explicitly shown but is part of the OPTION modules 512 in FIG. 5 receives the ROUTING OPTION header from the packet part 405. The step 802 also checks the SEGMENTS LEFT field at the packet part 405 and the ROUTE ADDRESS field at the packet part 407. If this check is satisfactory, then the step 802 indicates the subsequent NEXT HEADER value from the packet part 405 by writing the value onto the bus 511. A following step 803 (that is implemented by the fragmentation module 514 in FIG. 5) receives the packet parts 408-409, including the FRAGMENT OPTION header from 408. The step 803 also checks the IDENTIFICATION field at the packet part 409 to verify that it is consistent with the FRAGMENT OFFSET field at 408. A following step 410 (that is implemented by the fragmentation module 514 in FIG. 5) performs tests concerned with fragment handling, and adds data from the DATA packet part 410 to a fragment buffer (not shown) provided that the check carried out in the step 804 is valid. Thereafter, if all fragments have been received a step 805 indicates the subsequent NEXT HEADER value at 408 onto the bus 511. The step 805 also passes the reassembled packet to the appropriate transport protocol (515-517) depending on which protocol is defined by the aforementioned NEXT HEADER field. In contrast to the process in FIG. 2, it is apparent that the process 800, which comprises the steps 801-805, accesses the packet parts 401-410 of the packet 400 in a linear fashion. Thus, for example, once the packet parts 401-404 have been processed in the step 801, the packet parts 401-404 are not required by other (later) steps in the process 800. Because of this linear packet part access, provided by the disclosed modular approach, processors for IPv6 applications using the modular architecture typically do not require a control module. Furthermore, it is relatively straightforward to tailor the structure of the IPv6 processing machine to specific circumstances by adding and/or removing modules on a customised basis. FIG. 9 shows a representative process flow 900 for processing an IPv6 packet. FIG. 9 depicts an architecture having the IPv6 receive module 501, a routing module 911, the fragmentation module 514 and the UDP module 516 (see FIG. 5). In a first step 901 the receive module 501 receives a packet (such as 400 in FIG. 4) on the data bus DB that forms part of the bus 511 in FIG. 5. In a following step 902 the receive module 501 processes the header (at 401-404 in FIG. 4), and in a following step 903 the receive module 501 passes data from 405 onwards onto the data bus DB. In a subsequent step 904, the receive module 501 indicates the NEXT HEADER field (at 402) onto the address bus AB which forms part of the bus 511 of FIG. 5. In a step 916 the routing module 911 receives the routing NEXT HEADER information (from 402) on the address bus AB and in a following step 905 the routing module 911 processes this header. Thereafter, in a step 906 the routing module 911 indicates the NEXT HEADER (from 405 in FIG. 4) onto the address bus AB, after which in a step 913 the fragmentation module 514 receives that NEXT HEADER on the address bus AB from 405. In a following step 907 the fragmentation module 514 processes the aforementioned NEXT HEADER information, and in a following step 908 the fragmentation module 514 processes the data (from 410) associated with the next fragment, this data being read off the data bus DB. A re-entrant arrow 912 at the step 908 indicates that the aspect of packet de-fragmentation is performed iteratively across multiple packets until all fragments of the original fragmented data packet have been collected in the data fragment buffer. In a following step 909 the fragmentation module 514 indicates the subsequent NEXT HEADER onto the address bus AB after which in a step 914 the UDP module 516 receives this UDP header for processing. The NEXT HEADER indicating UDP is at the packet part 408 in the packet 400. The UDP header itself is at the start of the packet part 410. In a subsequent step 910 the fragmentation module 514 streams data from 410 onto the data bus DB after which the UDP module 516 in a step 915 receives the data from the data bus DB and processes the data. It is apparent from FIG. 9 that the packet process 900 involves communication between successive modules that move in a rightward direction in FIG. 9. Thus, while initial communication takes place between the receive module 501 and the routing and fragmentation modules 911, 514, the receive module 501 is no longer involved after the step 905 takes place. Thus the communication flow between the modules is far more linear than that described in regard to FIG. 3. FIG. 10 shows a representative process flow 1000 for a system in which the IPv6 receive module 501, the routing module 911, an IPSec module 1012, and the UDP module 516 are present. The packet being considered in FIG. 10 differs from the packet 400 in FIG. 4 by containing different OPTIONS, one relating to the routing OPTION that is addressed by the routing module 911, and one relating to the IPSec functionality that is addressed by the IPSec module 1012. In a step 1001 the receive module 501 receives the noted packet on the data bus DB that forms part of the bus 511 in FIG. 5. In a following step 1002 the receive module 501 processes the header and in a following step 1003 the receive module 501 starts streaming packet data onto the data bus DB. In a step 1014 the IPSec module 1012 picks this data off the data bus DB and commences processing the data. In a following step 1004 the receive module 501 places the subsequent NEXT HEADER onto the address bus AB. In the present example this NEXT HEADER relates to the routing OPTION. Accordingly, in a step 1013 the routing module 911 picks the aforementioned NEXT HEADER off the address bus AB. Furthermore, the IPSec module 1012 also receives in a step 1015 the aforementioned NEXT HEADER that relates to the ROUTING option from the address bus AB. In a following step 1005 the routing module 911 commences processing of the aforementioned NEXT HEADER, as does the IPSec module 1012 in a step 1016. Thereafter in a step 1006 the routing module 911 places the subsequent NEXT HEADER, this relating to the IPSec OPTION onto the address bus AB. The IPSec 1012 receives the aforementioned NEXT HEADER off the address bus AB in a step 1017, and continues processing this in a following step 1007. In a following step 1008 the IPSec module 1012 processes the remainder of the packet data which is being streamed onto the data bus DB. In a following step 1009 the IPSec module 1012 streams this packet data onto the data bus DB, after which the IPSec module 1012 places a subsequent NEXT HEADER onto the address bus AB in a step 1010. This NEXT HEADER relates to the particular transport protocol being considered in this example, which as shown in FIG. 10 is the UDP protocol. Accordingly, the UDP module 516 picks the aforementioned NEXT HEADER off the address bus AB in a step 1018, and processes this NEXT HEADER in a subsequent step 1011. FIG. 11 shows a top level process 1100 for processing packet parts according to the disclosed modular architecture. The process 1100 commences with a test step 1101 wherein a particular hardware processing module listens on the common communication medium (such as 609 in FIG. 6) in order to determine if a next header field (from a received packet part) associated with the hardware processing module in question has been broadcast. If this is not the case, then the process 1100 is directed by a NO arrow to a step 1102 in which the hardware processing module in question ignores any next header fields that may have been received, and the process 1100 is directed back to the step 1101. If however the step 1101 returns a logical TRUE value, then the process 1100 is directed by a YES arrow to a step 1103 in which the hardware processing module in question processes the associated received packet part(s). In a following step 1104 the hardware processing module determines if the received packet part(s) have been completely processed, and if not, then the process 1100 follows a NO arrow back to the step 1103. If however the aforementioned processing of the received packet part(s) has been completed, then the process 1100 is directed by a YES arrow to a step 1105 in which the hardware processing module in question broadcasts the next header field of the subsequent received packet part(s) onto the common communication medium. Typically, the hardware processing module in question will now have completed it's processing of the current packet, as described in relation to FIGS. 9 and 10 for example. Other hardware processing modules then follow a similar process to 1100 in order to perform their part of processing the relevant packet parts of the packet in question. In practical terms, ASIC devices for IPv6 applications are often designed and tested using Field Programmable Gate Array (FPGA) or equivalent technology. The design stage (referred to in this description as the synthesis stage) typically involves a functional design flow commencing with (a) development of the initial system concept, then moving to (b) design of the overall architecture and individual blocks, followed by (c) preparation of an RTL description, and then (d) hardware synthesis. The disclosed modular approach enables desired modules to be defined at a number of points in this synthesis process. When designing and fabricating a customised IPv6 processing system or device using the disclosed modular architecture, one particularly convenient point for defining the desired modules is at the RTL description stage. An RTL description for an IPv6 device that is designed using the disclosed modular approach is a specialised RTL description in which undesired modules have, for example, been “commented out”. Alternately, the RTL description sections relating to undesired modules can simply be removed. Another option is to use known-capabilities of the RTL descriptive language to generate the desired modules, while omitting undesired modules. The use of common communication media and uniform module interfaces enable a specialised IPv6 device to be designed and built, using the modular approach. Modules are added or removed without requiring additional adjustment to other modules or to the overall device. In some situations, a small amount of “glue logic” may be required in order to enable module removal and/or addition. Thus, where certain components will only interface with one type of bus, and the bus systems associated with the noted components are of a similar but not identical type, bridging glue logic can be used to connect the components to a bus so that both the modules and the rest of the system using the bus will work together. An example of bus types that may be connected like this are AMBA™ and CoreConnect™. INDUSTRIAL APPLICABILITY It is apparent from the above that the arrangements described are applicable to the computer and data processing industries. The foregoing describes only some embodiments of the present invention, and modifications and/or changes can be made thereto without departing from the scope and spirit of the invention, the embodiments being illustrative and not restrictive.

<SOH> BACKGROUND <EOH>FIG. 1 shows a communication packet 100 based on Version 4 of the Internet Protocol (hereinafter referred to as IPv4). The packet 100 has packet parts 101 - 108 . When considering how such packets are processed in hardware, the OPTIONS packet parts 106 - 107 are of particular importance as will be explained in regard to FIGS. 2 and 3 . FIG. 2 shows an example of how the packet 100 of FIG. 1 can be processed in an IPv4 environment. The process 200 comprises process steps 201 - 206 . A dashed arrow 207 on the right-hand side of the process step 201 indicates that the process step 201 makes use of information in the packet parts 101 - 105 of the packet 100 of FIG. 1 . Similar dashed arrows are associated with the process steps 202 and 204 - 206 and in each case relate to the packet parts that are required by the corresponding process step. The first step 201 reads the header of the packet 100 . The header comprises the packet parts 101 - 105 . The step 201 checks the DESTINATION ADDRESS at 105 , and calculates the header checksum. In order to determine the header checksum all the packet parts 101 - 105 and 106 - 107 are required. Accordingly, the checksum is determined over the entire header, including the options. Thereafter, a step 202 processes OPTIONS fields in the packet parts 106 - 107 . In the present packet example 100 , the OPTION relates to the IPv4 ROUTING option. The subsequent step 203 discards the packet 100 if the header checksum calculated in the step 201 is incorrect. A following step 204 performs operations concerned with fragment handling. This relates to the situation in which the packet 100 is one of a number of packets associated with a source data packet (not shown) that has been fragmented. The step 204 thus involves consideration of the PACKET IDENTIFICATION field and the FRAGMENT OFFSET field at 102 to check that fragmentation integrity has been maintained. Thereafter, a step 205 adds data from the DATA packet part 108 to a fragment buffer (not shown), provided that the check carried out in the step 204 is valid. A following step 206 establishes whether the data fragment carried in the packet 100 is the final fragment from the source data packet. If this is the case, then the data payload in the packet part 108 , plus other information from the packet header is sent to the transport layer for sending to the next destination. The process 200 can be realized using one or more processing modules implemented as state machines. It is apparent that the process 200 accesses and operates upon the packet parts 101 - 108 of the packet 100 in a non-linear fashion. Thus, for example, even though the packet parts 101 - 105 are processed in the step 201 , the packet part 102 is again processed by the step 204 . Because of the non-linear packet part access that is required for IPv4 processing, practical implementations of processors for IPv4 packets typically include a control module as well as other modules. The control module is generally responsible, among other things, for scheduling the flow of packet data among the other processing modules. A multiplicity of communication paths are required for the aforementioned non-linear packet part access and processing between the control module and the other processing modules. Processing and communication also takes place between the other processing modules themselves. The arrangement of the communication paths and the data and control flows are dependent upon the type of packets being processed, and in particular, dependent upon the OPTIONS included in the packets. Thus, it is difficult to customise the structure of an IPv4 processing machine to specific circumstances. FIG. 3 shows a representative prior art process flow for processing an IPv4 packet, using hardware processing modules in the IPv4 environment. FIG. 3 depicts an architecture having a control module 308 , an IPv4 module 309 , a routing module 310 and a fragmentation module 312 . In a first step 301 the control module 308 receives the packet (such as 100 in FIG. 1 ) from a data bus that is depicted a “B” in a circle. In a following step 302 the control module 308 sends IP header data onto the data bus “B”. The IPv4 module 309 reads the header data from the bus “B” and processes the header data in a step 313 . The aforementioned steps 301 - 302 and 313 correspond to the step 201 in FIG. 2 . In a next step 303 the control module 308 checks the OPTION field in the packet 100 , and then a step 304 sends routing option data to the routing module 310 over the bus “B”. The routing module 310 processes the received routing data in a step 314 . The steps 303 - 304 and 314 correspond to the step 202 in FIG. 2 . The next step 305 again checks the OPTION field in the packet 100 after which a step 306 send fragmentation option data to the fragmentation module 312 . The fragmentation module 312 processes the fragmentation data in a step 315 . The steps 305 - 306 and 315 correspond to the steps 204 - 206 in FIG. 2 . A re-entrant arrow 311 indicates that the processing of fragmentation data (ie adding data to the fragment buffer referred to in relation to FIG. 2 ) is associated with a corresponding process step for the next packet if not all fragments have yet been received. A final step 307 sends data to the transport module (not shown). It is apparent from FIG. 3 that the packet process 300 involves repeated communication between the control module 308 and the other modules 309 , 310 and 312 . Furthermore, the accesses to the packet parts 101 - 108 of the packet 100 are non-linear.

<SOH> SUMMARY OF THE INVENTION <EOH>This specification describes a hardware architecture that facilitates customisation of IP processing machines to specific circumstances. The architecture can be decomposed into “essential” and “selectable” processing modules. Typically the “essential” modules in any system, (having regard to the receive side 504 of the system 500 in FIG. 5 for example), are the IPv6 receive module 501 , and at least one transport module such as the TCP receive module 517 . Having regard to the transmit side 505 of the system 500 , the “essential” modules are the IPv6 send module 526 , and at least one transport layer module such as the TPC send module 522 , as well as the IPv6 scheduler with neighbour discovery 519 (see FIG. 5 ). Essential modules are required in every IPv6 processing machine, while selectable modules may be included or omitted depending upon the particular application. The selectable modules are often, but not always, associated with the presence or absence of various OPTIONS fields in the packets being considered (IPv6 packets will be described in more detail in regard to FIG. 4 ). Selectable processing modules may be included or omitted from the disclosed arrangements without requiring extensive reworking of inter-module communication and data flows. In some cases selectable modules can be added or omitted with only minor changes to “glue” logic in order to accommodate the change to the architecture. In many cases, even these minor logic changes are not required. This architecture is referred to as the “modular architecture” in this description. According to one arrangement, the modular functionality is provided by broadcasting NEXT HEADER fields to a set of processing modules, one of which seizes control according to the specifics of the broadcast NEXT HEADER field. According to another arrangement, an a-priori sequence of processing modules is established according to the order of the packet parts of an incoming packet. In the modular architecture, the flow of packet data (see 410 in FIG. 4 ) and the direction of inter-module hand-over of processing control generally takes place in one direction along a logical processing path. However, in some cases, control information may also flow in the opposite direction along the logical processing path. OPTION packet parts (such as 405 - 407 and 408 - 409 in FIG. 4 ) in each packet (such as 400 in FIG. 4 ) can be ordered differently within the packet 400 . Furthermore, not all packets 400 in a packet stream need have the same options. However, the modular architecture provides, in regard to each packet, a packet-specific logical processing path in which the uni-directional processing and hand-over of processing control described above is performed. The NEXT HEADER fields (at 405 and 408 in FIG. 4 ) that are present for each IPv6 OPTION, facilitate provision of the packet-specific linear logical processing path. Once a “current” processing hardware module has performed an associated processing operation on an associated packet part of the current IPv6 packet, that current hardware module is no longer needed to process the packet in question. The current module then “hands over” the processing and control role, and any data that is required, to the relevant “next” processing module. Similarly, once the next processing hardware module has performed an associated processing operation on the associated next packet part, the next module then hands over the processing and control role, and any data that is required, to the relevant subsequent processing module and so on. A common communication medium and uniform module interfaces are used to implement the modular architecture. The modular architecture enables IPv6 packets with any one of a variety of upper layer protocols (such as TCP, ICMP, UDP and so on) and one or more IPv6 OPTIONS to be processed. If a particular application needs a specific IPv6 stack, the architecture can be realised in a modular fashion, incorporating only those processing modules which are needed for the particular processing stack. Modules which are not required for the application in question can be easily and transparently omitted from the implemented system, without impairing the function of the overall system and without requiring extensive reworking of the communication and control paths in the system. This approach allows, for example, an optimised Application Specific Integrated Circuit (ASIC) to be implemented for a specific application without incorporating unnecessary processing modules. According to a first aspect of the present disclosure, there is provided a method for processing a packet comprising an ordered sequence of packet parts using a set of hardware processing modules, the method comprising the steps of: broadcasting the next header field of a received packet part to the set of processing modules; and processing the received packet part by a sub-set of the modules dependent upon the broadcast next header field. According to another aspect of the present disclosure, there is provided a method for processing an IPv6 packet for sending, the packet comprising an ordered sequence of packet parts, using a set of processing modules, the method comprising the steps of: (a) handing control to a current one of the set of modules, wherein said current module: (i) processes a corresponding packet part; (ii) appends, to the packet part, a next header field referencing said current module; (iii) concatenates, if a received packet part has been obtained, the packet part with the received packet part to form a composite packet part; and (iv) sends the composite packet part to a subsequent one of the set of processing modules; (b) handing control to the subsequent one of the set of processing modules which is thereby designated ; and (c) repeating the steps (a)-(b) until the packet is completely processed. According to another aspect of the present disclosure, there is provided a modular apparatus for processing a packet comprising an ordered sequence of packet parts, the apparatus comprising: a set of hardware processing modules; means for broadcasting the next header field of a received packet part to the set of processing modules; and means for processing the received packet part by a sub-set of the modules dependent upon the broadcast next header field. According to another aspect of the present disclosure, there is provided a modular apparatus for processing, using a notionally indexed sequence of processing modules, a packet comprising a correspondingly notionally indexed sequence of packet parts, said apparatus comprising: the indexed sequence of processing modules; and means for repeatedly assigning a sub-set of said modules for processing a corresponding sub-set of said packet parts until all the packet parts have been processed; wherein: a lowest index of each successive said sub-set of modules is greater than a lowest index of a previous said sub-set of modules; and a lowest index of each successive said sub-set of packet parts is greater than a lowest index of a previous said sub-set of packet parts. Other aspects of the invention are also disclosed.

20061110

20110913

20070419

65251.0

H04L1256

AGA, SORI A

MODULAR APPROACH TO THE TCP/IPV6 HARDWARE IMPLEMENTATION

UNDISCOUNTED

ACCEPTED

H04L

ACCEPTED

Treatment of Aqueous Chemical Waste

A method for the treatment of an aqueous stream containing both anionic and cationic species is provided. The method comprises the following steps. Circulating water continuously through an essentially closed loop, the loop incorporating an ion adsorption unit which, in turn, comprises a water permeable layer of an ion adsorbing material. Feeding an aqueous solution containing the anionic and the cationic species to the essentially closed loop. Passing the circulating water, including the aqueous solution containing the ionic and the cationic species, through the ion adsorbing material in the ion adsorption unit in a continuous manner. Whilst at the same time applying an electric potential across the thickness of the layer of ion adsorbing material and removing from the ion adsorption unit more concentrated aqueous solutions of the separate ionic species. Discharging each of the aqueous solutions from the ion adsorption unit. Passing the more concentrated solution of the other ionic species through a reaction unit in which the ionic species reacts to form a water-insoluble solid material. Recycling eluate from the reaction unit to the ion adsorption unit; and, if necessary, adding a quantity of water to the closed loop, this quantity corresponding the quantity of aqueous solution removed from the reaction unit.

1. A method for the treatment of an aqueous stream containing both anionic and cationic species, the method comprising the steps of: continuously circulating water through an essentially closed loop incorporating an ion adsorption unit comprising a water permeable layer of an ion adsorbing material; feeding to the essentially closed loop an aqueous solution containing the anionic and the cationic species; continuously passing the circulating water including the aqueous solution containing the ionic and the cationic species through the ion adsorbing material in the ion adsorption unit while applying an electric potential across the thickness of the layer of ion adsorbing material and removing from the ion adsorption unit more concentrated aqueous solutions of the separate ionic species; continuously discharging from the ion adsorption unit the more concentrated aqueous solution of one ionic species; continuously discharging from the ion adsorption unit the aqueous solution depleted in anionic and cationic species; continuously passing the more concentrated solution of the other ionic species through a reaction unit in which the ionic species reacts to form a water-insoluble solid material; continuously recycling eluate from the reaction unit to the ion adsorption unit; and, if necessary, adding to the closed loop a quantity of water corresponding to the quantity of aqueous solution removed from the reaction unit. 2. A method according to claim 1, wherein the anionic species is ammonium and the cationic species is fluoride. 3. A method according to claim 2, wherein a concentrated aqueous ammonium solution is continuously discharged from the ion adsorption unit. 4. A method according to claim 2, wherein a concentrated aqueous fluoride solution is continuously passed from the ion adsorption unit into a calcium precipitation unit thereby to form CaF2. 5. A method according to claim 4, wherein a source of calcium as a solution or slurry is continuously admitted to the calcium precipitation unit. 6. A method according to claim 5, wherein the source of calcium is a slurry of calcium carbonate or of calcium hydroxide. 7. A method according to claim 5, wherein depleted aqueous solution continuously discharged from the ion adsorption unit is used to prepare the solution or slurry of calcium. 8. A method according to claim 5, wherein eluate from the calcium precipitation unit is used to prepare the solution or slurry of calcium. 9. A method according to claim 5, wherein the amount of calcium admitted to the calcium precipitation unit is less than the stoichiometric amount for capturing fluoride and wherein the fluoride containing eluate from the precipitation unit is recycled to the ion adsorption unit to combine with the concentrated fluoride solution. 10. An apparatus for use in treating an aqueous stream containing both anionic and cationic species, the apparatus comprising: an essentially closed loop circulation system containing (i) an ion adsorption unit comprising a water permeable zone of an ion adsorbing material and means for enabling an electrical potential to be applied across the thickness of that zone and (ii) a reaction unit in which one of the anionic and cationic species is rendered substantially insoluble; a pump for continuously circulating aqueous solution around the closed loop; an inlet for an aqueous solution containing anionic and cationic species to the closed loop circulation system; an outlet for concentrated aqueous solution of one ionic species from the ion adsorption unit; an outlet for depleted aqueous solution from the ion adsorption unit; an outlet for solid from the reaction unit; and an inlet for water into the closed loop circulation system. 11. Apparatus according to claim 10, wherein the reaction unit is a calcium fluoride precipitation unit which comprises an inlet for an aqueous solution or slurry of a calcium source, an inlet for concentrated aqueous fluoride solution, an outlet for calcium fluoride and an outlet for aqueous fluoride eluate. 12. Apparatus according to claim 11, wherein the inlet for the aqueous solution or slurry of the calcium source is operatively connected to a mixing vessel in which the calcium source is mixed with water. 13. Apparatus according to claim 12, wherein the mixing vessel is operatively connected to the outlet for depleted aqueous solution from the ion adsorption unit. 14. Apparatus according to claim 12, wherein the mixing vessel is operatively connected to the outlet for aqueous fluoride eluate from the calcium fluoride precipitation unit.

BACKGROUND OF THE INVENTION This invention relates to the treatment of toxic and/or environmentally hazardous or harmful materials and more especially to the treatment of aqueous solutions of hazardous waste arising from various chemical processes. The chemical processing industry in general generates vast quantities of by-products and waste materials many of which represent environmental hazards and which must be neutralised or destroyed as an essential part of their ultimate disposal. The oil and gas processing industries, for example, invest heavily in plant and equipment designed specifically to prevent or minimise the release of harmful largely organic materials into the environment. The microelectronics and semi-conductor device manufacturing industries, for example, make similar investments in order to scrub or otherwise treat exhaust gas streams containing generally inorganic materials from chemical processing units prior to the release of those exhaust gases into the atmosphere. Compounds containing heavy metals and halogen-, sulphur-, phosphorus- and nitrogen-containing compounds can be especially toxic and their removal is the subject of a considerable amount of technical research and of much environmental protection legislation. Many of the procedures utilised in the microelectronics and semi-conductor device manufacturing industries use fluorine-containing compounds. Unused fluorine-containing compounds and fluorine-containing products and by-products are generally discharged from the process or from a subsequent exhaust treatment, for example scrubbers and other adsorption systems, as an aqueous waste stream. This aqueous waste stream will generally contain fluorine in the form of HF. However, cationic species such as NH4+ may also be present, in addition to fluoride in the form of bifiuoride ions, HF2−. Current practise in such manufacturing and disposal facilities involves treating the aqueous fluoride stream with magnesium or calcium salts in order to precipitate the sparingly soluble MgF2 and CaF2, usually the latter. The solid material can then be compacted and dried for ease of transport for disposal or further use. However, the water stream will still have a fluoride content of some 20 to 30 ppm which continues to present a disposal problem with discharge limits of 3 ppm being more generally imposed. Further, some legislative areas prohibit the dilution of certain waste streams (for example, aqueous fluoride with an aqueous stream containing no fluoride) for disposal purposes and in other areas allowable discharge is based on the quantity of discharged species and not their concentrations. The safe disposal of hazardous and harmful materials therefore presents ever increasing problems. A further difficulty is that effluent from recently developed procedures which use a mixture of ammonium bifiuoride and HF cannot be accommodated in a calcium precipitation installation because CaF2 will not form at pH below 12 and such high pH values favour the dissociation of ammonium species to produce ammonia gas. Additional facilities are then required to remove and separate NH4+and F−before they can be treated to form solid waste. This can be achieved using traditional ion exchange techniques but the plant will be large in that it will require separate beds for the two ion exchange species and duplex systems with further chemical feeds for their periodic regeneration. A recently developed system that is capable of removing both anionic and cationic species from aqueous solutions without requiring further chemical additives makes use of a technique known as electrochemical deionisation which involves ion exchange and electrolytic separation technologies. In this system cations or anions of interest are adsorbed from dilute aqueous solution onto an ion exchange medium, transported through that medium by an applied electric field and continuously eluted as a concentrated stream. Such a procedure is described in EP 0680932B. There are many examples within the existing literature of electrochemical cells that combine adsorption and ion separation and EP 0680932B illustrates one such ion removal/separation/concentration process. Other approaches will be known to those skilled in the art and can also be used. Such systems have been applied with some success on a continuous basis to minimise water consumption and to concentrate anions or cations for ease of subsequent handling in our copending Patent Application No. GB 0300793.7. That application demonstrates especially that fluoride ions can be concentrated and removed from a closed loop circulation system. Further work has now revealed that the techniques and procedures described in GB 0300793.7 may be applied successfully to the problems described above. In this respect the structure of the electrochemical deionisation cell described and illustrated in GB 0300793.7 has been modified to permit the simultaneous removal of both anions and cations. BRIEF SUMMARY OF THE INVENTION In accordance with the invention, there is now provided a method for the treatment of aqueous streams containing both anionic and cationic species, the method comprising the steps of: continuously circulating water through an essentially closed loop incorporating an ion adsorption unit comprising a water permeable layer of an ion adsorbing material; feeding to the essentially closed loop an aqueous solution containing the anionic and the cationic species; continuously passing the circulating water including the aqueous solution containing the an ionic and the cationic species through the ion adsorbing material in the ion adsorption unit while applying an electric potential across the thickness of the layer of ion adsorbing material and removing from the ion adsorption unit more concentrated aqueous solutions of the separate ionic species; continuously discharging from the ion adsorption unit the more concentrated aqueous solution of one ionic species; continuously discharging from the ion adsorption unit the aqueous solution depleted in anionic and cationic species; continuously passing the more concentrated solution of the other ionic species through a reaction unit in which the ionic species reacts to form a water-insoluble solid material; continuously recycling the eluate from the reaction unit to the ion adsorption unit; and, if necessary, adding to the closed loop a quantity of water corresponding to the quantity of aqueous solution removed from the closed loop with the solids in the reaction unit. In a separate aspect, the invention provides also apparatus for use in carrying out the method described above, the apparatus comprising: an essentially closed loop circulation system containing (i) an ion adsorption unit comprising a water permeable zone of an ion adsorbing material and means for enabling an electrical potential to be applied across the thickness of the ion adsorbing zone and (ii) a reaction unit in which one of the anionic and cationic species is rendered substantially insoluble; a pump for continuously circulating aqueous solution around the closed loop; an inlet for an aqueous solution containing anionic and cationic species to the closed loop circulation system; an outlet for concentrated aqueous solution of one ionic species from the ion adsorption unit; an outlet for depleted aqueous solution from the ion adsorption unit; an outlet for solid from the reaction unit; and an inlet for water into the closed loop circulation system. The ion adsorption unit employed as an essential aspect of the method and apparatus of the invention preferably incorporates both anion adsorbing and cation adsorbing capabilities in the unit. However, if necessary or desirable, it may be advantageous to use two separate ion adsorption units disposed in series one for anion adsorption and the other for cation adsorption. Still further, an ion adsorption unit having both anion adsorbing and cation adsorbing capabilities may be supplemented by a series-connected ion adsorption unit having only an anion adsorbing or a cation adsorbing capability. The precise arrangement will depend upon the relative concentrations of the anionic and cationic species in the aqueous solution fed to the ion adsorption units, the efficiency of the ion adsorption units in removing anions and/or cations of interest from the aqueous solution and the residual concentrations of the anions and the cations in the depleted aqueous solution having regard to any further treatment to which that solution may be subjected. In general terms, however, the skilled person will have no special difficulty in selecting the most appropriate combination of ion adsorption units and ion adsorbing materials for the particular situation and circumstances. The ion adsorbing materials serve to capture the ions of interest and are preferably ion exchange materials such as ion exchange resins in the form of particles or beads or other materials that can provide: a solution permeable medium; an ion adsorption medium (to remove the anions or cations); an ion conducting medium whereby the ions may be moved by the imposed electrical field into a separate solution. The particles or beads of the resins are preferably in a coherent form, that is to say they are not mobile or loose but are constrained in a predetermined configuration. For example, the particles of beads may be bound together with a binder or held between layers of a mesh or membrane so as to be permeable to the aqueous solution containing the ions, the mesh or membrane being permeable as appropriate for the removal and concentration of the ions of interest. The electrical potential which is applied across the thickness of the layer of ion adsorbing material serves to drive the captured ions through the ion adsorbing material towards one or other of the electrodes through which the potential is applied. The electrical potential may be generated from a pair of electrodes arranged to form an electrolysis cell or by any alternative arrangement, for example in the form of an electrophoresis cell. It will be understood that the ion adsorption unit consisting of ion exchange material is, in operation, self-regenerating in that it effectively transports the captured cations and/or anions through its bulk for discharge as a concentrated aqueous solution, and will regenerate to its hydrogen or hydroxide form when no other cationic or anionic species is present. Such an electrically regenerating ion exchange unit is referred to hereinafter as an ERIX unit for the sake of brevity. Such units may comprise many ion removal and concentration channels in parallel and will be known to those skilled in the art. It has been found that using the method and apparatus according to the invention it is possible to effect continuous separation of anions and cations with a closed loop circulation system without any need for regenerating or periodically replacing the ion adsorbing materials. The efficiency of the method and apparatus will depend upon the nature of the ion adsorbing materials and of the ions to be captured, the concentration of the ions in the solution and other factors such as flow rates and electrical potentials but initial indications are that ion extraction rates of up to 98% per pass can be achieved. With such high extraction rates, the removal of acid anions such as F−as well as SO42−and NO3−will have a dramatic effect upon improving the service life of the equipment in the circulating system, such as pumps, meters, valves and baffles. The method of the invention is applicable to a wide variety of anionic species such as sulphate, sulphite, nitrate, nitrite, phosphate, phosphite and halides, that is to say fluoride, chloride, bromide and iodide as well as cationic species especially metals and more especially heavy metals. The invention does, however, have particular applicability to fluoride such as that generated as a by-product of the semi-conductor device manufacturing industry and which produces aqueous hydrofluoric acid as a result of reaction followed by dissolution in a gas scrubbing plant. The invention is most especially useful for aqueous solutions containing both fluoride and ammonium ions which have been difficult to separate in a satisfactory manner by more traditional techniques, as described above. In its preferred aspect, therefore, the invention permits the separation of ammonium and fluoride ions from aqueous solution using an electrically regenerating ion exchange (ERIX) system. By incorporating the ERIX unit into a recirculation loop, the concentrated fluoride solution can be passed through a calcium precipitation unit thereby capturing fluoride in solid form. The eluate from the precipitation unit can then be recycled to the ERIX unit in combination with additional waste water feed. In this manner, fluoride is safely and efficiently removed from the waste water as solid CaF2, ammonium ions are separated and discharged and purified water is obtained. In an especially preferred method, the amount of calcium admitted to the precipitation unit is significantly less than that required by stoichiometric considerations for capturing all of the fluoride ions in the concentrated stream discharged from the ERIX unit. In this way, the fluoride ion concentration in the effluent from the precipitation unit can be maintained at a level such that the concentration of calcium in that effluent is extremely low. This in turn helps to safeguard the ERIX unit which could rapidly become clogged, or at least severely contaminated, by solid calcium deposits derived from soluble calcium in the effluent. The calcium that is fed to the precipitation unit for the formation of CaF2 is preferably in soluble form but simple economic considerations may demand the use of calcium in an insoluble or sparingly soluble form. For example, calcium hydroxide slurries and calcium carbonate slurries may be used with advantage. However, a considerable quantity of water will be required to form such slurries and it may therefore be advantageous to use at least some of the treated water exiting the ERIX unit for this purpose. In this manner there is little or no necessity to introduce fresh water into the loop. In an alternative arrangement, fluoride-containing eluent from the precipitation unit may be recycled for the purpose of forming the calcium slurry. This alternative has the advantage of consuming some of the fluoride exiting the precipitation unit and thereby reducing the fluoride burden on the ERIX unit. BRIEF DESCRIPTION OF THE DRAWINGS The invention is described below in greater detail by way of example only with reference to the accompanying drawings, in which: FIG. 1 is a schematic representation of a closed loop circulation treatment apparatus according to the invention. FIG. 2 is a schematic representation of a preferred form of closed loop circulation treatment apparatus according to the invention. FIG. 3 is a schematic representation of a further form of closed loop circulation treatment apparatus according to the invention. FIG. 4 is a schematic representation of an example of an electrochemical cell which may be used in the apparatus shown in FIGS. 1, 2 and 3. DETAILED DESCRIPTION OF THE INVENTION Referring to the drawings, in FIG. 1 there is shown a schematic representation of apparatus according to the invention. An aqueous ion containing solution containing fluoride and ammonium ions is admitted into an ion adsorption unit 3 (ERIX unit) forming part of a closed loop circulation system 1, via line 2. Within the ERIX unit 3 (an example of which is described in detail by reference to FIG. 4 of the drawings) the aqueous solution is treated and separated to form a concentrated ammonium solution which is discharged through line 4, a concentrated fluoride solution which is discharged through line 6 and a depleted aqueous solution which is discharged through line 5. The line 6 containing the concentrated fluoride solution forms part of the closed loop circulation system 1 and leads to a circulation pump (not shown) for maintaining circulating flow within the loop. A separate line may be provided for make-up water, if required, although such make-up water can be admitted at almost any part of the loop system 1. Downstream of the pump there is a precipitation unit 9 containing a suitable source of calcium (preferably in soluble form) which reacts with the fluoride solution to form insoluble CaF2. Such precipitation units are well known to those skilled in the art and do not require detailed description here. Precipitated CaF2 is removed through line 7. The eluate from the precipitation unit 9 contains only 20 to 30 ppm F−and passes by way of line 8 to the line 2 through which fresh fluoride/ammonium solution enters the system. If desired, some of the fluoride containing eluate in line 8 may be admitted to the fluoride concentrate side of the ERIX unit 3 via line 10. A modified and preferred form of apparatus is represented schematically in FIG. 2. That apparatus is similar in most respects to that shown in FIG. 1 except that some of the water exiting the ERIX unit through line 5 is taken via a bleed line 11 to a mixing tank 12 where it is used to form the source of calcium as solution or slurry. That in turn is passed through line 13 to the precipitation unit 9. In this manner, the water balance of the system is more easily controlled and maintained. A still further modification of the apparatus is shown in FIG. 3. In this case, however, the calcium hydroxide is slurried not with water exiting the ERIX unit via line 5 but with recycled water from the calcium fluoride precipitation unit taken from line 8 through line 14. As noted above, this arrangement reduces the burden on the ERIX unit by reducing significantly the quantity of aqueous fluoride recycled through the ERIX unit. In fact, as shown in FIG. 3, the recycled aqueous fluoride can be cycled entirely past the back surface of the ion exchange material in the ERIX unit so that it is not subjected to the ion exchange process. Turning now to FIG. 4 of the drawings, there is shown an example of an electrochemical cell suitable for incorporation into the closed loop circulation systems shown in FIGS. 1 to 3. The electrochemical cell 30 shown in FIG. 4 comprises an electrode assembly 11 and an electrode assembly 31 spaced apart by a dividing section 32 which incorporates an inlet port 33 and an outlet port 35 for aqueous solution. The electrode assemblies 11 and 31 and dividing section 32 together define a solution compartment 37. The electrode assemblies are separated from the solution compartment by suitable ion permeable membranes, 12 and 13, that allow cations to move into a cathode compartment 34 and anions to move into an anode compartment 14. The anode compartment 14 contains an anode 20 and the cathode compartment 34 contains a cathode 39. Catholyte solution can be introduced and removed from the cathode compartment 34 through ports 15 and 16 and anolyte solution can be introduced and removed from the anode compartment 14 through ports 18 and 19. The solution compartment 37 is filled with suitable ion exchange material for the anions and cations to be adsorbed. The aqueous solution of fluoride and ammonium ions passes continuously through the compartment 37 via inlet 33 and outlet 35 and within the cell the ions are adsorbed onto the resin. An electrical potential between the electrodes 20 and 39 causes fluoride ions to be adsorbed on and to pass through the ion exchange layer to membrane 12 and through that membrane into the anode compartment 14, and ammonium ions to be adsorbed on and to pass through the ion exchange layer to membrane 13 and through that membrane into the cathode compartment 34, generating concentrated fluoride and ammonium solutions in the anode and cathode compartments, respectively. Aqueous solution depleted in fluoride ions and ammonium ions flows out of the cell through outlet port 35, In an example of the method of the invention, carried out using apparatus as shown in FIG. 2 of the drawings, a waste water feed of 10,000 litres per hour containing 500 ppm fluoride was passed into the ERIX unit which achieved a fluoride removal efficiency of 100%, i.e. the treated water exiting the ERIX unit was free of fluoride ions. 6,300 litres per hour of 1500 ppm calcium hydroxide liquor was passed to the precipitation unit which achieved 100% removal of precipitated solids. 6,300 litres per hour of fluoride containing liquor from the precipitation unit was recycled to the ERIX unit.

<SOH> BACKGROUND OF THE INVENTION <EOH>This invention relates to the treatment of toxic and/or environmentally hazardous or harmful materials and more especially to the treatment of aqueous solutions of hazardous waste arising from various chemical processes. The chemical processing industry in general generates vast quantities of by-products and waste materials many of which represent environmental hazards and which must be neutralised or destroyed as an essential part of their ultimate disposal. The oil and gas processing industries, for example, invest heavily in plant and equipment designed specifically to prevent or minimise the release of harmful largely organic materials into the environment. The microelectronics and semi-conductor device manufacturing industries, for example, make similar investments in order to scrub or otherwise treat exhaust gas streams containing generally inorganic materials from chemical processing units prior to the release of those exhaust gases into the atmosphere. Compounds containing heavy metals and halogen-, sulphur-, phosphorus- and nitrogen-containing compounds can be especially toxic and their removal is the subject of a considerable amount of technical research and of much environmental protection legislation. Many of the procedures utilised in the microelectronics and semi-conductor device manufacturing industries use fluorine-containing compounds. Unused fluorine-containing compounds and fluorine-containing products and by-products are generally discharged from the process or from a subsequent exhaust treatment, for example scrubbers and other adsorption systems, as an aqueous waste stream. This aqueous waste stream will generally contain fluorine in the form of HF. However, cationic species such as NH 4 + may also be present, in addition to fluoride in the form of bifiuoride ions, HF 2 − . Current practise in such manufacturing and disposal facilities involves treating the aqueous fluoride stream with magnesium or calcium salts in order to precipitate the sparingly soluble MgF 2 and CaF 2 , usually the latter. The solid material can then be compacted and dried for ease of transport for disposal or further use. However, the water stream will still have a fluoride content of some 20 to 30 ppm which continues to present a disposal problem with discharge limits of 3 ppm being more generally imposed. Further, some legislative areas prohibit the dilution of certain waste streams (for example, aqueous fluoride with an aqueous stream containing no fluoride) for disposal purposes and in other areas allowable discharge is based on the quantity of discharged species and not their concentrations. The safe disposal of hazardous and harmful materials therefore presents ever increasing problems. A further difficulty is that effluent from recently developed procedures which use a mixture of ammonium bifiuoride and HF cannot be accommodated in a calcium precipitation installation because CaF 2 will not form at pH below 12 and such high pH values favour the dissociation of ammonium species to produce ammonia gas. Additional facilities are then required to remove and separate NH 4 + and F − before they can be treated to form solid waste. This can be achieved using traditional ion exchange techniques but the plant will be large in that it will require separate beds for the two ion exchange species and duplex systems with further chemical feeds for their periodic regeneration. A recently developed system that is capable of removing both anionic and cationic species from aqueous solutions without requiring further chemical additives makes use of a technique known as electrochemical deionisation which involves ion exchange and electrolytic separation technologies. In this system cations or anions of interest are adsorbed from dilute aqueous solution onto an ion exchange medium, transported through that medium by an applied electric field and continuously eluted as a concentrated stream. Such a procedure is described in EP 0680932B. There are many examples within the existing literature of electrochemical cells that combine adsorption and ion separation and EP 0680932B illustrates one such ion removal/separation/concentration process. Other approaches will be known to those skilled in the art and can also be used. Such systems have been applied with some success on a continuous basis to minimise water consumption and to concentrate anions or cations for ease of subsequent handling in our copending Patent Application No. GB 0300793.7. That application demonstrates especially that fluoride ions can be concentrated and removed from a closed loop circulation system. Further work has now revealed that the techniques and procedures described in GB 0300793.7 may be applied successfully to the problems described above. In this respect the structure of the electrochemical deionisation cell described and illustrated in GB 0300793.7 has been modified to permit the simultaneous removal of both anions and cations.

<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>In accordance with the invention, there is now provided a method for the treatment of aqueous streams containing both anionic and cationic species, the method comprising the steps of: continuously circulating water through an essentially closed loop incorporating an ion adsorption unit comprising a water permeable layer of an ion adsorbing material; feeding to the essentially closed loop an aqueous solution containing the anionic and the cationic species; continuously passing the circulating water including the aqueous solution containing the an ionic and the cationic species through the ion adsorbing material in the ion adsorption unit while applying an electric potential across the thickness of the layer of ion adsorbing material and removing from the ion adsorption unit more concentrated aqueous solutions of the separate ionic species; continuously discharging from the ion adsorption unit the more concentrated aqueous solution of one ionic species; continuously discharging from the ion adsorption unit the aqueous solution depleted in anionic and cationic species; continuously passing the more concentrated solution of the other ionic species through a reaction unit in which the ionic species reacts to form a water-insoluble solid material; continuously recycling the eluate from the reaction unit to the ion adsorption unit; and, if necessary, adding to the closed loop a quantity of water corresponding to the quantity of aqueous solution removed from the closed loop with the solids in the reaction unit. In a separate aspect, the invention provides also apparatus for use in carrying out the method described above, the apparatus comprising: an essentially closed loop circulation system containing (i) an ion adsorption unit comprising a water permeable zone of an ion adsorbing material and means for enabling an electrical potential to be applied across the thickness of the ion adsorbing zone and (ii) a reaction unit in which one of the anionic and cationic species is rendered substantially insoluble; a pump for continuously circulating aqueous solution around the closed loop; an inlet for an aqueous solution containing anionic and cationic species to the closed loop circulation system; an outlet for concentrated aqueous solution of one ionic species from the ion adsorption unit; an outlet for depleted aqueous solution from the ion adsorption unit; an outlet for solid from the reaction unit; and an inlet for water into the closed loop circulation system. The ion adsorption unit employed as an essential aspect of the method and apparatus of the invention preferably incorporates both anion adsorbing and cation adsorbing capabilities in the unit. However, if necessary or desirable, it may be advantageous to use two separate ion adsorption units disposed in series one for anion adsorption and the other for cation adsorption. Still further, an ion adsorption unit having both anion adsorbing and cation adsorbing capabilities may be supplemented by a series-connected ion adsorption unit having only an anion adsorbing or a cation adsorbing capability. The precise arrangement will depend upon the relative concentrations of the anionic and cationic species in the aqueous solution fed to the ion adsorption units, the efficiency of the ion adsorption units in removing anions and/or cations of interest from the aqueous solution and the residual concentrations of the anions and the cations in the depleted aqueous solution having regard to any further treatment to which that solution may be subjected. In general terms, however, the skilled person will have no special difficulty in selecting the most appropriate combination of ion adsorption units and ion adsorbing materials for the particular situation and circumstances. The ion adsorbing materials serve to capture the ions of interest and are preferably ion exchange materials such as ion exchange resins in the form of particles or beads or other materials that can provide: a solution permeable medium; an ion adsorption medium (to remove the anions or cations); an ion conducting medium whereby the ions may be moved by the imposed electrical field into a separate solution. The particles or beads of the resins are preferably in a coherent form, that is to say they are not mobile or loose but are constrained in a predetermined configuration. For example, the particles of beads may be bound together with a binder or held between layers of a mesh or membrane so as to be permeable to the aqueous solution containing the ions, the mesh or membrane being permeable as appropriate for the removal and concentration of the ions of interest. The electrical potential which is applied across the thickness of the layer of ion adsorbing material serves to drive the captured ions through the ion adsorbing material towards one or other of the electrodes through which the potential is applied. The electrical potential may be generated from a pair of electrodes arranged to form an electrolysis cell or by any alternative arrangement, for example in the form of an electrophoresis cell. It will be understood that the ion adsorption unit consisting of ion exchange material is, in operation, self-regenerating in that it effectively transports the captured cations and/or anions through its bulk for discharge as a concentrated aqueous solution, and will regenerate to its hydrogen or hydroxide form when no other cationic or anionic species is present. Such an electrically regenerating ion exchange unit is referred to hereinafter as an ERIX unit for the sake of brevity. Such units may comprise many ion removal and concentration channels in parallel and will be known to those skilled in the art. It has been found that using the method and apparatus according to the invention it is possible to effect continuous separation of anions and cations with a closed loop circulation system without any need for regenerating or periodically replacing the ion adsorbing materials. The efficiency of the method and apparatus will depend upon the nature of the ion adsorbing materials and of the ions to be captured, the concentration of the ions in the solution and other factors such as flow rates and electrical potentials but initial indications are that ion extraction rates of up to 98% per pass can be achieved. With such high extraction rates, the removal of acid anions such as F − as well as SO 4 2− and NO 3 − will have a dramatic effect upon improving the service life of the equipment in the circulating system, such as pumps, meters, valves and baffles. The method of the invention is applicable to a wide variety of anionic species such as sulphate, sulphite, nitrate, nitrite, phosphate, phosphite and halides, that is to say fluoride, chloride, bromide and iodide as well as cationic species especially metals and more especially heavy metals. The invention does, however, have particular applicability to fluoride such as that generated as a by-product of the semi-conductor device manufacturing industry and which produces aqueous hydrofluoric acid as a result of reaction followed by dissolution in a gas scrubbing plant. The invention is most especially useful for aqueous solutions containing both fluoride and ammonium ions which have been difficult to separate in a satisfactory manner by more traditional techniques, as described above. In its preferred aspect, therefore, the invention permits the separation of ammonium and fluoride ions from aqueous solution using an electrically regenerating ion exchange (ERIX) system. By incorporating the ERIX unit into a recirculation loop, the concentrated fluoride solution can be passed through a calcium precipitation unit thereby capturing fluoride in solid form. The eluate from the precipitation unit can then be recycled to the ERIX unit in combination with additional waste water feed. In this manner, fluoride is safely and efficiently removed from the waste water as solid CaF 2 , ammonium ions are separated and discharged and purified water is obtained. In an especially preferred method, the amount of calcium admitted to the precipitation unit is significantly less than that required by stoichiometric considerations for capturing all of the fluoride ions in the concentrated stream discharged from the ERIX unit. In this way, the fluoride ion concentration in the effluent from the precipitation unit can be maintained at a level such that the concentration of calcium in that effluent is extremely low. This in turn helps to safeguard the ERIX unit which could rapidly become clogged, or at least severely contaminated, by solid calcium deposits derived from soluble calcium in the effluent. The calcium that is fed to the precipitation unit for the formation of CaF 2 is preferably in soluble form but simple economic considerations may demand the use of calcium in an insoluble or sparingly soluble form. For example, calcium hydroxide slurries and calcium carbonate slurries may be used with advantage. However, a considerable quantity of water will be required to form such slurries and it may therefore be advantageous to use at least some of the treated water exiting the ERIX unit for this purpose. In this manner there is little or no necessity to introduce fresh water into the loop. In an alternative arrangement, fluoride-containing eluent from the precipitation unit may be recycled for the purpose of forming the calcium slurry. This alternative has the advantage of consuming some of the fluoride exiting the precipitation unit and thereby reducing the fluoride burden on the ERIX unit.

20070518

20120821

20071025

71990.0

C02F142

RAPHAEL, COLLEEN M

TREATMENT OF AQUEOUS CHEMICAL WASTE

UNDISCOUNTED

ACCEPTED

C02F

ACCEPTED

Use of eukaryotic genes affecting cell cycle control or cell cycle progression for diagnosis and treatment of proliferative diseases

The present invention relates to the significant functional role of several C. elegans genes and of their corresponding gene products in cell cycle progression during cell division that could be identified by means of RNA-mediated interference (RNAi) and to the identification and isolation of functional orthologs of said genes including all biologically functional derivatives thereof. The invention further relates to the use of said genes and gene products (including said orthologs) in the development or isolation of anti-proliferative agents, particularly their use in appropriate screening assays, and their use for diagnosis and treatment of proliferative and other diseases. In particular, the invention relates to the use of small interfering RNAs derived from said genes for the treatment of proliferative diseases.

1-25. (canceled) 26. A method for inhibiting cell cycle progression, comprising administering to a patient in need thereof an effective amount of a molecule selected from the group consisting of: (1) an isolated nucleic acid molecule comprising a nucleic acid molecule with a sequence selected from the group of sequences consisting of: (a) the nucleic acid sequences presented in SEQ ID NOs. 5, 7, 9, 11, 13, 1, 3; (b) nucleic acid sequences encoding polypeptides that exhibit a sequence identity with the protein encoded by a nucleic acid according to (1)(a) of at least 25% over 100 residues and/or which are detectable in a computer aided search using the BLAST sequence analysis programs with an e-value of at most 10−5, (c) sequences of nucleic acid molecules which are capable of hybridizing with the nucleic acid molecules with sequences corresponding to (1)(a) or (b) under conditions of medium or high stringency, (d) the antisense-sequence of any of the sequences as defined in (1)(a), (b) or (c), (e) fragments of (1)(a), (b), (c) or (d), and (f) double-stranded RNA or single-stranded RNA in the antisense or sense direction corresponding to any of the sequences as defined in (1)(a), (b), (c), (d), or (e), (2) an isolated peptide or polypeptide comprising a peptide or polypeptide with a sequence selected from the group consisting of: (a) a sequence as disclosed in SEQ ID NOs. 6, 8, 10, 12, 14, 2, 4; (b) a sequence that exhibits a sequence identity with any of the sequences according to (2)(a) of at least 25% over 100 residues, and (c) fragments of the sequences defined in (2)(a) or (b), and (3) an antibody which is directed against at least one peptide or polypeptide with a sequence as defined in (2)(a) to (c) above. 27. The method according to claim 26, wherein the isolated nucleic acid molecule comprises small interfering RNA with a sequence corresponding to any of the sequences according to claim 26 or wherein the nucleic acid molecule is contained in at least one nucleic acid expression vector which is capable of producing a double-stranded RNA-molecule comprising a sense-RNA-strand and an antisense-RNA-strand under suitable conditions, wherein each RNA-strand, independently from the other, has a length of 19 to 31 nucleotides or wherein the nucleic acid molecule is contained in at least one nucleic acid expression vector comprising a first expression cassette containing the nucleic acid corresponding to the sense-RNA-strand under the control of a first promoter and a second expression cassette containing the nucleic acid corresponding to the antisense-RNA-strand under the control of a second promoter, or wherein the nucleic acid molecule is contained in at least one nucleic acid expression vector comprising an expression cassette containing the nucleic acid corresponding to the sense-RNA-strand and the antisense-RNA-strand under the control of a promoter leading to a single-stranded RNA-molecule and wherein the single-stranded RNA-molecule is capable of forming a back-folded stem-loop-structure. 28. The method according to claim 27, wherein each RNA-strand, independently from the other, has a length of 20 to 25 nucleotides. 29. The method according to claim 27, wherein each RNA-strand, independently from the other, has a length of 26 to 28 nucleotides. 30. The method according to claim 26, wherein the method is for the treatment of a proliferative disease. 31. The method according to claim 30, wherein the disease is coronary restenosis or a neoplastic disease. 32. The method according to claim 31, wherein the neoplastic disease is selected from the group consisting of lymphoma, lung cancer, colon cancer, ovarian cancer and breast cancer 33. A method for the activation of cell cycle progression, comprising administering to a patient in need thereof an effective amount of a molecule selected from the group consisting of: (1) an isolated nucleic acid molecule comprising a nucleic acid with a sequence selected from the group of sequences consisting of: (a) the nucleic acid sequences presented in SEQ ID NOs. 5, 7, 9, 11, 13, 1, 3; (b) nucleic acid sequences encoding polypeptides that exhibit a sequence identity with the protein encoded by a nucleic acid according to (1)(a) of at least 25% over 100 residues and/or which are detectable in a computer aided search using the BLAST sequence analysis programs with an e-value of at most 10−5, (c) sequences of nucleic acid molecules which are capable of hybridizing with the nucleic acid molecules with sequences corresponding to (1)(a) or (b) under conditions of medium or high stringency, (d) the antisense-sequence of any of the sequences as defined in (1)(a), (b) or (c), (e) fragments of (1)(a), (b), (c) or (d), and (f) RNA sequences corresponding to any of the sequences as defined in (1)(a), (b), (c), (d), or (e), (2) an isolated peptide or polypeptide comprising a peptide or polypeptide with a sequence selected from the group consisting of: (a) a sequence as disclosed in SEQ ID NOs. 6, 8, 10, 12, 14, 2, 4; (b) a sequence that exhibits a sequence identity with any of the sequences according to (2)(a) of at least 25% over 100 residues, and (c) fragments of the sequences defined in (2)(a) or (b), and (3) an antibody which is directed against at least one peptide or polypeptide with a sequence as defined in claim (2)(a) to (c) above. 34. The method according to claim 33, wherein the method is for the treatment of a disease characterized by increased apoptosis, growth retardation, or slowed wound healing. 35. A method for the in vitro diagnosis of a proliferative disease or a disease associated with abnormal cell cycle progression, wherein the method comprises obtaining a sample tissue or cells thereof, and determining the amount of the nucleic acid molecule or of the protein or peptide as defined in claim 26 in the sample tissue or cells. 36. The method according to claim 35, wherein the disease is coronary restenosis or a neoplastic disease. 37. The method according to claim 36, wherein the neoplastic disease is selected from the group consisting of lymphoma, lung cancer, colon cancer, ovarian cancer and breast cancer. 38. A method for the identification and characterization of drugs that inhibit or activate cell cycle progression, wherein the method comprises using the molecule as defined in claim 26 in a screening assay for the identification of said drug, and analyzing the cell cycle progression.

The present invention relates to the use of agents interfering with cell cycle control or cell cycle progression for the treatment of diseases, especially proliferative diseases. Metazoan cell division (mitosis) consists of an extremely complex, highly regulated set of cellular processes which must be tightly co-ordinated, perfectly timed, and closely monitored in order to ensure the correct delivery of cellular materials to daughter cells. Defects in these processes are known to cause a wide range of so-called proliferative diseases, including all forms of cancer. Since cell division represents one of the few, if not the only cellular process that is common to the aetiology of all forms of cancer, its specific inhibition has long been recognised as a preferred site of therapeutic intervention. Although mitotic inhibitor drugs are recognised as one of the most promising classes of chemotherapeutic agents, screening attempts to find new drug candidates in this class have been undermined by the strong inherent tendency of such screens to identify agents that target a single protein, tubulin. Tubulin polymerises to form microtubules, the primary cytoskeletal elements needed for mitotic spindle function and chromosome segregation. Microtubules as such, however, are ubiquitously needed in almost all cell types, whether dividing or not, a fact which therefore explains many of the unwanted side effects caused by anti-tubulin drugs. Perhaps the best known example of a highly successful anti-neoplastic drug that targets tubulin is paclitaxel, and its marketed derivative, Taxol. Its applicability has indeed been seriously limited by difficulties in determining an adequate dosing regimen due to a range of problematic side effects. Taxol treatment has resulted in anaphylaxis and severe hypersensitivity reactions characterised by dyspnea and hypotension requiring treatment, angioedema, and generalised urticaria in 2-4% of patients in clinical trials. Although Taxol is administered after pretreatment with corticosteroids, fatal reactions have occurred. Severe conductance abnormalities resulting in life-threatening cardiac arrhythmia occur in less than 1 percent of patients and must be treated by insertion of a pacemaker. Taxol can cause fetal harm or fetal death in pregnant women. Furthermore, administration is commonly accompanied by tachycardia, hypotension, flushing, skin reactions and shortness-of-breath (mild dyspnea). Reasons for these strong side-effects may be that since tubulin does not only play an essential role in spindle formation, but also plays significant roles in other cellular processes like for instance cytoskeleton generation and intracellular protein transport Consequently, although Taxol has been hailed by many as the most successful new anti-cancer therapeutic of the last three decades, there is still a need for anti-cancer drugs that do not show the disadvantages of Taxol. Therefore, the problem underlying the present invention resides in providing improved potent anti-cancer drugs, particularly with less severe side effects. The problem is solved by the use of an isolated nucleic acid molecule comprising a sequence selected from the group of sequences consisting of: a) the nucleic acid sequences presented in SEQ ID NO. 5, 7, 9, 11, 13, 1, 3; b) nucleic acid sequences encoding polypeptides that exhibit a sequence identity with the protein encoded by a nucleic acid according to a) of at least 25% over 100 residues and/or which are detectable in a computer aided search using the BLAST sequence analysis programs with an e-value of at most 10−5, c) sequences of nucleic acid molecules which are capable of hybridizing with the nucleic acid molecules with sequences corresponding to (a) or (b) under conditions of medium or high stringency, d) the antisense-sequence of any of the sequences as defined in (a), (b) or (c), e) fragments of (a), (b), (c) or (d), f) double-stranded RNA or single-stranded RNA in the antisense or sense direction corresponding to any of the sequences as defined in (a), (b), (c), (d), or (e) for the manufacture of a medicament for the inhibition of cell cycle progression. The present invention is based on the concept to provide agents interfering with cell cycle progression. Cell cycle progression is an essential part of cell division. Since cell cycle progression—in contrast to microtubule formation—is a cell division-specific process, the inhibition of target proteins involved in cell cycle progression results in an efficient impairment of mitosis as well as in a reduced number of side effects caused by the inhibition of other significant cellular processes. The present invention discloses for the first time for a variety of proteins and genes that they are involved in cell cycle progression. Although cell division and cell cycle progression have already been thoroughly studied, the present invention provides several classes of target genes, corresponding gene products and other agents that had previously not been implicated in cell division, particularly not in cell cycle progression. The newly identified function of these target genes and their corresponding gene products, any homologs, orthologs and derivatives thereof enables their use in the development of a wide range of medicaments against proliferative diseases including cancer. These medicaments could be used in treatment of proliferative diseases, particularly in those cases where the disorder relates to cell division, regulation of cell division, or is dependent on cell cycle control or cell cycle progression. Furthermore, the newly identified function enables the use in diagnosis and the development of diagnostic agents. For the identification of target genes being involved in cell cycle control or cell cycle progression, a large-scale RNAi technique-based screen was performed for 19514 (that means 99.7%) of the predicted open reading frames in the C. elegans genome. For the performance of this large-scale screen double-stranded RNA corresponding to the individual open reading frames was produced and micro-injected into adult C. elegans hermaphrodites, and the resulting embryos were analysed 24 hours later using time-lapse DIC microscopy. The nematode C. elegans exhibits an almost entirely translucent body throughout its development, thereby offering unparalleled microscopic access for exquisitely detailed cytological documentation, even for the earliest steps of embryogenesis. This important feature, along with its short life cycle (3-5 days), its ease of cultivation, and its low maintenance costs, has helped make C. elegans arguably the best studied of all metazoans. Also, sequence data are now available for over 97% of the C. elegans genome (C. elegans Sequencing Consortium. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282, 2012-2018 (1998)). Thus, C. elegans is an ideal organism for applying the new technique of RNA-mediated interference (RNAi). This technique consists in the targeted, sequence-specific inhibition of gene expression, as mediated by the introduction into an adult worm of double-stranded RNA (dsRNA) molecules corresponding to portions of the coding sequences of interest (Fire et al., Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806-811 (1998)). For the vast majority of C. elegans genes tested to date, this has been shown to yield a sequence-specific inhibition of the targeted gene's expression, accompanied by clearly detectable loss of function phenotypes in the treated worm's F1 progeny (and even in some cases, in the treated worm itself). In the context of the present invention, a screening assay in C. elegans based on ‘genomic RNA mediated interference (RNAi)’ combined with a highly probative microscopic assay for documenting the first rounds of embryonic cell division was used (Sulston et al., The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev. Biol. 100, 64-119 (1983); Gönczy et al., Dissection of cell division processes in the one cell stage Caenorhabditis elegans embryo by mutational analysis. J Cell Biol 144, 927-946 (1999)). With this combination of techniques a selected gene and also a variety of selected genes can be functionally characterized with unprecedented speed and efficiency. The DIC microscopy generated movies were analyzed to identify those samples whereby cell division was altered or disrupted. In order to perform the analysis in a robust, consistent and reproducible fashion, each movie was analyzed with regard to 47 different parameters. In other words, 47 features of normal cell division (i.e. cell division in wild type worms) were scored for every RNAi phenotype generated by the genome-wide application of RNAi across the entire C. elegans genome. A powerful confirmation and validation of the DIC assay, and the depth of information that the assays yield, was that equivalent phenotypes were found to represent closely related proteins, proteins within the same family or functionally equivalent proteins. In other words, if the RNAi-induced phenotypes of two separately analyzed genes are the same, it is very likely that the two proteins are either within the same protein class or share a similar function or at the very least, are both involved in the same biological mechanism or process. Therefore, the screen can be used to class or group proteins according to their function. Consequently, any genes that give rise to similar RNAi phenotypes are related and are justified to be considered within single functional classes. “Nucleic acids” according to the present invention comprises all known nucleic acids such as DNA, RNA, peptide nucleic acids, morpholinos, and nucleic acids with backbone structures other than phosphodiesters, such as phosphothiates or phosphoramidates. “inhibition of cell cycle progression” according to the present invention includes halting or arresting as well as retarding or slowing down of cell cycle progression. Particularly, “inhibition of cell cycle progression” relates to an arrest, retardation or slowing down of cell cycle progression at an early stage, preferably before nuclear division and particularly before division of the cytoplasm (cytokinesis). In a preferred embodiment of the invention, the nucleic acid molecule comprises a nucleic acid molecule with a sequence selected from the group of sequences as presented in SEQ ID NO. 5, 7, 9, 11, 13, 1, 3. Preferably, the nucleic acid molecule consists of a nucleic acid molecule with a sequence selected from said group of sequences. The term “comprise” preferably refers to nucleic acids in which the nucleic acids with the described sequences are functionally relevant, e.g. for diagnostic use or therapeutic use, such as vectors for therapeutical use or expression of corresponding RNAs or proteins. Preferably, any additional nucleic acids upstream or downstream of the sequence are not longer than 20 kb. More preferred, the term “comprise” does not relate to large constructs accidentally including the sequence, such as genomic BAC or YAC clones. In detail, the individual SEQ ID No. denotes the following sequences: SEQ ID NO. 1 the nucleotide sequence of the C. elegans gene F59E12.11 (Wormbase accession No. CE28570) SEQ ID NO. 2 the deduced amino acid sequence of the C. elegans gene F59E12.11 (accession No. CE28570) SEQ ID NO.3 the nucleotide sequence of the human ortholog of F59E12.11 (GenBank accession No. NM—058169) SEQ ID NO. 4 the deduced amino acid sequence of the human ortholog of F59E12.11 (GenBank accession No. NP—477517) SEQ ID NO. 5 the nucleotide sequence of the C. elegans gene Y71H2B.3 (Wormbase accession No. CE24630) SEQ ID NO. 6 the deduced amino acid sequence of the C. elegans gene Y71H2B.3 (Wormbase accession No. CE24630) SEQ ID NO. 7 the nucleotide sequence of the human ortholog of Y71H2B.3 (GenBank accession No. NM—001551) SEQ ID NO. 8 the deduced amino acid sequence of the human ortholog of Y71H2B.3 (GenBank accession No. NP—001542) SEQ ID NO. 9 the nucleotide sequence of the rat ortholog of Y71H2B.3 (GenBank accession No. NM—031624) SEQ ID NO. 10 the deduced amino acid sequence of the rat ortholog of Y71H2B.3 (GenBank accession No. AAD05364 or NP—113812) SEQ ID NO. 11 the nucleotide sequence of the Drosophila ortholog of Y71H2B.3 (GenBank accession No. AAF003639) SEQ ID NO. 12 the deduced amino acid sequence of the Drosophila ortholog of Y71H2B.3 (GenBank accession No. AAF53289) SEQ ID NO. 13 the nucleotide sequence of the yeast ortholog of Y71H2B.3 (GenBank accession No. NC—001145, base pairs 327481 to 328581) SEQ ID NO. 14 the deduced amino acid sequence of the yeast ortholog of Y71H2B.3 (GenBank accession No. NP—013741) Unless otherwise specified, the manipulations of nucleic acids and polypeptides/-proteins can be performed using standard methods of molecular biology and immunology (see, e.g. Maniatis et al. (1989), Molecular cloning: A laboratory manual, Cold Spring Harbor Lab., Cold Spring Harbor, N.Y.; Ausubel, F. M. et al. (eds.) “Current protocols in Molecular Biology”. John Wiley and Sons, 1995; Tijssen, P., Practice and Theory of Enzyme Immunoassays, Elsevier Press, Amsterdam, Oxford, N.Y., 1985). The present invention describes genes identified as having essential functions in cell division in the model organism C. elegans. The basis for performing research in model organisms is that the newly discovered functions for the genes in C. elegans will be conserved in other species including humans. Cell division as well as cell cycle control and progression are highly conserved during evolution and therefore the approach of discovering a gene function in C. elegans and using the information to characterise or assign functions for human homologs or orthologs is well justified. One theme of conservation is that the gene function can be conserved with substantial divergence of sequence. In the present invention this theme of conservation is not defined. However, if other genes are discovered to have functions that result in the gene product being identified as the same gene product as those claimed in the present invention then the present claims also apply to such genes. However, the most frequent theme of conservation of genes during evolution is that the gene sequence is conserved. This theme of conservation is particularly frequent for genes involved in highly conserved processes such as cell division. This means that the DNA nucleotide sequence or the protein coding sequence of the gene are very similar in different species, which in turn suggests that the function of the gene is the same in the different species. Therefore, in a further preferred embodiment, the nucleic acid molecule has a sequence that encodes a polypeptide exhibiting a sequence identity with a protein encoded by SEQ ID NO. 5, 7, 9, 11, 13, 1, 3 of at least 25% over 100 residues, preferably of at least 30% over 100 residues, more preferably of at least 50% over 100 residues, particularly of at least 70% over 100 residues on amino acid level. These very high sequence similarities are usually shown by polypeptides which are orthologs or homologs of the above sequences. A homolog is a protein with similar sequence from the same or another species (an homolog's sequence similarity originates from a speciation event or from a gene duplication, i.e. a homolog is a related protein in any species or the same protein in another species). A subgroup of homologs are defined as orthologs. An ortholog is essentially the same protein as the one it is compared to, but it is derived from another species (an ortholog's sequence similarity originates from a speciation event rather than a gene duplication). It is known to a person skilled in the art, that in a conserved process such as cell division, homologous and orthologous proteins, particularly orthologous proteins, are very likely to serve the same biological function. In the present case, the most relevant biological function is the involvement in, particularly the requirement for, cell cycle control or progression. Advantageously, it could already be shown that human orthologs of the C. elegans genes identified in the context of this invention are required for proliferation, cell survival and mitosis (see Example 6). This finding indicates that the human orthologs are required for cell cycle control or progression and can be used in the context of diagnosis and treatment of proliferative diseases. The person skilled in the art is familiar with different methods and criteria to identify homologs and orthologs. In the context of the present invention, homologs and orthologs were identified based on sequence similarity according to the procedure described in Example 1. The nucleic acid molecule may also comprise a sequence that is detectable in a computer aided database search/alignment with an e-value of at most 10−5, preferably with an e-value of at most 10−12, particularly with an e-value of at most 10−20 or fragments thereof whereby the database sequences are compared to the sequences as defined under a). The nucleic acid molecule may also comprise a sequence that is considered an ortholog according to the criteria of the present invention (see Example 1). Generally, the grade of sequence identity can be calculated by any software program that is capable to perform protein sequence alignments known in the art. Hereby it is also included that identical amino acid regions are interrupted by gaps that can be variable in their length. For this kind of analysis or alignments the “BLAST sequence analysis programs” are particularly preferred. The “BLAST sequence analysis programs” which may be used for sequence analysis are publically available and known to anyone skilled in the art. Known analysis programs for sequence alignments, particularly the “BLAST sequence analysis programs”, calculate so called “e-values” to characterize the grade of homology between the compared sequences. Generally, a small e-value characterizes a high sequence similarity, whereas larger e-values characterize lower sequence similarity. The degree of similarity required for the sequence variant will depend upon the intended use of the sequence. It is well within the capability of a person skilled in the art to effect mutational, insertional and deletional mutations which are designed to improve the function of the sequence or otherwise provide a methodological advantage. The aforementioned grades of sequence identities with proteins encoded by the above SEQ IDs are characteristic for such polypeptides that are strongly homologous to the above sequences, in particular for polypeptides that are “orthologous” or “homologous” to the polypeptides of a). Table 1 shows the e-values that have been calculated for the alignments on amino acid level with homologs and orthologs of the corresponding C. elegans gene. Hereby, e-values lower than 10−5 on amino acid level characterize homologs of the corresponding C. elegans genes. If the C. elegans gene is itself a reciprocal hit of the identified homolog with an e-value of less than 10−5, then the homolog is identified as an ortholog (see also Example 1). TABLE 1 Sequence similarities between the C. elegans genes F59E12.11, Y71H2B.3 and their human, rat, Drosophila, and yeast homologs and orthologs. C. elegans gene e-value for the alignment with the C. elegans gene on amino acid level F59E12.11 Human ortholog 1 * 10−7 Y71H2B.3 Human ortholog 1 * 10−39 Rat ortholog 2 * 10−31 Drosoph. ortholog 1 * 10−21 Yeast ortholog 3 * 10−13 According to a further preferred embodiment, the nucleic acid molecule comprises a nucleotide sequence which is capable of hybridizing with the nucleic acid sequences of (a) or (b) under conditions of medium/high stringency. In such hybrids, duplex formation and stability depend on substantial complementarity between the two strands of the hybrid and a certain degree of mismatch can be tolerated. Therefore, the nucleic acid molecules and probes of the present invention may include mutations (both single and multiple), deletions, insertions of the above identified sequences, and combinations thereof as long as said sequence variants still have substantial sequence similarity to the original sequence which permits the formation of stable hybrids with the target nucleotide sequence of interest. Suitable experimental conditions for determining whether a given DNA or RNA sequence “hybridizes” to a specified polynucleotide or oligonucleotide probe involve presoaking of the filter containing the DNA or RNA to examine for hybridization in 5×SSC (sodium chloride/sodium citrate) buffer for 10 minutes, and prehybridization of the filter in a solution of 5×SSC, 5× Denhardt's solution, 0.5% SDS and 100 mg/ml of denaturated sonicated salmon sperm DNA (Maniatis et al., 1989), followed by hybridization in the same solution containing a concentration of 10 ng/ml of a random primed (Feinberg, A. P. and Vogelstein, B. (1983), Anal. Biochem. 132:6-13), 32P-dCTP-labeled (specific activity>1×109 cpm/μg) probe for 12 hours at approximately 45° C. The filter is then washed twice for 30 minutes in 2×SSC, 0.5% SDS at at least 55° C. (low stringency), at least 60° C. (medium stringency), preferably at least 65° C. (medium/high stringency), more preferably at least 70° C. (high stringency) or most preferably at least 75° C. (very high stringency). Molecules to which the probe hybridizes under the chosen conditions are detected using an x-ray film or a “phosphor imager”. According to a further preferred embodiment, the nucleic acid molecules may also have the antisense-sequence of any of the sequences as defined in (a), (b) or (c). According to a further preferred embodiment, fragments of the nucleic acid molecules as described above may be used. The term “fragment” as used according to the present invention can have different meanings depending on the molecule and purpose referred to. A person skilled in the art knows how to choose appropriate fragments for the relevant purpose. Preferably, a fragment should be specific for the sequence it is derived from. The meaning of the term “specific” is known in the art. Preferably, specific in this context means that in a BLAST search performed with the sequence fragment, the original sequence (from which the fragment is derived) would be identified with a lower e-value than all other sequences relevant in the context of the current use (e.g. all other sequences of nucleic acids present in the investigated sample). More preferably, the original sequence should be identified with the lowest e-value compared to all other sequences identified. Alternatively, “specific” means that, under the applied conditions, the fragment binds only to the nucleic acid molecule it is derived from. The criterion of specificity is usually achieved by fragments larger than 15 nucleotides, preferably larger than 19 nucleotides. Preferably, the fragments are chosen from sequence regions of high complexity. Low complexity regions can be identified by database searches or low complexity filters available in standard sequence analysis programs. “Biologically active” fragments or derivatives can be generated by a person skilled in the art. Hereby, the fragments or derivatives should have a similar “biological function” as the nucleic acid they are derived from. According to the present invention the most relevant biological function is the involvement in, inhibition of; activation of, or requirement for cell cycle control, particularly for cell cycle progression The isolated nucleic acid molecules defined as under (a) to (e) may be used for influencing cell division and/or cell proliferation, particularly by inhibiting cell cycle progression, either in vitro or in vivo. Inhibition of cell cycle progression using said nucleic acid molecules can be achieved by different ways familiar to the person skilled in the art. For example, the isolated nucleic acid molecules may be inserted downstream of a strong promotor to overexpress the corresponding protein or polypeptide. Overexpression of the protein or polypeptide may lead to suppression of the endogenous protein's biological function. By introducing deletions or other mutations into the nucleic acids, or by using suitable fragments, it is possible to generate sequences encoding dominant-negative peptides or polypeptides. Such dominant-negative peptides or polypeptides can inhibit the function of the corresponding endogenous protein. Certain nucleic acids can be used to inhibit expression (transcription and/or translation) of the endogenous genes to inhibit cell cycle progression. E.g. peptide nucleic acids comprising sequences as identified above can suppress expression of the corresponding endogenous gene by forming DNA triplex structures with the gene. Other nucleic acids, such as antisense morpholino oligonucleotides or ribozymes, can be used to interfere with RNA transcribed from the endogenous gene. The application of automated gene synthesis provides an opportunity for generating sequence variants of the naturally occurring genes. It will be appreciated that polynucleotides coding for synthetic variants of the corresponding amino acid sequences can be generated which, for example, will result in one or more amino acids substitutions, deletions or additions. Also, nucleic acid molecules comprising one or more synthetic nucleotide derivatives (including morpholinos) which provide said nucleotide sequence with a desired feature, e.g. a reactive or detectable group, can be prepared. Synthetic derivatives with desirable properties may also be included in the corresponding polypeptides. All such derivatives and fragments of the above identified genes and gene products showing at least part of the biological activity or biological function of the naturally occurring sequences or which are still suitable to be used, for example, as probes for, e.g. identification of homologous genes or gene products, are included within the scope of the present invention. Also included are such derivatives and fragments whose activity or function is counteracting to the biological activity or biological function of the naturally occurring sequences, e.g. derivatives and fragments that encode dominant-negative molecules. Having herein provided the nucleotide sequences of various genes functionally involved in cell cycle control, particularly cell cycle progression, it will be appreciated that automated techniques of gene synthesis and/or amplification may be used to isolate said nucleic acid molecules in vitro. Because of the length of some coding sequences, application of automated synthesis may require staged gene construction, in which regions of the gene up to about 300 nucleotides in length are synthesized individually and then ligated in correct succession for final assembly. Individually sythesized gene regions can be amplified prior to assembly, using polymerase chain reaction (PCR) technology. The technique of PCR amplification may also be used to directly generate all or part of the final genes/nucleic acid molecules. In this case, primers are synthesized which will be able to prime the PCR amplification of the final product, either in one piece or in several pieces that may be ligated together. For this purpose, either cDNA or genomic DNA may be used as the template for the PCR amplification. The cDNA template may be derived from commercially available or self-constructed cDNA libraries. According to a further preferred embodiment, the invention relates to the use of the above identified nucleic acid molecules or fragments thereof in form of RNA, particularly antisense RNA and double-stranded RNA, for the manufacture of a medicament for the inhibition of cell cycle progression. Also ribozymes can be generated for the above identified sequences and used to degrade RNA transcribed from the corresponding endogenous genes. As stated above, double-stranded RNA oligonucleotides effect silencing of the expression of gene(s) which are highly homologous to either of the RNA strands in the duplex. Recent discoveries had revealed that this effect, called RNA interference (RNAi), that had been originally discovered in C. elegans, can also be observed in mammalian, particularly in human cells. Thus, inhibition of a specific gene function by RNA interference can also be performed in mammalian cells, particularly also in human cells. As shown in FIG. 1, the inhibition of a nucleic acid molecule as defined under (a) to (f) by RNAi in C. elegans inhibits cell division by impairing cell cycle progression. Particularly preferred is the use of these RNA molecules in a therapeutical application of the RNAi technique, particularly in humans or in human cells. An RNAi technique particularly suited for mammalian cells makes use of double-stranded RNA oligonucleotides known as “small interfering RNA” (siRNA). Therefore, according to a further preferred embodiment, the invention relates to the use of nucleic molecules comprising small interfering RNA with a sequence corresponding to any of the sequences identified above. These siRNA molecules can be used for the therapeutical silencing of the expression of the genes of the invention comprising nucleic acid sequences as defined under (a) to (f), in mammalian cells, particularly in human cells, particularly for the therapy of a proliferative disease. The inhibition of a specific target gene in mammals is achieved by the introduction of an siRNA-molecule having a sequence that is specific (see above) for the target gene into the mammalian cell. The siRNAs comprise a first and a second RNA strand, both hybridized to each other, wherein the sequence of the first RNA strand is a fragment of one of the sequences as defined in a) to f) and wherein the sequence of the second RNA strand is the antisense-strand of the first RNA strand. The siRNA-molecules may possess a characteristic 2- or 3-nucleotide 3′-overhanging sequence. Each strand of the siRNA molecule preferably has a length of 19 to 31 nucleotides. The siRNAs can be introduced into the mammalian cell by any suitable known method of cell transfection, particularly lipofection, electroporation or microinjection. The RNA oligonucleotides can be generated and hybridized to each other in vitro or in vivo according to any of the known RNA synthesis methods. The possibility to inhibit gene expression of disease-associated genes also in mammalian cells and in particular in human cells, make siRNAs or vector systems capable of producing siRNAs, having the sequence of those disease-associated genes, an interesting therapeutical agent for pharmaceutical compositions. Particularly siRNAs having sequences as defined in the present invention or that are homologous or orthologous to one of those genes can be used for the manufacture of medicaments for the inhibition of cell cycle progression and for the therapy of diseases, particularly proliferative diseases. Similarly, nucleic acid vectors capable of producing those siRNAs can be used for the manufacture of such medicaments. In another embodiment, the invention relates to the use of a nucleic acid molecule as defined above, wherein the nucleic acid molecule is contained in at least one nucleic acid expression vector which is capable of producing a double-stranded RNA-molecule comprising a sense-RNA-stand and an antisense-RNA-strand under suitable conditions, wherein each RNA-strand, independently from the other, has a length of 19 to 31 nucleotides. In this alternative method (also described in Tuschl, Nature Biotechnology, Vol. 20, pp. 446-448), vector systems capable of producing siRNAs instead of the siRNAs themselves are introduced into the mammalian cell for downregulating gene expression. The preferred lengths of the RNA-strands produced by such vectors correspond to those preferred for siRNAs in general (see below). “Suitable conditions” for the production of the above double-stranded RNA-molecule are all in vivo or in vitro conditions that according to the state of art allow the expression of a first and a second RNA-strand with the above sequences and lengths that—when hybridized—form a double-stranded RNA-molecule. Particularly preferred “suitable conditions” for the production of the above double-stranded RNA-molecule are the “in vivo conditions” in a living human or animal cell or the “in vitro conditions” in cultured human or animal cells. The “nucleic acid expression vector” may be an extrachromosomal entity, the replication of which is independent of chromosomal replication, e.g. a plasmid. Alternatively, the vector may be one which, when introduced into a host cell, particularly into a mammalian host cell, is integrated into the host cell genome and replicated together with the chromosome(s) into which it has been integrated. Preferably, the “nucleic acid expression vector” may be an expression vector which is usually applied in gene therapeutic methods in humans, particularly a retroviral vector or an adenoviral vector. The coding sequence of interest may, if necessary, be operably linked to a suitable terminator or to a polyadenylation sequence. In the case of RNA, particularly siRNA, “coding sequence” refers to the sequence encoding or corresponding to the relevant RNA strand or RNA strands. Further, the vector may comprise a DNA sequence enabling the vector to replicate in the mammalian host cell. Examples of such a sequence—particularly when the host cell is a mammalian cell—is the SV40 origin of replication. A number of vectors suitable for expression in mammalian cells are known in the art and several of them are commercially available. Some commercially available mammalian expression vectors which may be suitable include, but are not limited to, pMC1neo (Stratagene), pXT1 (Stratagene), pSG5 (Stratagene), pcDNAI (Invitrogen), EBO-pSV2-neo (ATCC 37593), pBPV-1(8-2) (ATCC 37110), pSV2-dhfr (ATCC 37146). Preferred are all suitable gene therapeutic vectors known in the art. In a particularly preferred embodiment of the invention the vector is a retroviral vector. Retroviruses are RNA-viruses possessing a genome that after the infection of a cell, such as a human cell, is reversely transcribed in DNA and subsequently is integrated into the genome of the host cell. Retroviruses enter their host cell by receptor-mediated endocytosis. After the endocytosis into the cell the expression of the retroviral vector may be silenced to ensure that only a single cell is infected. The integration of the viral DNA into the genome is mediated by a virus-encoded protein called integrase, wherein the integration locus is not defined. Retroviral vectors are particularly appropriate for their use in gene therapeutic methods, since their transfer by receptor-mediated endocytosis into the host cell, also known to those skilled in the art as “retroviral transduction” is particularly efficient A person skilled in the art also knows how to introduce such retroviral vectors into the host cell using so called “packaging cells”. In another particularly preferred embodiment of the invention, the vector is an adenoviral vector or a derivative thereof Adenoviral vectors comprise both replication-capable and and replication-deficient vectors. The latter include vectors deficient in the E1 gene. The recombinant vector is preferably introduced into the mammalian host cells by a suitable pharmaceutical carrier that allows transformation or transfection of the mammalian, in particular human cells. Preferred transformation/transfection techniques include, but are not limited to liposome-mediated transfection, virus-mediated transfection and calcium phosphate transfection. In a preferred embodiment, the invention relates to the use of a vector system capable of producing siRNAs as defined above, wherein the nucleic acid corresponding to the siRNA is contained in at least one nucleic acid expression vector comprising a first expression cassette containing the nucleic acid corresponding to the sense-RNA-strand under the control of a first promoter and a second expression cassette containing the nucleic acid corresponding to the antisense-RNA-strand under the control of a second promoter. In the above mentioned vector system, the vector comprises two individual promoters, wherein the first promoter controls the transcription of the sense-strand and the second promoter controls the transcription of the antisense strand (also described in Tuschl, Nature Biotechnology, Vol. 20, pp. 446-448). Finally the siRNA duplex is constituted by the hybridisation of the first and the second RNA-strand. The term “expression cassette” is defined herein to include all components which are necessary or advantageous for the expression of a specific target polypeptide. An “expression cassette” may include, but is not limited to, the nucleic acid sequence of interest itself (e.g. encoding or corresponding to the siRNA or polypeptide of interest) and “control sequences”. These “control sequences” may include, but are not limited to, a promoter that is operatively linked to the nucleic acid sequence of interest, a ribosome binding site, translation initiation and termination signals and, optionally, a repressor gene or various activator genes. Control sequences are referred to as “homologous”, if they are naturally linked to the nucleic acid sequence of interest and referred to as “heterologous” if this is not the case. The term “operably linked” indicates that the sequences are arranged so that they function in concert for their intended purpose, i.e. expression of the desired protein, or, in case of RNA, transcription of the desired RNA. The promoter used in the aforementioned “expression cassettes” may be any DNA sequence which shows transcriptional activity in a host cell of choice, preferably in a mammalian host cell, particularly in a human host cell. The promoter may be derived from genes encoding proteins either homologous or heterologous to the host cell. As a promoter in general every promoter known in the prior art can be used that allows the expression of the gene of interest under appropriate conditions in a mammalian host cell, in particular in a human host cell. Particularly promoters derived from RNA polymerase III transcription units, which normally encode the small nuclear RNAs (snRNAs) U6 or the human RNAse P RNA H1, can be used as promoters to express the therapeutic siRNAs. These particularly preferred promoters U6 and H1 RNA which are members of the type III class of Polymerase III promoters are—with the exception of the first transcribed nucleotide (+1 position)—only located upstream of the transcribed region. In a preferred embodiment, the invention relates to the use of a vector system capable of producing siRNAs for the above identified nucleic acid sequences, wherein the sequence is contained in at least one nucleic acid expression vector comprising an expression cassette containing the sequence of the sense-RNA-strand and of the antisense-RNA-strand under the control of a promoter leading to a single-stranded RNA-molecule and wherein the single-stranded RNA-molecule is capable of forming a back-folded stem-loop-structure. In this vector system (also described in Tuschl, Nature Biotechnology, Vol. 20, pp. 446-448), only a single RNA-strand is produced under the control of a single promoter, wherein the RNA strand comprises both the sense- and of the antisense-strand of the final double-stranded siRNA molecule. This structure leads to a back-folding of the RNA-strand by hybridisation of the complementary sense- and antisense-sequences under stem-loop formation. Finally the intracellular processing of this fold-back stem-loop-structure gives rise to siRNA. In another preferred embodiment according to the present invention, the “nucleic acid expression vector” comprises an expression cassette containing the sequence of the sense-RNA-strand and of the antisense-RNA-strand both under the control of a single promoter leading to a single-stranded RNA-molecule. This single-stranded RNA-molecule is hereby capable to form a back-folded stem-loop-structure. These expressed “hairpin RNA-molecules” subsequently give rise to siRNAs after intracellular processing. In a preferred embodiment of the invention the nucleic acid expression vector that gives rise to the expression of siRNAs according to the present invention is first introduced into therapeutic, non-toxic virus particles or virus-derived particles that are suitable for gene therapeutic applications and that can infect mammalian, in particular human target cells, such as packaging cells etc. In a preferred embodiment, the first and the second RNA strand of the siRNA may have, independently from the other, a length of 19 to 25 nucleotides, more preferred of 20 to 25 nucleotides, and most preferred of 20 to 22 nucleotides. In another preferred embodiment, the first and the second RNA strand of the siRNA may have, independently from the other, a length of 26 to 30 nucleotides, more preferred of 26 to 28 nucleotides, and most preferred of 27 nucleotides. The present invention also relates to the use of and/or methods involving proteins, polypeptides and peptides encoded by the above defined sequences. In another aspect, the invention relates to the use of isolated proteins or polypeptides comprising a sequence of the group selected of: (a) a sequence as disclosed in SEQ ID NO. 6, 8, 10, 12, 14, 2, 4; (b) a sequence that exhibits a sequence identity with any of the sequences according to (a) of at least 25% over 100 residues, (c) or fragments of the sequences defined in (a) or (b), for the manufacture of a medicament for the inhibition of cell cycle progression Proteins, polypeptides and peptides can be introduced into the cells by various methods known in the art. For example, amphiphilic molecules may be membrane permeable and can enter cells directly. Membrane-bound proteins or polypeptides (usually lipophilic molecules or containing transmembrane domains) may insert directly into cell membranes and can thus exert their biological function. Other ways of introduction or intracellular uptake include microinjection, lipofection, receptor-mediated endocytosis, or the use of suitable carrier-molecules, particularly carrier-peptides. Suitable carrier-peptides include or can be derived from HIV-tat, antennapedia-related peptides (penetratins), galparan (transportan), polyarginine-containing peptides or polypeptides, Pep-1, herpes simplex virus VP-22 protein. Another possible introduction method is to introduce nucleic acid vectors capable of expressing such proteins, polypeptides or peptides Suitable methods to produce isolated polypeptides are known in the art. For example, such a method may comprise transferring the expression sector with an operably linked nucleic acid molecule encoding the polypeptide into a suitable host cell, cultivating said host cells under conditions which will permit the expression of said polypeptide or fragment thereof and, optionally, secretion of the expressed polypeptide into the culture medium. Depending on the cell-type different desired modifications, e.g. glycosylation, can be achieved. The proteins, polypeptides and peptides may also be produced synthetically, e.g. by solid phase synthesis (Merrifield synthesis). The polypeptides used in the invention may also include fusion polypeptides. In such fusion polypeptides another polypeptide may be fused at the N-terminus or the C-terminus of the polypeptide of interest or fragment thereof. A fusion polypeptide is produced by fusing a nucleic acid sequence (or a portion thereof) encoding another polypeptide to a nucleic acid sequence (or a portion thereof) of the present invention. Techniques for producing fusion polypeptides are known in the art and include ligating the coding sequences so that they are in frame and the expression of the fusion polypeptide is under control of the same promotor(s) and terminator. Expression of the polypeptides of interest may also be performed using in vitro produced synthetic mRNA. Synthetic mRNA can be efficiently translated in various cell-free systems, including but not limited to, wheat germ extracts and reticulocyte extracts, as well as efficiently translated in cell based systems including, but not limited to, microinjection into frog oocytes, preferably Xenopus laevis oocytes. Inhibition of cell cycle progression using said isolated proteins or polypeptides can be achieved by different ways familiar to the person skilled in the art: Overexpression of the protein or polypeptide may lead to suppression of the endogenous protein's biological function. By introducing deletions or other mutations, or by using suitable fragments, it is possible to generate sequences encoding dominant-negative peptides or polypeptides. Such dominant-negative peptides or polypeptides can inhibit the function of the corresponding endogenous protein. For example, fragments or mutants can be generated which consist only of binding domains but are enzymatically inactive (i.e. partially lacking their biological function). Such dominant-negative molecules may interfere with the biological function of the endogenous proteins or polypeptides by binding to intracellular binding partners and thus blocking activation of the endogenous molecule. In another aspect, the invention relates to the use of an antibody which is directed against at least one polypeptide comprising a sequence as defined above for the manufacture of a medicament for the inhibition of cell cycle progression. The term “antibody” as used herein includes both polyclonal and monoclonal antibodies, as well as fragments thereof, such as Fv, Fab and F(ab)2 fragments that are capable of binding antigen or hapten. The present invention also contemplates “humanized” hybrid antibodies wherein amino acid sequences of a non-human donor antibody exhibiting a desired antigen-specificity are combined with sequences of a human acceptor antibody. The donor sequences will usually include at least the antigen-binding amino acid residues of the donor but may comprise other structurally and/or functionally relevant amino acid residues of the donor antibody as well. Such hybrids can be prepared by several methods well known in the art Specifically, said antibodies or suitable fragments thereof, particularly in humanized form, may be used as therapeutic agents in a method for treating cancer and other proliferative diseases. The use of said antibodies may also include the therapeutical inhibition of the above identified nucleic acid molecules or their corresponding polypeptides. In particular, this use may be directed to a proliferative disease. The antibodies or fragments may be introduced into the body by any method known in the art. Delivery of antibodies, particularly of fragments, into live cells may be performed as described for peptides, polypeptides and proteins. If the antigen is extracellular or an extracellular domain, the antibody may exert its function by binding to this domain, without need for intracellular delivery. Antibodies can be coupled covalently to a detectable label, such as a radiolabel, enzyme label, luminescent label, fluorescent label or the like, using linker technology established for this purpose. Labeling is particularly useful for diagnostic purposes (see below) or for monitoring the distribution of the antibody within the body or a neoplastic tumor, e.g. by computed tomography, PET positron emission tomography), or SPECT (single photon emission computed tomography). In another embodiment, the invention relates to the use of nucleic acid molecules, peptides, polypeptides, proteins, or antibodies, as defined above, for the manufacture of a medicament for the treatment or therapy of a proliferative disease. In a preferred embodiment, the disease is coronary restenosis or a neoplastic disease, the latter preferably selected from the group consisting of lymphoma, lung cancer, colon cancer, ovarian cancer and breast cancer (see above). “Proliferative diseases” according to the present invention are diseases associated with excessive cell division or proliferation as for example cancer. Preferably, the proliferative disease is restenosis, particularly coronary restenois, or a neoplastic disease, the latter preferably selected from the group consisting of lymphoma, lung cancer, colon cancer, ovarian cancer and breast cancer. Restenosis is a re-narrowing of a blood vessel due to growth of tissue at the site of angioplasty or stent implantation. Stents are tiny metal tubes to hold the previously blocked arteries open. However, restenosis still develops in many patients with implanted stents, thus necessitating second angioplasty, stent implantation or even coronary bypass surgery. Neoplastic diseases are diseases caused by newly forming tissue or cells. In the context of the present invention, the most relevant neoplastic diseases are neoplastic tumors, particularly selected from the group consisting of lymphoma, lung cancer, colon cancer, ovarian cancer and breast cancer. In another aspect, the invention relates to the use of an isolated nucleic acid molecule comprising a nucleic acid with a sequence selected from the group of sequences consisting of: a) the nucleic acid sequences presented in SEQ ID NO. 5, 7, 9, 11, 13, 1, 3; b) nucleic acid sequences encoding polypeptides that exhibit a sequence identity with the protein encoded by a nucleic acid according to a) of at least 25% over 100 residues and/or which are detectable in a computer aided search using the BLAST sequence analysis programs with an e-value of at most 10−5, c) sequences of nucleic acid molecules which are capable of hybridizing with the nucleic acid molecules with sequences corresponding to (a) or (b) under conditions of medium or high stringency, d) the antisense-sequence of any of the sequences as defined in (a), (b) or (c), e) fragments of (a), (b), (c) or (d), f) RNA sequences corresponding to any of the sequences as defined in (a), (b), (c), (d), or (e), for the manufacture of a medicament for the activation of cell cycle progression. In another aspect, the invention relates to the use of a an isolated peptide or polypeptide comprising a peptide or polypeptide with a sequence selected from the group consisting of: (a) a sequence as disclosed in SEQ ID NO. 6, 8, 10, 12, 14, 2, 4; (b) a sequence that exhibits a sequence identity with any of the sequences according to (a) of at least 25% over 100 residues. (c) fragments of the sequences defined in (a) or (b), for the manufacture of a medicament for the activation of cell cycle progression. In another aspect, the invention relates to the use of an antibody which is directed against at least one peptide or polypeptide with a sequence as defined above for the manufacture of a medicament for the activation of cell cycle progression. Thus, another use or method involving the above identified nucleic acid sequences, peptides, polypeptides, proteins, and antibodies is directed towards the treatment of a disease in which cell cycle progression, is abnormal, deficient or negatively affected. Diseases with abnormal, deficient or negatively affected cell cycle progression may be characterized by increased apoptosis and developmental disorders, in particular growth retardation, or slowed wound healing. Therefore, a preferred embodiment of the present invention relates to a use or method of the treatment of a disease, wherein the disease is characterized by increased apoptosis, growth retardation, or slowed wound healing. “Activation of cell cycle progression” includes both initiation and stimulation of cell cycle progression. The use may include, but is not limited to, the use of said nucleic acid molecules and their corresponding polypeptides for direct or indirect activation of the expression of said target genes and/or for activation of the function of said target genes. In particular, the use may include the replacement for or the complementation of a lack of function or activity of an endogenous gene involved in cell cycle control or, particularly, in cell cycle progression. Expression of RNA or polypeptides may be achieved by introduction of genomic DNA or cDNA containing suitable promoters, preferably constitutive or homologous promoters. Alternatively, any suitable nucleic acid expression vector can be used (see also above). The encoded protein or polypeptide may be full-length or a fragment or peptide with a similar biological function in cell cycle control or progression, particularly with the capability to activate cell cycle progression. All gene therapy techniques known in the art can be used to introduce the sequences into cells or tissues of a subject suffering from a disease negatively affecting cell cycle progression. Particularly useful for introduction of the above identified sequences are viral vectors, e.g. retroviral or adenoviral vectors, lipofection and electroporation. The proteins, polypeptides or peptides may also be generated by any known in vivo or in vitro method and introduced directly into the cells (see above). It is known that suitable antibodies can be used to activate the biological function of target proteins they bind to. Activation may occur by inducing conformational changes upon binding to the target protein. Another possibility is that the antibody binds two or more target proteins and brings them into sufficiently close physical proximity to induce interaction of the target proteins. The latter mode of activation is particularly known for membrane-bound dimeric receptors. With respect to the specific embodiments relating to the used nucleic acids, peptides, polypeptides, proteins, and antibodies the same applies as defined above for the other uses of the invention. In another embodiment, the invention relates to a medicament containing an isolated nucleic acid molecule, peptide, polypeptide, or antibody selected from the group consisting of a) nucleic acid molecules or nucleic acid expression vectors as defined above, b) a peptide or polypeptide comprising a sequence as defined above, c) an antibody directed against at least one peptide or polypeptide according to (b). Preferably this isolated nucleic acid molecule is an RNA molecule and preferably is double-stranded. Particularly the isolated nucleic acid molecule is an siRNA molecule according to the present invention. The medicaments may be used or applied in methods for the therapy of any kind of proliferative disease, such as cancer, preferably for the therapy of diseases in which cell cycle control or cell cycle progression play a role, particularly for the therapy of a lymphoma, lung cancer, colon cancer, ovarian cancer or breast cancer. The medicaments may also be used or applied in methods for the therapy of any kind of disease associated with abnormal or deficient cell cycle progression, particularly diseases characterized by increased apoptosis, developmental disorders or abnormalities particularly growth retardation) and slowed wound healing. The following considerations for medicaments and their administration apply also to the medicaments of the invention as to the above disclosed uses. The medicament preferably comprises additionally a suitable pharmaceutically acceptable carrier, preferably virus-particles or virus-derived particles that may harbour the viral vectors, transfection solutions comprising liposomes, particularly cationic liposomes, calcium phosphate etc. Preferably a carrier is used, which is capable of increasing the efficacy of the expression vector or virus particles containing the expression vector to enter the mammalian target cells. The medicament may additionally comprise other carrier substances, preferably starch, lactose, fats, stearin acid, alcohol, physiological NaCl-solutions or further additives, in particular stabilizers, preservatives, dyes and flavourings. The medicaments may also comprise other suitable substances. For example, RNA or siRNA containing medicaments may contain substances which stabilize double-stranded RNA molecule and/or which enable the double-stranded RNA molecule or DNA expression vector to be transfected or to be injected into the human or animal cell. Administration can be carried out by known methods, wherein a nucleic acid is introduced into a desired cell in vitro or in vivo. For therapeutic applications, the medicament may be in form of a solution, in particular an injectable solution, a cream, ointment, tablet, suspension, granulate or the like. The medicament may be administered in any suitable way, in particular by injection, by oral, nasal, rectal application. The medicament may particularly be administered parenteral, that means without entering the digestion apparatus, for example by subcutaneous injection. The medicament may also be injected intravenously in the form of solutions for infusions or injections. Other suitable administration forms may be direct administrations on the skin in the form of creams, ointments, sprays and other transdermal therapeutic substances or in the form of inhalative substances, such as nose sprays, aerosoles or in the form of microcapsules or implantates. The optimal administration form and/or administration dosis for a medicament either comprising double-stranded RNA molecules with the above sequences or comprising nucleic acid vectors capable to express such double-stranded RNA molecules depend on the type and the progression of the disease to be treated. Preferably, the activator or inhibitor is administered in pharmaceutically effective amount. As used herein, a “pharmaceutically effective amount” of an activator or inhibitor is an amount effective to achieve the desired physiological result, either in cells treated in vitro or in a subject treated in vivo. Specifically, a pharmaceutically effective amount is an amount sufficient to positively influence, for some period of time, one or more clinically defined pathological effects associated with a proliferative disease or a disease associated with abnormal, deficient or negatively affected cell cycle progression. The pharmaceutically effective amount may vary depending on the specific activator or inhibitor selected, and is also dependent on a variety of factors and conditions related to the subject to be treated and the severity of the disease. For example, if the activator or inhibitor is to be ministered in vivo, factors such as age, weight, sex, and general health of the patient as well as dose response curves and toxicity data obtained in pre-clinical animal tests would be among the factors to be considered. If the activator or inhibitor is to be contacted with cells in vitro, one would also design a variety of pre-clinical in vitro studies to asses parameters like uptake, half-life, dose, toxicity etc. The determination of a pharmaceutically effective amount for a given agent (activator or inhibitor) is well within the ability of those skilled in the art Preferably, the activator or inhibitor is present in a concentration of 0.1 to 50% per weight of the pharmaceutical composition, more preferably 10 to 30%. An inhibitor, activator, or drug according to the present invention may also be a “small molecule”. Small molecules are molecules which are not proteins, peptides antibodies or nucleic acids, and which exhibit a molecular weight of less than 5000 Da, preferably less than 2000 Da, more preferably less than 2000 Da, most preferably less than 500 Da. Such small molecules may be identified in high throughput procedures/screening assays starting from libraries. Such methods are known in the art. Suitable small molecules can also be designed or further modified by methods known as combinatorial chemistry. The genes/proteins that are provided by the current application and that possess one of the sequences as defined in (a) to (f), can be used in a high-throughput or other screen for new agents that inhibit or activate cell cycle progression. Particularly inhibitors of cell cycle progression identified by such a screen may be used as medicaments for the therapy of proliferative diseases, particularly for the therapy of a disease in which cell cycle control or cell cycle progression play a role. In another aspect, the present invention relates to the use of an isolated nucleic acid molecule comprising a sequence as defined above or the use of a ligand binding specifically at least one polypeptide comprising a sequence as defined above for the in vitro diagnosis of a proliferative disease or a disease associated with abnormal cell cycle progression. In a preferred embodiment, diagnosis relates to proliferative diseases as defined above. In another preferred embodiment, diagnosis relates to diseases associated with abnormal, deficient or negatively affected cell cycle progression, as they are described above. Diseases with “abnormal” cell cycle progression include diseases in which cell cycle progression is deficient or negatively affected. In a proliferative disease, expression of endogenous genes corresponding to the above identified sequences may be increased. In a disease in which cell cycle progression is abnormal, deficient or negatively affected, expression of the corresponding endogenous genes may be lowered. Furthermore, the corresponding endogenous gene may be mutated, rendering the corresponding protein less active or non-functional. The diagnostic use of the above identified nucleic acid molecules and probes may include, but is not limited to the quantitative detection of expression of said target genes in biological probes (preferably, but not limited to tissue samples, cell extracts, body fluids, etc.), particularly by quantitative hybridization to the endogenous nucleic acid molecules comprising the above-characterized nucleic acid sequences (particularly cDNA, RNA) Expression of the endogenous genes or their corresponding proteins can be analyzed in vitro in tissue samples, body fluids, and tissue and cell extracts. Expression analyis can be performed by any method known in the art, such as RNA in situ hybridization, PCR (including quantitative RT-PCR), and various serological or immunological assays which include, but are not limited to, precipitation, passive agglutination, enzyme-linked inmnunosorbent antibody (ELISA) technique and radioinmunoassay techniques. The diagnostic use may also include the detection of mutations in endogenous genes corresponding to the above identified nucleic acid sequences. Suitable nucleic acid probes may be synthesized by use of DNA synthesizers according to standard procedures or, preferably for long sequences, by use of PCR technology with a selected template sequence and selected primers. The probes may be labeled with any suitable label known to those skilled in the art, including radioactive and non-radioactive labels. Typical radioactive labels include 32p, 125I, 35S, or the like. A probe labeled with a radioactive isotope can be constructed from a DNA template by a conventional nick translation reaction using a DNase and DNA polymerase. Non-radioactive labels include, for example, ligands such as biotin or thyroxin, or various luminescent or fluorescent compounds. The probe may also be labeled at both ends with different types of labels, for example with an isotopic label at one end and a biotin label at the other end. The labeled probe and sample can then be combined in a hybridization buffer solution and held at an appropriate temperature until annealing occurs. Such nucleic acid probes may also be used for other than diagnostic purposes, e.g. for the identification of further homologs or orthologs. “Ligands” binding specifically to said polypeptides are known in the art Such ligands include proteins or polypeptides, for example intracellular binding partners, antibodies, molecular affinity bodies, and small molecules. Specifically binding ligands can be identified by standard screening assays known in the art (see also below), for example by yeast two-hybrid screens and affinity chromatography. A specifically binding ligand does not need to exert another function such as inhibiting or activating the molecule with which it interacts. In a preferred embodiment, the ligand is an antibody binding specifically at least one polypeptide comprising a sequence as defined above. “Specific binding” according to the present invention means that the polypeptide to be identified (the target polypeptide) is bound with higher affinity than any other polypeptides present in the sample. Preferred is at least 3 times higher affinity, more preferred at least 10 times higher affinity, and most preferred at least 50 times higher affinity. Non-specific binding (“cross-reactivity”) may be tolerable if the target polypeptide can be identified unequivocally, e.g. by its size on a Western blot Preferably the specifically binding ligands can be labeled, e.g. with fluorescent labels, enzymes, molecular tags (e.g. GST, myc-tag or the like), radioactive isotopes, or with labeled substances, e.g. labeled secondary antibodies. For MRI (magnetic resonance imaging), the ligands may be chelated with gadolinium, superparamagnetic iron oxide or lanthanides. For PET (positron emission tomography) or SPECT (single photon emission computed tomography) commonly used isotopes include 11C, 18F, 15O, 13N, 86Y, 90Y, and 16Co. In another aspect, the present invention relates to a diagnostic kit containing an isolated nucleic acid molecule as defined above and/or a ligand which is directed against at least one polypeptide as defined above for the in vitro diagnosis of a proliferative disease or a disease associated with abnormal cell cycle progression. Diagnostic kits may comprise suitable isolated nucleic acid or amino acid sequences of the above identified genes or gene products, labelled or unlabelled, and/or specifically binding ligands (e.g. antibodies) thereto and auxiliary reagents as appropriate and known in the art. The assays may be liquid phase assays as well as solid phase assays (i.e. with one or more reagents immobilized on a support). The diagnostic kits may also include ligands directed towards other molecules indicative of the disease to be diagnosed. In another aspect, the invention relates to the use of an isolated nucleic acid molecule or a nucleic acid expression vectors as defined above or of an antibody which is directed against at least one polypeptide comprising a sequence as defined above, in a screening assay for the identification and characterization of drugs that inhibit or activate cell cycle progression. In another aspect, the invention relates to the use of a peptide, polypeptide or protein with a sequence as defined above in a screening assay for interacting drugs, that inhibit or activate cell cycle progression. Such interacting molecules may also be used as ligands for diagnosis as described above. “Screening assay” according to the present invention relates to assays which allow to identify substances, particularly potential drugs, that inhibit or activate cell cycle progression by screening libraries of substances. “Screening assay” according to the present invention also relates to assays to screen libraries for substances capable of binding to the nucleic acids, polypeptides, peptides or antibodies defined above. Suitable libraries may, for example, include small molecules, peptides, polypeptides or antibodies. The invention relates to assays for identification as well as to assays for characterization of substances that inhibit or activate cell cycle progression or bind to said nucleic acids, polypeptides, peptides or antibodies. Particularly, the invention relates to screening assays for drugs. Such drugs may be identified and characterized from libraries of unspecified compounds as well as libraries of drugs which are already known for treatment of other diseases. For such known drugs also potential side-effects and therapeutically applicable doses are known. Suitable drugs include “interacting drugs”, i.e. drugs that bind to the polypeptides or nucleic acids identified above. Such interacting drugs may either inhibit or activate the molecule they are bound to. Examples for interacting substances are peptide nucleic acids comprising sequences identified above, antisense RNAs, siRNAs, ribozymes, aptamers, antibodies and molecular affinity bodies (CatchMabs, Netherlands). Such drugs may be used according to any aspect of the present invention, including use for the manufacture of medicaments and methods of treatment of proliferative diseases. It is known that such interacting drugs can also be labeled and used as ligands for diagnosis of a disease associated with cell cycle control or cell cycle progression. Suitable screening assays are known in the art For example, in a preferred embodiment of the invention the screening method for the identification and characterization of an inhibitor or an activator molecule that inhibits or activates cell cycle progression comprises the following steps: a) transformation of a nucleic acid molecule or a nucleic acid expression vector as defined above into a host cell or host organism, b) cultivation of the host cell or host organism obtained in step a) under conditions that allow the overexpression of the polypeptide or RNA encoded by or corresponding to the nucleic acid of step (a) either in the presence or in the absence of at least one candidate for an inhibitor- or activator-molecule, and c) analysis of the cell cycle progression in the cultivated cell or organism and thereby identification of an inhibitor or activator of cell cycle progression. The term “expression vector” as used herein does not only relate to RNA or siRNA expressing vectors, but also to vectors expressing peptides, polypeptides or proteins. The transfer of the expression vector into the host cell or host organism hereby may be performed by all known transformation or transfection techniques, including, but not limited to calcium phosphate transformation, lipofection, microinjection. Host cell/host organisms may be all suitable cells or organisms that allow detection of impaired cell division, preferably of impaired cell cycle control or cell cycle progression. A particularly preferred host organism is C. elegans, since its translucent body allows an easy detection of failures during cell division, including cell cycle progression. Vertebrate cells, preferably mammalian, more preferably human cells, in particular human cell lines are also preferred host cells. The expression vector may be any known vector that is suitable to allow the expression of the nucleic acid sequence as defined above. Preferred expression vectors possess expression cassettes comprising a promoter that allows an overexpression of the RNA, peptide or polypeptide as defined above. After the transfer of the expression vector into the host cell/host organism one part of the host cells or host organisms are cultured in the presence of at least one candidate of an inhibitor- or activator-molecule and under culture conditions that allow the expression, preferably the overexpression of the RNA, peptide or polypeptide as defined above. The other part of the transfected host cells are cultured under the same culture conditions, but in the absence of the candidate of an inhibitor- or activator-molecule. Finally, after an appropriate incubation time/culture period the proliferation state and/or cell divisions for host cells or host organisms that had been cultured in the presence or in the absence of the at least one candidate for an inhibitor or an activator molecule are detected or preferably quantified. This detection or quantification step is preferably done by time lapse fluorescence or DIC microscopy, particularly in those cases when the host organism is C. elegans or another mostly translucent organism that is available to be analysed by time lapse fluorescence or DIC microscopy. The detection /quantification step may also be done by any other technique known to the state of the art that is suitable to analyse the proliferation state or the extent of cell division, preferably all kinds of microscopic techniques. In another preferred embodiment, the screening method for the identification and characterization of an interacting molecule that inhibits or activates cell cycle progression from a library of test substances comprises the following steps: a) recombinantly expressing a polypeptide encoded by a nucleic acid molecule sequence as defined above in a host cell, b) isolating and optionally purifying the recombinantly expressed polypeptide of step (a), c) optionally labelling of the test substances and/or labelling of the recombinantly expressed polypeptide, d) immobilizing the recombinantly expressed polypeptide to a solid phase, e) contacting of at least one test substance with the immobilized polypeptide, f) optionally one or more washing steps, g) detecting the binding of the at least one test substance to the immobilized polypeptid at the solid phase, and h) performing a functional assay for inhibition or activation of cell cycle progression. Step a) includes the recombinant expression of the above identified polypeptide or of its derivative from a suitable expression system, in particular from cell-free translation, bacterial expression, or baculuvirus-based expression in insect cells. Step b) comprises the isolation and optionally the subsequent purification of said recombinantly expressed polypeptides with appropriate biochemical techniques that are familiar to a person skilled in the art. Alternatively, these screening assays may also include the expression of derivatives of the above identified polypeptides which comprises the expression of said polypeptides as a fusion protein or as a modified protein, in particular as a protein bearing a “tag”-sequence. These “tag”-sequences consist of 'short nucleotide sequences that are ligated ‘in frame’ either to the N- or to the C-terminal end of the coding region of said target gene. Commonly used tags to label recombinantly expressed genes are the poly-Histidine-tag which encodes a homopolypeptide consisting merely of histidines, particularly six or more histidines, GST (glutathion S-transferase), c-myc, FLAG®, MBP (maltose binding protein), and GFP. In this context the term “polypeptide” does not merely comprise polypeptides with the nucleic acid sequences of SEQ ID No. 1 to 31, their naturally occuring homologs, preferably orthologs, more preferably human orthologs, but also derivatives of these polypeptides, in particular fusion proteins or polypeptides comprising a tag-sequence. These polypeptides, particularly those labelled by an appropriate tag-sequence (for instance a His-tag or GST-tag), may be purified by standard affinity chromatography protocols, in particular by using chromatography resins linked to anti-His-tag-antibodies or to anti-GST-antibodies which are both commercially available. Alternatively, His-tagged molecules may be purified by metal chelate affinity chromatography using Ni-ions. Alternatively to the use of ‘label-specific’ antibodies the purification may also involve the use of antibodies against said polypeptides. Screening assays that involve a purification step of the recombinantly expressed target genes as described above (step 2) are preferred embodiments of this aspect of the invention. In an—optional—step c) the compounds tested for interaction may be labelled by incorporation of radioactive isotopes or by reaction with luminescent or fluorescent compounds. Alternatively or additionally also the recombinantly expressed polypeptide may be labelled. In step d) the recombinantly expressed polypeptide is immobilized to a solid phase, particularly (but not limited) to a chromatography resin. The coupling to the solid phase is thereby preferably established by the generation of covalent bonds. In step e) a candidate chemical compound that might be a potential interaction partner of the said recombinant polypeptide or a complex variety thereof (particularly a drug library) is brought into contact with the immobilized polypeptide. In an—optional—step f) one or several washing steps may be performed. As a result just compounds that strongly interact with the immobilized polypeptide remain bound to the solid (immobilized) phase. In step g) the interaction between the polypeptide and the specific compound is detected, in particular by monitoring the amount of label remaining associated with the solid phase over background levels. Such interacting molecules may be used without functional characterization for diagnostic purposes as described above. In step h) the interacting molecule is further analyzed for inhibition or activation of cell cycle progression. Such analysis or functional assay can be performed according to any assay system known in the art A suitable assay may include the cultivation of a host cell or host organism in the presence (test condition) or absence (control condition) of the interacting molecule, and comparison of cell cycle progression under test and control conditions. In another aspect, the invention relates to a method for the preparation of a pharmaceutical composition wherein an inhibitor or activator of cell cycle progression is identified according to any of the screening methods described above, synthesized in adequate amounts and formulated into a pharmaceutical composition. Suitable methods to synthesize the inhibitor or activator molecules are known in the art. For example, peptides or polypeptides can be synthesized by recombinant expression (see also above), antibodies can be obtained from hybridoma cell lines or immunized animals. Small molecules can be synthesized according to any known organic synthesis methods. Adequate amounts relate to pharmaceutically effective amounts. Similarly, said inhibitor or activator may be provided by any of the screening methods described above and formulated into a pharmaceutical composition. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows DIC microscopy images taken from time-lapse recording of the first round of cell division in C. elegans F1 progeny from an F0 parent treated with dsRNA (RNAi) directed against F59E12.11. FIG. 2 shows an amino acid sequence alignment of F59E12.11 and the corresponding human ortholog. FIG. 3 shows DIC microscopy images taken from time-lapse recording of the first two rounds of cell division in C. elegans F1 progeny from F0 a parent treated with dsRNA (RNAi) directed against Y71H2B.3. FIG. 4 shows an amino acid sequence alignment of Y71H2B.3 and its corresponding human and Drosophila orthologs. FIG. 5 shows DIC microscopy images taken from time-lapse recording of the first two rounds of cell division in wild type untreated C. elegans. FIG. 6: shows the remaining mRNA levels after RNAi treatment of HeLa cells. RNAi treatment of HeLa cells with siRNAs directed against NP—477517.1 and NP—001542.1, the human orthologs of C. elegans genes F59E12.11 and Y71H2B.3, respectively, results in the specific reduction to mRNA levels below 10% compared control treated samples. mRNA, remaining mRNA levels (% of negative control treated sample); pos. ctrl., positive control; neg. ctrl., negative control FIG. 7: shows the effect of RNAi treatment on cell proliferation, apoptosis, and mitosis in HeLa cells. For graphical presentation, proliferation, apoptosis rate, and MI of untreated cells were set to 100. prolif., cell proliferation; apopt., apoptosis; MI; mitotic index; %, percent of untreated sample; scr. ctrl., scrambled control; untrtd., untreated. The following examples illustrate the present invention without, however, limiting the same thereto. EXAMPLE 1 Protocol for Identifying Functional Orthologs in Other Species To identify orthologous genes, the following procedure was used: The identified homologous amino acid sequences themselves were used for BLAST searches. If the original C. elegans protein was (re-)identified by a BLAST hit with an e-value of less than 10−5, the identified homolog was defined as an ortholog. The BLAST search was performed with the default parameters and the low complexity filter on. An alternative parameter for identification of homologous genes can be the percentage of sequence identity. Over 100 residues, a sequence identity of 30% defines a homologous gene. After the BLAST search is completed, multiple sequence alignment is performed using appropriate software (for example, CLUSTALW) and a neighbour joining phylogenetic tree is generated. Any person skilled in the art can identify the human ortholog from a phylogenetic tree. Essentially, the human sequence that is separated on the tree by a single speciation event or most closely related on the tree is likely to be an ortholog. EXAMPLE 2 Generation of dsRNA Molecules for RNAi Experiments First, oligonucleotide primer pair sequences were selected to amplify portions of the gene of interest's coding region using standard PCR techniques. Primer pairs were chosen to yield PCR products containing at least 500 bases of coding sequence, or a maximum of coding bases for genes smaller than 500 bases. In order to permit the subsequent use of the PCR product as a template for in vitro RNA transcription reactions from both DNA strands, the T7 polymerase promoter sequence “TAATACGACTCACTATAGG” was added to the 5′ end of forward primers, and the T3 polymerase promoter sequence “AATTAACCCTCACTAAAGG” was added to the 5′ end of reverse primers. The synthesis of oligonucleotide primers was completed by a commercial supplier (Sigma-Genosys, UK or MWG-Biotech, Germany). PCR reactions were performed in a volume of 50 μl, with Taq polymerase using 0.8 μM primers and approximately 0.1 μg of wild-type (N2 strain) genomic DNA template. The PCR products were EtOH precipitated, washed with 70% ETOH and resuspended in 7.0 μl TE. 1.0 μl of the PCR reaction was pipetted into each of two fresh tubes for 5 μl transcription reactions using T3 and T7 RNA polymerases. The separate T3 and T7 transcription reactions were performed according to the manufacturer's instructions (Ambion, Megascript kit), each diluted to 50 μl with RNase-free water and then combined. The mixed RNA was purified using RNeasy kits according to the manufacturer's instructions (Qiagen), and eluted into a total of 130 μl of RNase-free H2O. 50 μl of this was mixed with 10 μl 6× injection buffer (40 mM KPO4 pH 7.5, 6 mM potassium citrate, pH 7.5, 4% PEG 6000). The RNA was annealed by heating at 68° C. for 10 min, and at 37° C. for 30 min. Concentration of the final dsRNAs were measured to be in the range of 0.1-0.3 μg/μl. The products of the PCR reaction, of the T3 and T7 transcription reactions, as well as the dsRNA species were run on 1% agarose gels to be examined for quality control purposes. Success of double stranding was assessed by scoring shift in gel mobility with respect to single stranded RNA, when run on non-denaturing gels. EXAMPLE 3 Injections of dsRNA and Phenotypic Assays dsRNAs were injected bilaterally into the syncytial portion of both gonads of wild-type (N2 strain) young adult hermaphrodites, and the animals incubated at 20° C. for 24 hrs. Embryos were then dissected out from the injected animals and analyzed by time-lapse differential interference contrast videomicroscopy for potential defects in cell division processes, capturing 1 image every 5 seconds, as previously described (Gönczy et al., Dissection of cell division processes in the one cell stage Caenorhabditis elegans embryo by mutational analysis. J Cell Biol 144, 927-946 (1999)). For each experiment, embryos from at least 3 different injected worms were filmed in this manner, from shortly after fertilization until the four cell stage. Embryos from 2 additional injected worms were recorded for shorter periods, covering the 2 cell and the 4 cell stage, respectively, thus yielding documentation for at least 5 injected worms in each experiment. In some cases, embryos exhibited acute sensitivity to osmotic changes, as evidenced by their loss of structural integrity during the dissection of the injected animals. In order to overcome this limitation, injected animals were not dissected, but rather, anaesthetized for 10 min in M9 medium containing 0.1% tricaine and 0.01% tetramisole, and mounted intact on an agarose pad to observe the F1 embryogenesis in utero (Kirby et al., Dev. Biol. 142, 203-215 (1990)). The resolution achieved by viewing through the body wall does not equal that achieved by observing dissected embryos, and only limited phenotypic analysis was conducted in these cases. Three injected worms were also transferred to 3 fresh plates 24 hrs after injection of the dsRNA, and left at 18° C. Three days later, the plates were checked with a stereomicroscope (20-40× total magnification) for the presence of F1 larvae (L2's-L4's), as well as their developmental stage. Three days after that, the plates were inspected again for the presence of F1 adults, as well as their overall body morphology and the presence of F2 progeny. EXAMPLE 4 Characterization of the C. elegans Gene F59E12.11 dsRNA was designed and used to specifically silence the expression of the C. elegans gene by RNAi, thereby testing its functional involvement in the first round of embryonic cell division in this metazoan species. The dsRNA was synthesized in vitro from PCR-amplified wild type genomic DNA fragments of the F59E12.11 gene. For PCR, the following primer pair was used: “TAATACGACTCACTATAGGGGATTTCTTCAATCGGCTCA” with “AATTAACCCTCACTAAAGGTATGTCGTTCGTCCCATCAG” as forward and reverse primers, respectively. The dsRNA was purified, and injected into adult hermaphrodite worms. The phenotypic consequences of the RNAi treatment were documented 24 hours later in the F1 progeny of injected worms, using time-lapse differential interference contrast (DIC) microscopy. Embryo recordings started ˜20 minutes after fertilisation, while the female pronucleus is completing its meiotic divisions, until ˜15 to 20 minutes later. Control worms were either not injected, or injected with irrelevant dsRNA. Irrelevant dsRNA was made of the same nucleotide composition as the experimental dsRNA, but the nucleotides were in random order. In the F1 progeny of such control worms the cellular events of the first two rounds of embryonic cell division were found to exhibit very limited variability, as observed by DIC microscopy. All processes that were examined and scored for the possibility of phenotypic deviations are listed and illustrated in FIG. 5. Briefly, the antero-posterior polarity of the embryo is initially determined by the position of the male pronucleus at the cortex, shortly after entry into the egg. This is accompanied by a clear, coordinated flow of yolk granules through the central portion of the cytoplasm along the embryo's longitudinal axis towards the male pronucleus, and a concomitant series of cortical waves or ruffles progressing towards the anterior of the embryo. Shortly thereafter, the male and female pronuclei undergo highly patterned migrations resulting in their meeting within the posterior half of the embryo, followed by a centration and rotation of the pronuclear pair and associated centrosomes to set up the future mitotic spindle along the embryo's longitudinal axis. After synchronous breakdown of the pronuclear envelopes, the clearly bipolar mitotic spindle is initially short, but then rockingly elongates. These movements are accompanied by a slight posterior displacement of the posterior spindle pole, while the anterior spindle pole remains approximately stationary. This then results in an asymmetric positioning of the spindle during anaphase and telophase, thereby yielding an asymmetric placement of the cytokinetic furrow, and generating unequally-sized daughter cells: a smaller posterior P1 blastomere, and larger anterior AB blastomere. While the AB nucleus then migrates directly to the center of the AB cell, the P1 nucleus typically migrates further towards the posterior of that cell, before undergoing a pronounced 90° rotation while re-migrating to the anterior P1 cortex with one of its duplicated centrosomes leading. This insures that the P1 blastomere then divides along the embryo's longitudinal axis, perpendicular to that of the AB blastomere. These two divisions occur asynchronously, with P1 lagging 2-3 minutes behind AB. In the F1 embryos of worms injected with dsRNA, the following highly reproducible phenotypes are observed (FIG. 1). The embryos show an irregular cytoplasmic texture. At the poles, areas of uncondensed chromosomal material can be observed (arrows). The embryos arrest development before pronuclear formation The phenotype is accompanied by osmotic instability, which presented itself by the embryo filling the egg shell. The phenotype is embryonic lethal. All observed phenotypes indicate a requirement for F59E12.11 gene function in cell cycle progression during mitosis. Since this function is essential to cell division throughout metazoans, this gene and any homologs and derivatives thereof represent excellent tools for use in the development of a wide range of therapeutics including anti-proliferative agents. Analysis of the F59E12.11 gene sequence reveals a clear ortholog in human (GenBank Accession No. NP—477517), the sequence similarity being in the N-terminal half of the protein. The ortholog had no function ascribed to it until now. There has been no information linking the genes to cell cycle control or cell cycle progression. Based on the extremely high sequence conservation at the protein level, it can be concluded that the ortholog most likely encodes a protein with equivalent function in cell cycle progression in humans. EXAMPLE 5 Characterization of the C. elegans Gene Y71H2B.3 dsRNA was designed and used to specifically silence the expression of the C. elegans gene by RNAi, thereby testing its functional involvement in the first 2 rounds of embryonic cell division in this metazoan species. The dsRNA was synthesized in vitro from PCR-amplified wild type genomic DNA fragments of Y71H2B.3. For PCR, the following primer pair was used: “TAATACGACTCACTATAGGTGCGAAACCTGAATTTTTCC” with “AATTAACCCTCACTAAAGGGCTCATCAATTGAAACGGCT” as forward and reverse primers, respectively. The dsRNA was purified, and injected into adult hermaphrodite worms. The phenotypic consequences of the RNAi treatment were documented 24 hours later in the F1 progeny of injected worms, using time-lapse differential interference contrast (DIC) microscopy. Embryo recordings started ˜20 minutes after fertilisation, while the female pronucleus is completing its meiotic divisions, until the 4 cell stage, ˜30 minutes later. In the F1 progeny of control worms that were either not injected, or injected with irrelevant dsRNA, the cellular events of the first two rounds of embryonic cell division were found to exhibit very limited variability, as observed by DIC microscopy and described in Example 3. In the F1 embryos of worms injected with dsRNA, the following highly reproducible phenotypes are observed (FIG. 3). There is a lack of cortical ruffling (symbolized by the cross in FIG. 3A) with some irregular blebbing at the anterior end of the embryo, resulting in attenuated furrowing at the pseudo-cleavage stage (FIG. 3B, white arrow). Pronuclei are small and irregular in shape (FIGS. 3B and C, black arrows). Pronuclei meet but are not centred, the mitotic spindle is set up at the posterior end of the embryo. The spindle is short, poorly visible and lacks spindle rocking (FIG. 3E), resulting in chromosome segregation defects (FIGS. 3F and G). At the two-cell stage irregular cortical blebbing was observed (FIG. 3G, arrows). The P1 cell divides significantly later than normal (FIG. 3H, arrow). All observed phenotypes indicate a requirement for Y71H2B.3 gene function in gene function in cell cycle progression during cell division Since this function is essential to cell division throughout metazoans, this gene and any homologs and derivatives thereof represent excellent tools for use in the development of a wide range of therapeutics including anti-proliferative agents. Analysis of the Y71H2B.3 gene sequence has revealed orthologs in human (GenBank Accession No. NP—001542), rat (GenBank Accession No. AAD05364 or NP—113812), Drosophila (GenBank Accession No. AAF53289), and Saccharomyces cerevisiae (GenBank Accession No. NP—013741). The identified ortholog is immunoglobulin-binding protein 1, which is involved in IgR-mediated signal transduction in B-cells. There has been no information regarding Y71H2B.3 or these orthologs having a role in cell cycle progression or cell division. EXAMPLE 6 Effects of RNA; Treatment in Human Cells Design and Synthesis of siRNAs For all experiments in human cells short double stranded interfering RNAs (siRNAs) of 21 bases in length, comprised of a 19 bp core of complementary sequence and 2 bases overhang at the 3′ end, were designed by Cenix and chemically synthesized by Ambion Inc., Austin, Tex., USA. The following siRNA sequences were used: scrambled negative control 5-AGUACUGCUUACGAUACGGTT-3 3-TTUCAUGACGAAUGCUAUGCC-5 positive control (PCNA, proliferating cell nuclear antigen) 5-GGAGAAAGUUUCAGACUAUTT-3 3-GTCCUCUUUCAAAGUCUGAUA-5 NP_477517.1 5-GGGCUAUUGAGUGGCCAGATT-3 3-TTCCCGAUAACUCACCGGUCU-5 NP_001542.1 5-GGUGGAUUGAUAUCAGCUUTT-3 3-CTCCACCUAACUAUAGUCGAA-5 Transfection HeLa cells were treated with siRNAs at a final concentration of 100 nM using a lipofection based transfection protocol. 24 h before transfection, HeLa cells were seeded in 96 well plates at a density of 6,000 cells/well. On the day of transfection, the transfection mix was prepared as follows: 1 μl of a 10 μM stock of siRNA was diluted with 16 μl of Opti-MEM (Invitrogen Inc.), and 0.4 μl Oligofectamine transfection reagent (Invitrogen) were diluted with 2.4 μl of Opti-MEM. For complex formation, both solutions were gently mixed and incubated for 20 min at RT. Culture medium was removed from the cells and 80 μl of fresh medium (DMEM, Invitrogen) were added, followed by addition of 20 μl of transfection mix. Cells were incubated at 37° C. for 4 hours, 50 μl of fresh medium, supplemented with 30% fetal calf serum were added, followed by another incubation for 48-72 hours. Determination of Silencing Level by Quantitative RT-PCR (qRT-PCR) 48 hours after transfection, total RNA was extracted from RNAi treated cells using Invisorb kits (Invitek GmbH, Berlin), and cDNA was produced with ABI TaqMan reverse transcription reagents (Applied Biosystems, USA). In both cases the manufacturer's instructions were followed. Quantitative real-time PCR was performed using the following protocol: 5.5 μl of 2× SybrGreen PCR mix (Applied Biosystems) were mixed with 3 μl of sample cDNA and 2.5 μl of a 2 μM solution of gene specific PCR primers, followed by incubation in a ABI-7900-HT real-time PCR machine at 50° C. 2 min-95° C. 10 min-45 cycles (95° C. 15 sec—60° C. 1 min)-95° C. 15 sec-60° C. 15 sec-95° C. 15 sec. In addition to the gene specific reaction, a second, reference reaction was run for each cDNA sample, using primers for 18S rRNA. Amplification signals from different gene specific samples were normalized using the reference values on 18S rRNA for these respective samples, and compared to samples from control (scrambled siRNA from Ambion Inc.) treated cells. Proliferation Assay In order to quantify the number of living cells after RNAi treatment, ATP levels were measured 72 h after transfection using the ATPlite assay (Perkin Elmer). Cells were extracted and treated according to the manufacturer's instructions. Luminescence read out was performed on a Victor 2 multi label reader (Perkin Elmer). For graphical presentation purposes the proliferation of untreated cells was set to 100. Apoptosis Assay The levels of programmed cell death in RNAi treated cells were determined 72 hours after transfection, using the Caspase 3/7 specific fluorometric assay ApoOne by Promega, following the manufacturer's instructions. Read out was performed on a Victor 2 multi label reader (Perkin Elmer). For graphical presentation purposes the apoptosis rate of untreated cells was set to 100. Mitotic Index (MI) Phosphorylation at serin 10 of histone H3 is considered a hallmark of mitosis, appearing in early prophase and disappearing during telophase. Using immunofluorescence microscopy, mitotic cells can be revealed by an increased binding of a phospho-histone H3 antibody, detected by a suitable fluorescence labelled secondary antibody. RNAi treated cells in 96 well microscopy plates were stained using the following protocol: Cells were washed with PBS and fixed with 4% para-formaldehyde for 30 min at RT, followed by three washes with PBS. Cells were then permeabilised and blocked in the presence of 0.1% Triton X-100 and 2% BSA for 30 min. The supernatant was removed and anti Phospho Histone. H3 (mouse monoclonal antibody clone 6G3, Cell Signalling Technologies) was added at a dilution of 1:750 for 2 hours at RT, followed by three washes with PBS. For detection of Phosph Histone H3 labelled nuclei goat anti mouse antibody (1:500), coupled to Alexa Fluor 568 (Molecular Probes) was added in a solution supplemented with 0.5 μg/ml Dapi (4′,6-diamidino-2-phenylindole, dihydrochloride), FluoroPure™ grade, Molecular Probes) for detection of all nuclei. After incubation for 2 hours at RT, cells were washed four times and images were taken using an automated microscopy system (Discovery-1, Universal Imaging Inc.), acquiring a minimum of 6 images/well. Metamorph-HCS image processing software was used to determine the numbers of mitotic and overall nuclei. The Mitotic Index resembles the fraction of mitotic over all nuclei in a given cell population. For graphical presentation purposes the NI of untreated cells was set to 100. Effects of RNAi Treatment RNAi treatment of HeLa cells using an siRNA directed against NP—477517.1, the human ortholog of C. elegans gene F59E12.11, results in a 40% reduction of cell proliferation and a 2 fold increase in the rate of apoptosis. RNAi treatment of HeLa cells using an siRNA directed against NP—001542.1, the human ortholog of C. elegans gene Y71H2B.3, results in a 80% reduction of cell proliferation, a 2.5 fold increase in the rate of apoptosis, and a significant drop in the mitotic index.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 shows DIC microscopy images taken from time-lapse recording of the first round of cell division in C. elegans F1 progeny from an F0 parent treated with dsRNA (RNAi) directed against F59E12.11. FIG. 2 shows an amino acid sequence alignment of F59E12.11 and the corresponding human ortholog. FIG. 3 shows DIC microscopy images taken from time-lapse recording of the first two rounds of cell division in C. elegans F1 progeny from F0 a parent treated with dsRNA (RNAi) directed against Y71H2B.3. FIG. 4 shows an amino acid sequence alignment of Y71H2B.3 and its corresponding human and Drosophila orthologs. FIG. 5 shows DIC microscopy images taken from time-lapse recording of the first two rounds of cell division in wild type untreated C. elegans. FIG. 6 : shows the remaining mRNA levels after RNAi treatment of HeLa cells. RNAi treatment of HeLa cells with siRNAs directed against NP — 477517.1 and NP — 001542.1, the human orthologs of C. elegans genes F59E12.11 and Y71H2B.3, respectively, results in the specific reduction to mRNA levels below 10% compared control treated samples. mRNA, remaining mRNA levels (% of negative control treated sample); pos. ctrl., positive control; neg. ctrl., negative control FIG. 7 : shows the effect of RNAi treatment on cell proliferation, apoptosis, and mitosis in HeLa cells. For graphical presentation, proliferation, apoptosis rate, and MI of untreated cells were set to 100. prolif., cell proliferation; apopt., apoptosis; MI; mitotic index; %, percent of untreated sample; scr. ctrl., scrambled control; untrtd., untreated. detailed-description description="Detailed Description" end="lead"? The following examples illustrate the present invention without, however, limiting the same thereto.

20060915

20100119

20070118

81097.0

C12Q168

HALVORSON, MARK

THE USE OF EUKARYOTIC GENES AFFECTING CELL CYCLE CONTROL OR CELL CYCLE PROGRESSION FOR DIAGNOSIS AND TREATMENT OF PROLIFERATIVE DISEASES

SMALL

ACCEPTED

C12Q

ACCEPTED

Connecting Fastener And Fastener Holder

To improve the function whereby each of the nails (2) is retained at a position which is vertical to both belt-shaped bodies (5,5) in the connecting nail (1) which is provided with multiple nails (2) with a head part (3) attached and two band-shaped belt-shaped bodies (5,5) which are made of a synthetic resin. This invention is provided with two belt-shaped bodies (5,5) which are disposed so that they are separate from one another in the axial direction of the nail (2) and parallel to one another and at the same time, multiple nail through holes (6a) are formed at appropriate intervals. Multiple cylindrical gripping parts (7) which communicate with the nail through holes (6a) and which can grip the shaft part (4) of the nail (2) are formed on both belt-shaped bodies (5,5). The shaft part 4 of the nail (2) is supported at two locations: one location which approaches the heat part and another location which approaches the front end at two gripping parts (7,7) which are aligned in a single row along the axial direction of each of the nails (2) of both belt-shaped bodies (5,5).

1. A connecting fastener which is configured of (a) multiple fasteners which have a head part attached; and (b) a fastener holder which retains a group of these fasteners so that they form a set and so that they are at a position wherein they are disposed parallel to one another at appropriate intervals; by transferring them intermittently so that they are mounted on a power operated driving tool, the aforementioned fasteners are driven out one by one from the aforementioned power operated driving tool; the invention being characterized as follows: the aforementioned fastener holders are disposed so that they are separated in the axial direction of the aforementioned fastener and so that they are parallel and at the same time they are provided with multiple belt-shaped parts on which fastener through holes are formed at appropriate intervals; multiple cylindrical gripping parts—which communicate with the aforementioned fastener through holes and which can grip the shaft part of the aforementioned fastener—are formed on at least one belt-shaped part; 2. The composition of claim 1 wherein the aforementioned fastener holder is provided with two separate belt-shaped parts; these two belt-shaped parts are made of a soft synthetic resin; a group of the aforementioned gripping parts is burred on at least one of the belt shaped parts; weakened parts which are broken when the aforementioned fastener is driven are formed at locations between adjacent fastener through holes in both of the aforementioned belt-shaped parts. 3. A fastener holder which is made of a soft synthetic resin which retains multiple fasteners with head parts attached so that these are positioned so that they form a set and are disposed so that they are parallel to one another at appropriate intervals; the fastener holder is provided with multiple belt-shaped parts which have fastener through holes at appropriate intervals; multiple cylindrical gripping parts which communicate with the aforementioned fastener through holes and which can grip the shaft part of the aforementioned fastener are formed on the aforementioned belt-shaped part; the weakened parts which are cut when the aforementioned fasteners are driven are formed at locations between adjacent fastener through holes on the aforementioned belt-shaped part.

TECHNICAL FIELD The present invention relates to a connecting fastener which is used for a power operated driving tool which continuously drives fasteners such as nails and screws which have a head part on one end of a shaft part and particularly to a fastener holder used for this connecting fastener. BACKGROUND OF THE INVENTION In the prior art, connecting fasteners which are used in electric, pneumatic and other power operated driving tools were provided with (a) multiple fasteners with heads attached; (b) a fastener holder which retained these groups of fasteners so that they formed a set and so that the position was arrayed in parallel at appropriate intervals. An example of the connecting screw as this type of connecting fastener is disclosed in Patent Document 1. In this example, multiple screws are planted at appropriate intervals on a band-shaped body made of a soft synthetic resin. A cylindrical body which passes through the through holes which the screw passes through and which is able to grasp the shaft part of the screw is formed on the band-shaped body. Slits which make it easy for the head part of the screw to pass through are formed around each of the cylindrical parts. An example of a connecting nail which is used as a connecting fastener is disclosed in Patent Document 2. In this example, multiple nails are planted at appropriate intervals on a connecting body which when seen in schematic cross-section is shaped like a box with the left hand side missing which is made of a plastic sheet. Slits which make it easy for the head part of the nail to pass through are formed around through holes through which nails on the connecting body pass through. The connecting fastener described in Patent Document 1 and Patent Document 2 is mounted on a power-operated driving tool before using. By intermittently transferring the connecting fastener which is mounted on the power operated driving tool, the fasteners are driven out from the heads of the power operated driving tool. When the fasteners are being driven, the band-shaped body and the connecting body remain inside the power operated driving tool and only one fastener is driven to the outside. A structure which connects multiple nails by two connecting bodies is disclosed in Patent Document 3 as another example of the connecting nail. Both of the connecting bodies in this example have a structure which features adjacent thin ring-shaped unit holders which are disposed so that they are parallel to one another via a bridging part which cuts by driving using the power operated driving tool. Each of the nails fits into two unit holding parts which appear to overlap when seen from the direction in which both connecting bodies are arranged so that they are arranged at appropriate intervals. As a result, each of the nails supports (a) a part which approaches the head part of the shaft part and (b) a member which approaches the front end by two thin ring-shaped unit retaining parts. The connecting nail which is described in Patent Document 3 is used by mounting onto a nail driving device which is used as a power operated driving tool. When the nails are being driven, the bridging part which connects to each of the unit holding parts to the nails which have been driven are clamped between the head part of the aforementioned nail and the surface of the member. BRIEF DESCRIPTION OF THE INVENTION However, even when any of the structures indicated in Patent Documents 1 through 3 are used there were problems in that the band-shaped body and the connecting body could retain only a very small part of the shaft part of the nail so that the retaining performance whereby the fasteners are retained at a position which is vertical to the band-shaped body and the connecting body was poor and it was difficult to drive the fastener directly to the member (the fastener dangles and the driving performance is poor). Therefore, it is the technical objective of the present invention to resolve these problems and to provide a connecting fastener which is capable of carrying out the driving operations with a greater degree of precision. In order to solve these technical problems, the connecting fastener indicated in Claim 1 of the present invention is provided (a) multiple fasteners with head parts attached and (b) fastener holders which retain these groups of fasteners so that they are positioned to form a set and so that they are disposed so that they are parallel to each another at appropriate intervals. The aforementioned connecting fasteners are transferred intermittently in a state whereby they are retained so that they are mounted onto the power operated driving tool. In the invention indicated in Claim 1, the aforementioned fastener holder is disposed so that it separates from the axial direction of the aforementioned fastener so that it is parallel with it and it is provided with multiple belt-shaped parts on which are formed multiple fastener through holes at appropriate intervals. Then, many cylindrical grasping parts which communicate with the aforementioned fastener through holes and which can grasp the shaft part of the aforementioned fasteners are formed on at least one of the belt-shaped parts. In the invention indicated in Claim 2, the aforementioned fastener holder is provided with two separate belt-shaped parts on the connecting fastener described in Claim 1. The two belt-shaped parts are made of a soft synthetic resin. A group of the aforementioned gripping parts is burr processed on at least one belt-shaped part. Then, a weakened part which is broken when the aforementioned fastener is driven is formed at a site between the adjacent fastener through holes which are on the aforementioned belt-shaped part. The invention indicated in Claim 3 relates to a fastener holder which is made of a soft synthetic resin which retains the multiple fasteners with head parts attached so that they are positioned to form a set and so that they are parallel to one another at appropriate intervals. This fastener holder is provided with a belt-shaped part which is formed so that multiple fasteners through holes are formed at appropriate intervals. Multiple cylindrical gripping parts are formed on the aforementioned belt-shaped part so that they communicate with the aforementioned fastener and grip the shaft part of the aforementioned fastener. A weakened part which is cut when the aforementioned fastener is driven is formed at a site between adjacent fastener through holes of the aforementioned belt-shaped part. When the structure of the present invention is adopted, the multiple belt-shaped parts and the gripping parts which are formed on at least one belt-shaped part support multiple locations along the axial direction of a single fastener so that the gripping area relative to the shaft part of the fastener can be increased. This makes it possible to retain securely the group of the aforementioned fasteners at a position where they are vertical to the aforementioned multiple belt-shaped parts. As a result, the effect of driving one of the aforementioned fasteners straight toward the indicated location can be brought out to its fullest. In addition, the aforementioned group of fasteners can be connected and retained at a stable position by the aforementioned multiple belt-shaped parts. As a result, the connecting fastener can be manufactured by combining one type of fastener holder with a group of long fasteners with a long shaft part or with a group of fasteners with a short shaft part. This means that a fastener holder must be manufactured to fit the difference in the length of the shaft part of the fastener. This fastener holder is effective in that it has high flexibility of use and it can contribute to keeping manufacturing costs down. Next we shall describe a specific practical embodiment of the present invention based on figures. BRIEF EXPLANATION OF FIGURES FIG. 1 An inclined view of the connecting nail in the first practical embodiment of the present invention. FIG. 2 A plane view of the belt-shaped body. FIG. 3 A frontal view of the belt-shaped body. FIG. 4 A diagram indicating an example [of the nail] when being driven. FIG. 5 A diagram indicating the processing for the gripping part. FIG. 6 A diagram indicating another example [of the nail] when being driven. FIG. 7 A diagram indicating another example of the weakened part; (a) plane view; (b) frontal view. FIG. 8 A plane view of the belt-shaped body in the second practical embodiment of the present invention. FIG. 9 A frontal view of the belt-shaped body. FIG. 10 An inclined view of the connecting nail in the third practical embodiment. FIG. 11 A diagram indicating the connecting nail in another practical embodiment. BRIEF DESCRIPTION OF THE INVENTION FIG. 1 through FIG. 7 is diagrams of the first practical embodiment of the present invention which is applied to the connecting nail 1. FIG. 1 is an inclined view of the connecting nail in the first practical embodiment. FIG. 2 is a plane view of the belt-shaped body. FIG. 3 is a frontal view of the belt-shaped body. FIG. 4 is a diagram of an example of the invention while it is being driven. FIG. 5 is a diagram indicating the processing of the gripping part. FIG. 6 is a figure indicating another example of the gripping part while it is being driven. FIG. 7 is a diagram of another example of the weakened part. First, we shall give an outline description of the connecting nail 1 referring to FIG. 1 through FIG. 3. The connecting nail 1 in the first practical embodiment of the present invention is provided with (a) multiple nails 2 which are equipped with a head part 3 on one end of the shaft part 4 and (b) multiple belt-shaped parts 5 (in this embodiment, two parts). The two belt-shaped parts 5,5 are both made of a soft synthetic resin which is flexible (elastic). Thus, in the first practical embodiment of the present invention, the two belt-shaped bodies 5, 5 which correspond to the belt-shaped part which is described in the claims are made as separate pieces. The nail 2 corresponds to the fastener which is described in the claims. As indicated in FIG. 1, the two belt-shaped bodies 5, 5 are disposed so that they are parallel to one another at appropriate intervals. The group of nails 2 is positioned—vis-a-vis both of the belt-shaped bodies 5,5 which are in this state—so that the head part 3 is positioned on one side of one of the belt-shaped bodies 5 and the shaft part 4 passes through both belt-shaped bodies 5,5 and is inserted at appropriate intervals along the lengthwise direction of both belt-shaped bodies 5,5. In other words, the group of nails 2 is disposed in a state where they have a uniform position due to the two belt-shaped bodies 5,5 which are disposed so that they are separate from one another in the axial direction of the nail 2 and so that they are parallel to one another. Each of these belt-shaped bodies 5 is structured so that multiple adjacent unit retaining parts 6 which are thin and ring-shaped and which are disposed so that they are parallel to one another are linked via weakened part 8 which is cut by the driving of the nail using the power operated driving tool. A nail through hole 6a which the nail 2 goes through is formed at the schematic center of each of the unit retaining parts 6. A gripping part 7 which can grip the shaft part 4 of a single nail 2 is provided on a single side part of each of the unit retaining parts 6. This gripping part 7 communicates with the nail through hole 6a. The two gripping parts 7,7 which are arrayed in a single row along the axial direction (insertion direction) of each of the nails 7 of both belt-shaped bodies 5,5 are used to support the shaft part 4 of a single nail 2 at two locations: at one location which approaches the head part and at another location which approaches the front end. In the first practical embodiment of the present invention, the group of gripping parts 7,7 of both belt-shaped bodies 5,5 protrude in a direction so that they are opposite one another along the axial direction of each of the nails 2. We shall provide the details of these later on, however, each of the gripping parts 7 on the belt-shaped body 5 is formed by burring on a tie plate which is made of a synthetic resin or other material. As a result, the gripping part 7 is thinner than the other sites. The outside diameter of each of the unit retaining parts 6 is either schematically similar to the head part 3 of the nail 2 or is set to a dimension which is somewhat larger. The two weakened parts 8,8 are formed by opening a through hole 9 on the linking part of the adjacent unit retaining parts 6,6. Next, we shall describe an example of a mode wherein the nail 2 is driven by referring to FIG. 4. Here, both belt-shaped bodies 5,5 are made of a comparatively hard synthetic resin. Further, in the explanation given further on, we shall call the front side seen from the direction wherein the nail 2 is inserted in the belt-shaped body 5 “up” and the other side “down” for the sake of convenience. In the connecting nail 1, the nail 2 is attached to the pair of upper and lower gripping parts 7,7 and then is mounted on the driving device (not shown in figure) as a power operated driving tool and is then ready for use. This means that the connecting nail 1 which is mounted onto the driving device is transferred intermittently at a constant pitch to fit the row of intervals of the nail 2 and the nails 2 are provided one by one to the other side of the hammer plate 10 of the driving device. Next, the nail 2 is driven continuously into member A and member B by striking the head part 3 of the hammer plate 10 of the driving device in the axial direction. Both belt-shaped bodies 5, 5 are supported respectively by the guide body G indicated by the dot-and-chain-line in FIG. 4 (a) inside the magazine of the driving tool. When the nail 2 is driven in, the weakened parts 8, 8 which are linked to each of the unit retaining parts 6 relative to the nail 2 which has been driven are pushed onto the head part 3 of the nail 2 and are torn off starting from the top (see FIG. 4 (a)). The two unit retaining parts 6,6 are fitted into the shaft part 4 of the nail which has been driven. In the first practical embodiment of the present invention, both belt-shaped bodies 5, 5 are made of a hard synthetic plastic so that they are resistant to an external force in the axial direction (axial compression stress is great) and weak relative to a radial outside pushing stress (circumferential shearing stress). For this reason, both the upper and lower unit retaining parts 6,6 are split and broken so that the entire body is torn in the axial direction due to the pressing stress of the head part 3 of the nail 2 as the nailing progresses (see FIG. 4 (b)). The head part 3 of the nail 2 comes in close contact with the member A on the other side (see FIG. 4 (c). Further, since stress is concentrated when the nail is driven and each of the unit retaining parts 6 are readily torn, one or both of the sides of each of the unit retaining parts may have a notched groove (not shown in figure) formed on them. Thus, according to the structure of the connecting nail 1 which is applied to the present invention, the pair of unit retaining parts 6, 6—upper and lower—on both belt-shaped bodies 5,5 not only support two locations (a location approaching the head part and a location approaching the front end) along the axial direction on the single nail 2 but the gripping parts 7,7 as well which are formed on both unit retaining parts 6,6 support the aforementioned two locations. As a result, the shaft part 4 of the nail 2 can be gripped over a wide range by using these two sets of unit retaining parts 6—upper and lower—and the retaining parts 7. In other words, the gripping area of the nail relative to the shaft part 4 of the nail 2 increases markedly compared to that indicated in Patent Documents 1 through 3. This makes it possible to retain the nail 2 securely at a position which is vertical to the pair of upper and lower unit retaining parts 6, 6 (and by extension, both upper and lower belt-shaped bodies, 5,5). As a result, the nail 2 can be driven in a straight line (in a stable position) relative to the members A and B. In addition, in the first practical embodiment of the present invention, both the upper and lower belt-shaped bodies 5,5 are disposed so that the group of gripping parts 7,7 respectively protrude in a direction where they face each other along the axial direction of each of the nails 2. As a result, since the shaft part of the nail 2 is long, when the intervals at which both the upper and lower belt-shaped bodies 5,5 are disposed are made as large as possible, the weakened parts 8,8 which are linked to the upper unit retaining part 6 are torn off and even if they are at a position which retains the position of the nail 2 just by the unit gripping part 6 (see FIG. 4 (a)), the lower gripping part 7 can grip a range which is comparatively close to the center of gravity of the nail 2. As a result, the nail 2 can be retained at an exact position up to an interval where it separates from both belt-shaped bodies 5,5 (the position retaining function of the nail 2 can be maintained and secured as much as possible). In addition, since multiple nails 2 can be connected and retained at a stable vertical position on the two belt-shaped bodies 5,5, the group of one type of belt-shaped bodies 5,5 can be combined for example with a nail 2 which has a long shaft part and with a nail 2 which has a short shaft part and different types of connecting nails can be easily manufactured. This means that the belt-shaped body 5 need not be manufactured to fit the difference of the length of the nail 2 and the belt-shaped body 5 is flexible for various uses so that it contributes to keeping down manufacturing costs. Next, we shall explain an example of the manufacturing process involved in manufacturing the belt-shaped body 5. Each of the gripping parts 7 of the belt-shaped bodies 5 uses a punch 11 which is provided with a protruding shaft part 12 and a die 13 which is provided with a receiving hole 14 and it is formed by burring a tie plate 15 which is made of a flexible material such as synthetic resin and the like. The tie plate 15 which is made of a synthetic resin is provided with a substance which can be easily flared in a cylindrical die by using forced pressurization. As a result, by pressing out the appropriate locations on the tie plate 15 using a punch 11 looking across the spring back the gripping part 7 can be processed at a high degree of precision. Further, driving the peripheral part of the unit retaining part 6 and the through hole 9 is carried out either before or after the gripping part 7 is burred. Next, we shall explain another mode of driving the nail 1 referring to FIG. 6. In this embodiment, both belted bodies 5,5 are made of a comparatively soft synthetic resin such as polyethylene. When the nail is being driven, the weakened parts 8,8 which are linked to each of the unit retaining parts 6 relative to the nail 2 which has been driven are torn off from above. The two unit retaining parts 6,6 are inserted into the shaft part 4 of the nail 2 which has been punched out. Next, both the upper and lower gripping parts 7,7 which are made of a soft synthetic resin become swollen and deformed so that the middle piece along the axial direction spreads radially to the outside by the crushing action between the head part 3 of the nail 2 and the member A (see FIG. 6 (a)). Then, both the gripping parts 7,7 assume a position where they are folded in two at the stage when the driving is completed. The two unit retaining parts 6,6 clamp the gripping parts 7,7 so that they are folded in two between the head part 3 of the nail 2 and the member A (see FIG. 6 (b)). This makes it possible to bring out to the fullest extent the function as a washer which protects the member A from being damaged on the head part 3 of the nail 2. At the same time, a great elastic restitutive force acts relative to the head part 3 of the nail 2 and the member A so that the sealing function between the head part 3 of the nail 2 and the member A is improved. Thus, if a synthetic resin is used for the material of the belt-shaped body 5 using a synthetic resin substance (hard, weak), it is easy for the unit retaining part 6 to be left in a washer state and the entire body will be scattered. Further, the mode of the weakened parts 8,8 which connect the unit retaining parts 6,6 which are adjacent need not necessarily be limited to a bridging shape (narrow width) but a perforated shape or a thin shape or modes which are a combination of these may be used. For example, as indicated in FIG. 7 (a) and FIG. 7 (b), a notched groove 16 may be shaped on one or both of the upper and lower surfaces of the linking parts of the adjacent unit retaining parts 6,6 instead of the aforementioned through hole 7. FIG. 8 and FIG. 9 indicate a second embodiment of the connecting nail 21 which is configured so that the nail 2 is driven out from both the upper and lower belt-shaped bodies 5,5. FIG. 8 is a plane view of the belt-shaped body in the second practical embodiment of the present invention. FIG. 9 is a frontal view of the belt-shaped body. In the second practical embodiment of the present invention, no through hole is made on the lining part of the adjacent unit retaining parts 6,6 of each of the belt-shaped bodies 5. This means that the weakened parts have been eliminated. Then, multiple slits 22 (in this embodiment, four) which extend radially and small holes 23 which communicate with the front end of each of the slits 22 are formed on the periphery of each of the gripping parts 7 to make it easier for the head part 3 of the nail 2 to pass through. Each of the slits 22 extends as far as the center lengthwise on the gripping part 7. Each of the small holes 23 and the head part 3 of the nail 2 are set at a position wherein the outside edge of the head part 3 of the nail 2 overlaps with the small hole 23 when viewed on a plane. The rest of the structure is the same as that in the first practical embodiment of the present invention. Based on the aforementioned structure, when the nail 2 is being driven, only the nail 2 is pushed out without cutting off the unit retaining parts 6,6 which are arrayed in a row on the top and on the bottom from the belt-shaped bodies 5,5. Even in this case, the two unit retaining parts 6,6 on both belt-shaped bodies 5,5 and the gripping parts 7,7 which are formed on both unit retaining parts 6,6 support two locations along the axial direction of a single nail 2 so that a large gripping area relative to the heat part 4 of the nail 2 can be taken. As a result, the same type of action and effect can be obtained as in the first practical embodiment of the invention. Further, the mode for the slit 22 is by no means restricted to the aforementioned broken line shape and it may have a groove shape with some intervals open. The mode for the small holes 23 need not necessarily be restricted to a completely round shape and an oval shape or a triangular shape or other shape may also be used. The small holes 23 may be formed directly onto the gripping part 7 without setting in place any slits 22. FIG. 10 is a third practical embodiment of the present invention which applies the present invention to a connecting nail 31 on which the fastener holder shape is different from that in the first and second practical embodiments. In the third practical embodiment of the present invention, the connecting body 34 which is made of a flexible material such as synthetic resin and rubber and the like has a pair—upper and lower—of holder parts 36,36—which protrude in the same direction and which are formed on both side edges in the lengthwise direction of a back part 35 which extends so that it forms a schematic radial shape. As a result, the connecting body 34 is shaped like a box with the left hand side removed when seen in schematic cross-section. In the third practical embodiment of the present invention, the pair—upper and lower—of holder parts 36,36 corresponds to the belt-shaped part which is described in the claims. This group of holder parts 36 may have a structure whereby the adjacent [parts] are separated from one another by using slits and the like and may have a structure wherein they are linked to one another so that they form an integral piece. The group of nails 2 is in position where the head part 3 is positioned on one side of one of the holder parts 34 and the shaft part 4 passes through both holder parts 36,36 and are inserted at appropriate intervals along the lengthwise direction of both holder parts 36,36. A large number of nail through holes 36a through which the nail 2 is passed are made at appropriate intervals along the lengthwise direction of the holder part 36 A cylindrical gripping part 37 which grips the shaft part of a single nail 2 is provided on a single side of each of the holder parts 36. This gripping part 37 communicates with the nail through hole 36a. The two gripping parts 37, 37 which are arranged in a single row along the axial direction of each of the nails 2 of both holder parts 36,36 support a single nail 2 at two locations: one location which approaches the head part and another location which approaches the front end. Even in the third practical embodiment of the present invention, the group of gripping parts 37 on both holder parts 36,36 protrudes in a direction where they face one another along the axial direction of each of the nails 2. Multiple slits 38 (in this embodiment, four) which extend radially are formed around the gripping part 37 to make it easier for the head part 3 of the nail 2 to go through. Each of the slits 38 extends up to the middle—seen lengthwise—of the gripping part 37. By using this configuration, when the nail 2 is driven, only the nail 2 is driven out from the connecting body 34. Even in this case, the pair—upper and lower—of the holder parts 36,36 on the connecting body 34 and the gripping parts 37,37 which are formed on these holder parts 3,36 supports two locations along the axial direction of a single nail 2. As a result, the gripping area relative to the shaft part 4 of the nail 2 can be made larger. As a result, the same type of action and effect as the first practical embodiment can be obtained. The present invention may be applied to a variety of different modes in addition to the ones indicated in the practical embodiments. For example, the fastener need not be a nail but may be a screw, a pin or any other shape which has a head part on one end of the shaft part. In addition, the fastener holder is no by no means restricted to a synthetic resin, rubber or other material and it may be made of paper. When the fastener holder is made of synthetic resin, it need not necessarily be formed by burring but may be formed by injection. Both upper and lower belt-shaped bodies 5, 5 need not necessarily be disposed so that they force the group of gripping parts 7,7 respectively to protrude in a direction where they face each other along the axial direction of each of the nails 2. They may be disposed so that they protrude so that they face away from each other or disposed so that they face the same direction. There may be 3 or more belt-shaped bodies 5 in the first and second practical embodiments of the present invention. In this case, as indicated in FIG. 11 (b) and FIG. 11 (c), the gripping part 7 may be formed on at least one of the belt-shaped bodies 5. In addition, the disposition pattern of the belt which does not have a gripping part 7 and the belt-shaped body which does have a gripping part 7 attached may be set at will. The shape of the belt-shaped body 5 need not necessarily be restricted to the structure which links the adjacent unit retaining part 6 at the weakened part 8 and may just as well be shaped to form a rectangular plane. In this case, a latching groove which is used for transferring on the power operated driving tool may be shaped at an appropriate pitch. The mode of the gripping parts 7,37 need not necessarily be restricted to a cylindrical shape and may be shaped like an angular tube and other shapes. In addition, the height at which the gripping parts 7,37 protrude may be different for each belt-shaped body 5 (for example, see FIG. 11 (a)) and may just as well be changed for each gripping part 7,37. In FIG. 11 (a), the protruding height Hd of each of the gripping parts 7 on the lower belt-shaped body 5 has been set so that it is larger than the protruding height H of each of the gripping parts 7 on the upper belt-shaped body 5. The gripping parts 7,37 may be linked to a fastener holder by bonding using a bonding agent or bonding or other some such method using a heat seal. Even the gripping part 37 in practical embodiment 3 should be formed on at least one holder part 36.

<SOH> BACKGROUND OF THE INVENTION <EOH>In the prior art, connecting fasteners which are used in electric, pneumatic and other power operated driving tools were provided with (a) multiple fasteners with heads attached; (b) a fastener holder which retained these groups of fasteners so that they formed a set and so that the position was arrayed in parallel at appropriate intervals. An example of the connecting screw as this type of connecting fastener is disclosed in Patent Document 1. In this example, multiple screws are planted at appropriate intervals on a band-shaped body made of a soft synthetic resin. A cylindrical body which passes through the through holes which the screw passes through and which is able to grasp the shaft part of the screw is formed on the band-shaped body. Slits which make it easy for the head part of the screw to pass through are formed around each of the cylindrical parts. An example of a connecting nail which is used as a connecting fastener is disclosed in Patent Document 2. In this example, multiple nails are planted at appropriate intervals on a connecting body which when seen in schematic cross-section is shaped like a box with the left hand side missing which is made of a plastic sheet. Slits which make it easy for the head part of the nail to pass through are formed around through holes through which nails on the connecting body pass through. The connecting fastener described in Patent Document 1 and Patent Document 2 is mounted on a power-operated driving tool before using. By intermittently transferring the connecting fastener which is mounted on the power operated driving tool, the fasteners are driven out from the heads of the power operated driving tool. When the fasteners are being driven, the band-shaped body and the connecting body remain inside the power operated driving tool and only one fastener is driven to the outside. A structure which connects multiple nails by two connecting bodies is disclosed in Patent Document 3 as another example of the connecting nail. Both of the connecting bodies in this example have a structure which features adjacent thin ring-shaped unit holders which are disposed so that they are parallel to one another via a bridging part which cuts by driving using the power operated driving tool. Each of the nails fits into two unit holding parts which appear to overlap when seen from the direction in which both connecting bodies are arranged so that they are arranged at appropriate intervals. As a result, each of the nails supports (a) a part which approaches the head part of the shaft part and (b) a member which approaches the front end by two thin ring-shaped unit retaining parts. The connecting nail which is described in Patent Document 3 is used by mounting onto a nail driving device which is used as a power operated driving tool. When the nails are being driven, the bridging part which connects to each of the unit holding parts to the nails which have been driven are clamped between the head part of the aforementioned nail and the surface of the member.

<SOH> BRIEF DESCRIPTION OF THE INVENTION <EOH>However, even when any of the structures indicated in Patent Documents 1 through 3 are used there were problems in that the band-shaped body and the connecting body could retain only a very small part of the shaft part of the nail so that the retaining performance whereby the fasteners are retained at a position which is vertical to the band-shaped body and the connecting body was poor and it was difficult to drive the fastener directly to the member (the fastener dangles and the driving performance is poor). Therefore, it is the technical objective of the present invention to resolve these problems and to provide a connecting fastener which is capable of carrying out the driving operations with a greater degree of precision. In order to solve these technical problems, the connecting fastener indicated in Claim 1 of the present invention is provided (a) multiple fasteners with head parts attached and (b) fastener holders which retain these groups of fasteners so that they are positioned to form a set and so that they are disposed so that they are parallel to each another at appropriate intervals. The aforementioned connecting fasteners are transferred intermittently in a state whereby they are retained so that they are mounted onto the power operated driving tool. In the invention indicated in Claim 1 , the aforementioned fastener holder is disposed so that it separates from the axial direction of the aforementioned fastener so that it is parallel with it and it is provided with multiple belt-shaped parts on which are formed multiple fastener through holes at appropriate intervals. Then, many cylindrical grasping parts which communicate with the aforementioned fastener through holes and which can grasp the shaft part of the aforementioned fasteners are formed on at least one of the belt-shaped parts. In the invention indicated in Claim 2 , the aforementioned fastener holder is provided with two separate belt-shaped parts on the connecting fastener described in Claim 1 . The two belt-shaped parts are made of a soft synthetic resin. A group of the aforementioned gripping parts is burr processed on at least one belt-shaped part. Then, a weakened part which is broken when the aforementioned fastener is driven is formed at a site between the adjacent fastener through holes which are on the aforementioned belt-shaped part. The invention indicated in Claim 3 relates to a fastener holder which is made of a soft synthetic resin which retains the multiple fasteners with head parts attached so that they are positioned to form a set and so that they are parallel to one another at appropriate intervals. This fastener holder is provided with a belt-shaped part which is formed so that multiple fasteners through holes are formed at appropriate intervals. Multiple cylindrical gripping parts are formed on the aforementioned belt-shaped part so that they communicate with the aforementioned fastener and grip the shaft part of the aforementioned fastener. A weakened part which is cut when the aforementioned fastener is driven is formed at a site between adjacent fastener through holes of the aforementioned belt-shaped part. When the structure of the present invention is adopted, the multiple belt-shaped parts and the gripping parts which are formed on at least one belt-shaped part support multiple locations along the axial direction of a single fastener so that the gripping area relative to the shaft part of the fastener can be increased. This makes it possible to retain securely the group of the aforementioned fasteners at a position where they are vertical to the aforementioned multiple belt-shaped parts. As a result, the effect of driving one of the aforementioned fasteners straight toward the indicated location can be brought out to its fullest. In addition, the aforementioned group of fasteners can be connected and retained at a stable position by the aforementioned multiple belt-shaped parts. As a result, the connecting fastener can be manufactured by combining one type of fastener holder with a group of long fasteners with a long shaft part or with a group of fasteners with a short shaft part. This means that a fastener holder must be manufactured to fit the difference in the length of the shaft part of the fastener. This fastener holder is effective in that it has high flexibility of use and it can contribute to keeping manufacturing costs down. Next we shall describe a specific practical embodiment of the present invention based on figures.

20070809

20090414

20080207

71729.0

F16B1508

ACKUN, JACOB K

CONNECTING FASTENER AND FASTENER HOLDER

UNDISCOUNTED

ACCEPTED

F16B

ACCEPTED

Bipolar separator for fuel cell stack

It is described a bipolar separator for polymer membrane fuel cell stacks, delimited by two sheets provided with fluid passage holes connected by means of a corrugated element and comprising a passage section for a thermostatting liquid, which allows to achieve the withdrawal of heat from the adjacent cells and the humidification and distribution of gases with a single integrated piece, simplifying the assembly and the hydraulic sealing of the stack.

1. A bipolar separator for a fuel cell stack, comprising a cathode sheet and an anode sheet, at least one of said sheets provided with fluid passage holes, wherein said sheets are welded or metallurgically bonded through at least one corrugated conductive element and said sheets delimit a passage section of a cooling fluid. 2. The separator of claim 1, wherein said fluid passage holes are gas feed and/or discharge holes disposed in one or more peripheral regions of said at least one sheet. 3. The separator of claim 1 wherein said fluid passage holes comprise calibrated orifices for feeding a flow of said cooling fluid to the fuel cells. 4. The separator of claim 1 wherein said at least one corrugated conductive element adjoins said cathode and anode sheets generally along the whole surface of the separator and said cooling fluid passage section comprises channels delimited by the surface of said corrugated conductive element. 5. The separator of claim 1 wherein said at least one corrugated conductive element adjoins said cathode and anode sheets only in one or more peripheral regions of the separator. 6. The separator of claim 5 wherein said cooling fluid passage section comprises at least one reticulated element interposed between said cathode sheet and said anode sheet. 7. The separator of claim 6 wherein said at least one reticulated element is an electrically conductive, optionally metallic element. 8. The separator of claim 7 wherein said at least one conductive reticulated element is selected from the group consisting of metal foams, metal meshes, expanded sheets and sintered metallic materials. 9. The separator of claim 1 wherein at least one of the said anode and cathode sheets comprises a sealing gasket secured to the side opposite to the one whereto said corrugated conductive element is welded or metallurgically bonded. 10. The separator of claim 1 wherein at least one of the said anode and cathode sheets comprises a current collector welded or metallurgically bonded to the side opposite to the one whereto said corrugated conductive element is welded or metallurgically bonded. 11. The separator of claim 10 wherein said current collector is an electrically conductive reticulated element optionally selected from the group consisting of metal foams, metal meshes, expanded sheets and sintered metallic materials. 12. A fuel cell stack comprising at least one separator of claim 1. 13. The stack of claim 12 comprising at least one feed or discharge duct in communication with said fluid passage holes. 14. (canceled)

The present invention relates to a bipolar separation element between fuel cells, in particular polymer membrane fuel cells, laminated in a stack in a filter press configuration. As is known in the art, fuel cells are electrochemical generators converting the chemical energy of the reaction between a fuel and an oxidant to electrical energy, producing water as a by-product. Among the various known types of fuel cells, the polymer membrane type is the one which operates at the lowest temperature, typically 70-100° C., providing sensible advantages in terms of easiness and safety of operation, of material stability and especially of quickness in start-up and in reaching the final regime operating conditions. Among the main problems which have slowed the industrial diffusion of this technology, one of the most significant lies in the fact the energy produced by a single cell is obtained as direct current of relatively high intensity versus a very limited voltage (in any case lower than 1 V, and typically comprised between 0.5 and 0.8 V). This characteristic, whose reasons are of thermodynamic nature and thus intrinsic to the process, makes necessary the lamination of a certain number of cells in stacks assembled in accordance to a filter-press type arrangement. The stacks proposed for an industrial utilisation consist therefore of some tens of elements, not seldom exceeding one hundred single cells; this entails, besides the apparent problems associated with the constructive tolerances and with the tightening of the final module, also assembling times heavily affecting the final cost, each cell consisting of a multiplicity of pieces, including bipolar plates, gaskets, current collectors and electrochemical components such as electrodes and membranes. The constructive complexity of polymer membrane fuel cells is imposed by the multiplicity of functions required to make the reactions of fuel oxidation and oxidant reduction proceed with a high efficiency. Besides the optimum functioning of the electrodes which are the sites of the two reactions, and which must be provided with adequate catalysts, generally based on noble metals, a critical factor is given by the ion-exchange membrane acting as the solid electrolyte and which must provide for transporting the electrical current as a flow of ions; in particular, the protons generated by the oxidation of the fuel, that in the most common of cases consists of hydrogen, either pure or in admixture, have to cross the membrane thickness and be transported to the cathode side where they are consumed by the reaction with the oxidant, generally consisting of oxygen, also pure or in admixture. The ion-exchange membranes currently available on the market consist of a polymeric backbone, often perfluorinated for the sake of chemical stability, whereto anionic functional groups are attached, capable of bonding protons albeit to a sufficiently weak extent to allow the migration thereof under the effect of the electric field generated by the reactants. In order for this mechanism to be effective, in other words in order for the membrane ionic conductivity to be sufficient, it is necessary to maintain a high degree of hydration of the membrane during operation. For most of the operating conditions of practical interest, the water produced at the cathode by the reaction of oxygen with the protons coming from the anode side is not sufficient to guarantee that such hydration conditions are always maintained; the flow of gaseous reactants supplied to the cells tends in fact to favour a consistent evaporation, which must be somehow counterbalanced. Maintaining an adequate water balance furthermore implies an accurate thermal control of the cell, which constitutes another problem of no trivial solution. In conditions of electric power generation of practical use, the system irreversibilities generate in fact a much relevant amount of heat, which has to be effectively withdrawn from the cells. For the above stated reasons, polymer membrane fuel cells must be provided with adequate devices for the humidification of the gaseous reactants and for the withdrawal of the generated heat. This is evidently in contradiction with the demand, prescribed by the market, for the availability of more and more compact systems characterised by a quick and easy assembling. Whereas the first membrane electrochemical generators of the prior art were constructed with components of ribbed graphite subjected to further cumbersome machining, the most recent technological solutions provide the use of metallic materials with reduced thickness and more favourable mechanical characteristics. They are for instance configured as described in U.S. Pat. No. 5,578,388, providing the supply of previously humidified reactants to the two compartments, anodic and cathodic, of a stack of cells delimited by preferably metallic bipolar plates, coupled to frame-shaped planar gaskets suitable for housing an adequate current collector also acting as distributing chamber, besides ensuring the electrical continuity between the plate itself and the so-called electrochemical package; the latter consists of an ion-exchange membrane-gas diffusion electrode assembly. The current collector is a metallic reticulated element, which favours the delocalisation of the electrical contact and the distribution of the correspondent gas flow along the whole surface of the membrane-electrode assembly. The heat withdrawal is typically achieved through the circulation of water or other thermostatting fluid inside a serpentine embedded within the thickness of the metallic plate; this nevertheless entails the use of rather thick and heavy plates, expensive to manufacture since they are obtained by a delicate moulding operation. As an alternative, stack configurations alternating, within the same lamination, fuel cells to thermostatting cells crossed by water or other cooling fluid capable of exchanging heat through the walls of the metallic plates delimiting the various cells have been proposed. In this way, much thinner plates may be employed and moderate weight reductions of the structures can be obtained, especially important for mobile applications, for instance for fuel cells destined to electrical vehicle transportation. On the other hand, this solution does not offer a substantial improvement in terms of size, since the thickness reduction of the plates is obviously compensated by the addition of the thermostatting cells to the filter-press structure. Several cell designs have thus been proposed directed to decrease the weight and compact the fuel cell stacks integrating the different functions in the best way and minimising the unemployed volumes: for instance the co-pending international application PCT/EP 03/01207 provides exploiting the peripheral part of the thermostatting cells for distributing the gaseous reactants to the fuel cells, by means of a series of openings obtained on the separating plate outside the zone of circulation of the cooling fluid. For water-cooled cells, a still more advanced design, described in the co-pending international application PCT/EP03/06327, provides an exchange of matter, through appropriate calibrated holes, also inside the cooling region; in other words, part of the cooling water is allowed to penetrate inside the fuel cells, performing the gas humidification in situ while carrying out an even more effective cooling because of a partial evaporation within the fuel cells. Besides enhancing the heat withdrawal efficiency, this remarkably simplifies the overall system, allowing the elimination of the external humidification units; nevertheless, the two latter disclosed embodiments are rather complex under the standpoint of hydraulic sealing. One of the main problems in the manufacturing of filter-press structures with many laminated elements consists in fact of the coupling of a high number of elastic gaskets, which must be compressed in a uniform fashion once subjected to the tightening load, in order not to jeopardise the alignment of the rigid components (and indirectly the electrical contact), while ensuring the sealing of the different fluids, among which some are particularly critical such as hydrogen. Notwithstanding the consistent improvements in the gasket design and materials, it is very important to minimise their number in order to increase the reliability of the relevant systems. The findings disclosed in the international applications PCT/EP 03/01207 and PCT/EP03/06327 conversely present the evident drawback of a consistent amount of gas-liquid and gas-gas seals, for instance twice the amount of the invention of U.S. Pat. No. 5,578,388. Another disadvantage intrinsic to this types of design, and in general to any design providing the alternation of fuel cells and thermostatting cells, is given by the complexity of the assembly, which provides laminating a remarkable number of components, which must be accurately disposed and perfectly centred, in a fixed sequence. It is an object of the present invention to provide a fuel cell stack design overcoming the limitations of the prior art. It is a second object of the present invention to provide a fuel cell stack design of high efficiency comprising a minimal amount of laminated components and of relative hydraulic seals for a given amount of installed cells. It is a further object of the present invention to provide an integrated separator for fuel cells simultaneously achieving the internal circulation of a cooling fluid, the distribution of the gaseous reactants to the cells and optionally the humidification of the latter or of just one of them. Under a first aspect, the invention consists of a bipolar separator delimited by a cathode sheet and an anode sheet, at least one of which provided with fluid passage holes, wherein said sheets are welded or metallurgically bonded through a conductive corrugated element so as to delimit a cooling fluid passage section. Under a second aspect, the invention consists of a stack of fuel cells disposed in a filter-press arrangement and separated by an integrated conductive element performing, in the different embodiments, one or more functions among which the thermal regulation of the cell, the distribution and the humidification of the reactants without resorting to additional thermostatting cells. The separator of the invention is delimited by two conductive sheets, at least one of which is provided with fluid passage holes, respectively suitable for acting as cathode and anode sheet in a filter-press type bipolar arrangement. The two conductive sheets are mutually welded or otherwise secured through an interposed conductive element, whose geometry is of the corrugated type in order to determine, in a preferred embodiment, the formation of channels for the passage of a thermostatting fluid, preferably water in the liquid state. By corrugated element in this context it is intended a generic element, for instance obtained from a planar sheet, with an undulated or otherwise shaped profile so as to form projections and depressions; said projections and depressions are welded or otherwise secured alternatively to one or the other sheet delimiting the separator. The corrugated element has the dual purpose of mechanically adjoining the anode and cathode sheets and of ensuring the electrical continuity between the same. The corrugated element may be present just on a peripheral part of the separator, for instance in correspondence of two opposed sides, or it may be disposed along the whole surface of the sheets. In the latter case, the corrugated conductive element advantageously delimits channels which can be used for the circulation of a cooling fluid, preferably liquid water. In case the corrugated element is present just in a peripheral region of the separator, usually outside the cell's active area, the internal part may be advantageously filled with a reticulated material suitable for being employed for the circulation of a cooling fluid. As the reticulated material, metallic foams or meshes, expanded sheets, sintered porous materials may be advantageously used, also in mutual combination or juxtaposition; however, other types of reticulated materials may be employed without departing from the scope of the invention. As said above, one or both of the sheets delimiting the separator are provided with fluid passage holes; by fluid passage hole in this context it is intended a through opening of any shape or profile, obtained on the main surface of the corresponding sheet, suitable for being crossed by a liquid or a gas. In a particularly preferred embodiment, both of the sheets are provided with holes, preferably disposed along a peripheral region, in communication with a gas feeding duct; such holes can thus be employed to supply a gaseous reactant to the adjacent fuel cell, in a similar way as disclosed in PCT/EP 03/01207. Equivalent holes, in communication with a discharge duct, are preferably used for discharging exhaust reactants and reaction products. In a preferred embodiment, fluid passage holes, preferably in the form of calibrated orifices, are present in the internal part of the main surface of the separator, in correspondence of the cooling fluid passage section. This embodiment is particularly advantageous, especially in case the cooling fluid is liquid water, since the controlled passage of a portion of said cooling water from the inside of the separator to the outside, toward one or both the adjacent fuel cells, determines the humidification of one or both reactants, moreover contributing to the heat withdrawal by evaporation, in a similar manner as described in PCT/EP03/06327. The present invention thus exhibits the same advantageous features of the findings of PCT/EP 03/01207 and PCT/EP03/06327, making use however of an integrated separator directly interposed between the fuel cells, which replaces the thermostatting cells and the relative components to be individually assembled, simplifying the hydraulic sealing system by eliminating the relative gaskets and facilitating the assembly procedure to a radical extent. For the sake of further favouring a quick assembly, and an error-proof one in the component alignment, the separator of the invention may be also provided externally with current collectors and/or gaskets, welded or otherwise secured on one or preferably both of the cathode and anode sheets. In such a way, the assembly of a stack would be accomplished with the minimum possible number of pieces, in the most extreme of cases with just the separator provided with integrated collector and gasket besides the electrochemical package consisting of an activated membrane or a membrane-electrode assembly as known in the art. Some of the preferred embodiments will be now disclosed making reference to the attached figures, which have a merely exemplifying purpose and do not wish to constitute a limitation of the invention. FIG. 1 shows a fuel cell stack according to the prior art. FIG. 2 shows two embodiments of the separator of the invention. FIG. 3 shows two other embodiments of the separator of the invention, comprising integrated gaskets and current collectors. The fuel cell stack of FIG. 1 is configured in accordance with the most widespread teaching of the prior art, and comprises a juxtaposition of laminated single fuel cells (100), delimited by separators (1) in form of bipolar sheets, which enclose an electrochemical package (2) consisting of an ion-exchange membrane activated on the two faces with a catalyst or by an ion-exchange membrane/gas diffusion electrode assembly, as known in the art. The electrochemical package (2) divides the cell into two compartments, cathodic and anodic. The electrical continuity between the separators (1) and the electrochemical package (2) is ensured by the interposition of an appropriate current collector (3), which in the illustrated case is for instance a reticulated conductive material also acting as a gas distributor. The hydraulic sealing of the cells is ensured by suitable gaskets (4), usually plane gaskets. Each of the cells (100) is fed with a gaseous reactant, fuel and oxidant, in the respective anodic and cathodic compartments, by means of suitable ducts not shown in the figure, as known in the art of filter-press type module design. The discharge of the exhausts and of the reaction products is likewise carried out by means of a collecting duct. A design of this kind does not provide the integrated humidification of the reactants, which must be carried out externally, while the cell thermal regulation is typically carried out with serpentines, also not shown, embedded in the sheets acting as separators (1). Alternatively, thermostatting cells could have been intercalated to the fuel cells (100), delimited by the same separators (1) and internally crossed by a liquid coolant; in this case, the assembly and the hydraulic sealing would have obviously been complicated by the addition of the specified components. FIG. 2 shows two possible embodiments of the separator (1) of the invention; in both cases, the separator is delimited by sheets (5), one cathodic and one anodic, joined by means of a corrugated element (8) secured by weld spots (6, 9) or other forms of metallurgical bonding; in the case illustrated on the left hand side of the figure, the corrugated element (8) joins the cathode and anode sheets (5) along the whole surface delimiting a serpentine channel which may be advantageously crossed by a cooling fluid supplied from an appropriately connected circuit, not shown. In the case illustrated on the right hand side of the figure, the corrugated element is present only on a peripheral part of the separator (1), typically outside the cell's active area, while within the recess delimited by the two sheets (5) in the internal part, a reticulated element (10) is present, which can be crossed by a cooling fluid supplied from an appropriately connected circuit, not shown. In both of the illustrated embodiments, the separator is therefore capable of providing for the thermal regulation of the adjacent fuel cells. Furthermore, in both variants are present, in correspondence of a peripheral region of the separator (1), suitable holes (7) which can be employed for feeding gaseous reactants coming from gas feed ducts, not shown, in communication with said peripheral region, to the respective adjacent fuel cells. Likewise, the relevant holes (11) for the discharge of the exhausts and of the reaction products toward external discharge ducts, not shown, are present. In this way, the separator (1) of the invention performs the function of gas distributor to the cells, allowing to obtain a compact design taking advantage of what would otherwise be a dead zone. The constitutive elements of the separators (1) in FIG. 1 are evidently not reported in scale; the feed (7) and discharge holes (11), for example, are usually tiny, and have been magnified in the figure with respect to the typical situation in order to explain their function with better clarity. In the version illustrated at the right hand side, the communication holes between the inside and the outside of the separator (1) also comprise calibrated orifices (7′) which serve to allow a controlled passage of cooling water toward the adjacent fuel cells: in this case, the separator (1) performs also the function of humidifying the reactants of the adjacent cells; the heat withdrawal from said cells is moreover incremented by the evaporation of part of the water passing through the orifices (7′) inside the same cells. The different characteristics of the separators in FIG. 2 have been combined in a casual fashion, and what illustrated does not constitute a limitation of the invention; for instance, the calibrated orifices (7′) for feeding water could have been coupled to a corrugated element (8) present along the whole surface as in the case of the drawing on the left, and so on. FIG. 3 shows two embodiments equivalent to those of FIG. 2, further comprising the integration of the current collectors (3) and of the gaskets (4) of the fuel cells (100). In this way, the amount of components to be laminated for the realisation of the filter-press configuration is reduced to a minimum. The current collectors (3) may be integrated to the separator (1) of the invention by welding, also of the spot type, by soldering or other metallurgical bonding; the gaskets (4) may be integrated by moulding, gluing or by other systems known to those skilled in the art. Variations of the illustrated embodiments are evidently possible, without departing from the scope of the invention; for instance, the integrated bipolar separator (1) may comprise the current collectors (3) and not the gaskets (4) or vice versa, or again it may comprise one or both of those elements on both sides or on one side only. As is apparent for one skilled in the art, the invention may be practised making other variations or modifications to the cited examples. It must be intended therefore that the foregoing description does not wish to limit the invention, which may be employed according to different embodiments without departing from the scopes thereof, and whose extent is univocally defined by the appended claims. In the description and in the claims of the present application, the term “comprise” and its variations such as “comprising” and “comprises” are not intended to exclude the presence of other elements or additional components.

20060317

20100914

20061123

60821.0

H01M802

KWON, ASHLEY M

BIPOLAR SEPARATOR FOR FUEL CELL STACK

UNDISCOUNTED

ACCEPTED

H01M

ACCEPTED

Rope Game Device

The invention relates to a rope game device with an outer frame and with ropes rigged within the outer frame forming a spatial net and which are attached in a tensionable manner to specific node points of the outer frame. The invention has the object, to provide a new rope game device, which displays a distinct “fullness” of the spatial net and which manufacture has distinct technological and cost advantages compared to known devices. The object is solved by a rope game device, having an outer frame (1) and ropes, within the outer frame (1) and forming a spatial net (12) and which are attached in a tensionable manner to specific node points (2) of the outer frame (1), characterised in that the outer frame (1) has an icosahedron shape and the edges and the corners of the icosahedron shape are formed as frame elements (4) having the form of an equilaterial triangle comprising rods (3) and the node points (2), and that one or more hollow ball modules (11, 12), arranged within one another and having the spatial form of a truncated icosahedron, are arranged within the outer frame (1) and retained on the same in a tensionable manner.

1. Rope game device with an outer frame (1) and with ropes arranged within the outer frame (1) and forming a spatial net (12), and which are attached in a tensionable manner to specific node points (2) of the outer frame (1), characterised in that the outer frame (1) has an icosahedron shape and the edges and the corners of the icosahedron shape are formed as frame elements (4) having the shape of an equilateral triangle, comprising rods (3) and the node points (2) and that within the outer frame (1) one or more hollow ball modules (11, 12) are arranged and retained on the same in a tensionable manner, which are arranged within one another and have the spatial form of a truncated icosahedron. 2. Rope game device according to claim 1, characterised in that one outer hollow ball module (11) is retained in a tensionable manner by guy ropes (6) at twelve node points (2) of the icosahedron shape. 3. Rope game device according to claim 1, characterised in that an inner hollow ball module (12) is retained by connecting ropes at the outer hollow ball module (11). 4. Rope game device according to claim 1, characterised in that the outer frame (2) has thirty rods (3) of equal length, which ends are connected to the node points (2). 5. Rope game device according to claim 1, characterised in that the outer frame (2) has further stabilising elements. 6. Rope game device according to claim 1, characterised in that the hollow ball modules (11, 12) have twelve regular pentagons (8) and twenty regular hexagons (9). 7. Rope game device according to claim 1, characterised in that starting from the corners of each pentagon (8) of the outer hollow ball module (11), respectively, five guy ropes (6) are brought together in a pyramidic manner at the node point (2) and are retained there in a tensionable manner. 8. Rope game device according to claim 1, characterised in that the corners of each pentagon (8) of the outer hollow ball module (11) are, respectively, connected by five connecting ropes (7) to the corners of each pentagon (8) of one or further inner hollow ball modules (12). 9. Rope game device according to claim 1, characterised in that one hollow ball module (11, 12) is composed of two rope elements of different length and which are shorter for the inner hollow ball modules (12). 10. Rope game device according to claim 1, characterised in that the connecting ropes (7) are rigged guy ropes (6). 11. Rope game device according to claim 1, characterised in that the node points (2), connected to each other by rods (3), are formed as hollow bodies (13), containing the rope tensioning elements (18). 12. Rope game device according to claim 1, characterised in that the rods (3) are retained by threaded bolts (14) on a wall (17) of the hollow body (13). 13. Rope game device according to one of claim 1, characterised in that the rope tensioning elements (18) are retained in or at the wall (17) of the hollow body (13), respectively. 14. Rope game device according to claim 1, characterised in that one frame element (4) has a frame extension (21) connected to the node point (2). 15. Rope game device according to claim 1, characterised in that the frame extension (21) is formed as a spatial construction from rods (3) and node points (2). 16. Rope game device according to claim 1, characterised in that at least one equilateral triangle, formed by a frame element (4), has a two dimensional insert (20), especially from a fabric material, metal or plastic.

The invention relates to a rope game device with an outer frame and ropes arranged within the outer frame and forming a spatial net and which are attached in a tensionable manner to defined node points of the outer frame. Rope game devices are known. They are erected on children's play areas as well as on sport- and leisure facilities for climbing, working one's way along with one's hands and swinging. Climbing frames for children with a support frame defining the outer contour of the frame and a spatial rope net rigged therein, are known for example from DE-A 2046791. Between the node points of the support frame, formed as a cuboid or a octahedron, ropes are rigged as connecting element. In this case, also compression rods of the support frame can be partially omitted and can be substituted by an inner compression rod in the spatial rope net. The spatial net is, then, as a whole elastic and it can swing. The there described frame shape on the basis of a square is, as a single game device, however, not very attractive, as on the one hand no distinct spatial net volume is achieved and on the other hand the device can not be combined by a modular construction to larger units, so that besides a multiplication of the individual device no effect concerning the design of attractive spatial shapes can be achieved. In larger game devices, therefore, support frames are used according to the type of a polyhedron, in which internal space an individual, larger rope net is rigged in a stretched manner. In WO 02074392 A2 a rope game device is described, which has a support frame, which consists of pentagon frame elements, wherein within each frame element a separate rope net is rigged. For connecting the frame elements as well for the anchoring of individual ropes, the already known hollow ball connectors are used. This pentagon-like game devices, which refer back to the dodecahedron-series, have the disadvantage, that a larger number of rope elements and frame elements of different lengths are used, which make the manufacture of these devices technologically complex and costly. Furthermore, this rope game device is missing a specific “fullness” of the inner structure of the spatial net. The invention is based on the object, to provide a new rope game device, which is characterised by a particular “fullness” of the spatial net and which manufacture has distinctive technological as well as cost advantages compared to the known devices. The object is solved by the features of claim 1. Thus, the rope game device with outer frame is characterised in that the outer frame has an icosahedron shape, consisting of frame elements forming equilateral triangles and which triangle tips are connected at the node points to each other and that the inner structure of the spatial net has one or more football-like hollow ball modules arranged within one another and which are retained by guy ropes at the node points of the outer frame. Advantageous improvements are stated in the dependent claims. The advantages of the rope game device according to the invention are as follows: node points are used, which have all the same shape, for example a spherical node shape. Therefore, the manufacturing process (metal casting) of the node points formed generally as aluminium bodies is especially effective the outer frame is composed of rods of the same length the volume within the outer frame is used especially effective in the installation of a hollow ball module only two rope elements of different lengths are used for the manufacture of the spatial net structure, so that these nets can be assembled by the final user or by local users, respectively, themselves, which is reducing the costs. If further hollow ball modules are arranged within one another, the guy ropes have to be extended by connecting ropes accordingly. Additionally, for each further ball module only 12 shorter pentagon ropes are necessary. In an embodiment of the invention one outer hollow ball module is retained in a tensionable manner by means of guy ropes at twelve node points of the icosahedron shape. A further embodiment provides, that an inner hollow ball module is retained by connecting ropes at the outer hollow ball module. A further embodiment provides, that the outer frame has thirty rods of equal length, which ends are connected to the node points. In a further embodiment the outer frame has further stabilising elements. In an improvement the ball modules have twelve regular pentagons and twenty regular hexagons. A further embodiment provides, that, starting from the corners of each pentagon of the outer hollow ball module, respectively, five guy ropes are brought together in a pyramid manner at the node point and are retained there in a tensionable manner. In a further embodiment the corners of each pentagon of the outer hollow ball module are, respectively, connected to five connecting ropes to the corners of each pentagon of one or more inner hollow ball modules. In a further embodiment one hollow ball module is composed of two rope elements of different lengths and which are shorter concerning the inner hollow ball modules. A further embodiment provides, that the connecting ropes are extended guy ropes. A further embodiment is characterised in that the twelve node points, connected to each other by rods, are formed as hollow bodies, comprising the rope tensioning elements. A further embodiment is characterised in that the rods are retained by threaded bolts on a wall of the hollow body. A further embodiment provides, that the rope tensioning elements are retained in or at the wall of the hollow body, respectively. The hollow ball modules, achieved by shortening of an icosahedron structure, consisting of twelve pentagons and twenty hexagons, have the form and structure of a football. In contrast to the known spatial rope net modules based on an octahedron, which can be piled on top of each other, and thus, a spatial fullness is achieved, in this case the football-like hollow ball modules are arranged within one another. As in the icosahedron structures all corners are identical and, thus, also the guy points can be formed identically, the spatial nets contain repeatedly occurring identical rope elements, like guy ropes and connecting ropes. A small hollow ball module is formed only from two differently long guy ropes or connecting ropes, respectively: The guy rope, extending from tensioning point to tensioning point and simultaneously forms the edges of the hexagon (thirty pieces), and the connecting rope, forming the pentagon (twelve pieces). If in a larger device a further small hollow ball module should be arranged in the first larger hollow ball module, one only needs 12 times a further smaller pentagon rope position, while the guy ropes are additionally extended, to anchor the inner hollow ball module and to form the edges of the hexagon of the inner spatial ball net. The invention is explained in detail by means of the drawings and an exemplary description. It shows FIG. 1 a perspective representation of a rope game device with two hollow ball modules arranged within one another, FIG. 2 a perspective representation of a rope game device with the viewing direction of the equilateral triangle (triangular) face of the icosahedron, FIG. 3 a representation of the guy ropes or connecting ropes, respectively, and of the pentagon ropes, FIG. 4 a perspective representation of a rope game device with one hollow ball module, FIG. 5 a sectional view of a node point with rope tensioning device, FIG. 6 a view of rope tensioning elements in one node point, FIG. 7 a representation of the rope tensioning elements and rod attachment of a node point, FIG. 8 a perspective detailed representation of a node point with rope lugs and rod lugs, FIG. 9 a detailed representation with two hollow ball modules, FIG. 10 a perspective representation of a pyramidal frame extension of an icosahedron frame and FIG. 11 a perspective representation of an insert in a frame element. In FIG. 1 a rope game device with two hollow ball modules 11 and 12, arranged one within the other, is shown in the viewing direction of a node point 2. An outer frame 1 is combined from frame elements 4, which consist of equilateral triangles. The node points 2 are the connecting elements for rods 3, forming the frame elements 4. Furthermore, guy ropes 6 of a spatial net are attached at anchoring points 10 of the node points 2.The spatial net consists of a larger hollow ball module 11 and a smaller hollow ball module 12 arranged therein. The two hollow ball modules 11 and 12, arranged within each other, have, respectively, twelve pentagons 8, formed by means of pentagon ropes 5, and, respectively, twenty hexagons 9, which are, respectively, formed by the guy ropes 6 or their connecting ropes 7. In FIG. 2 the same device is shown with a viewing direction into the frame element 4 formed as an equilateral triangle. FIG. 3 shows rope positions in a detailed manner in a side view with two hollow ball modules 11 and 12. In this case the guy ropes 6 or the connecting ropes 7, extending these, also form the edges of the hexagons 9, and the pentagons 8, formed by the pentagon ropes 5, are shown. Five of the guy ropes 6 are emphasized, which are connected to the emphasized pentagons 8. In the representation of FIG. 4 the rope positions are shown again in a perspective view for rope game devices with one hollow ball module 11. FIG. 5 shows a node point 2, formed as a spherical hollow body 13. To a wall 17 of the hollow body 13 the rods 3 of the outer frame 1 are attached by threaded bolts. The operation of the threaded bolts is achieved via an opening 19 in the hollow body 13 closable by a lid 15. FIG. 6 shows a possible variant of the arrangement of rope tensioning elements 18 on the spherical hollow body 13. The guy ropes 6 extended through the wall 17 of the hollow body 13 are tightened by a tightening bolt, which is operable through the opening 19. In FIG. 7 the arrangement of the attachment of the rods 3 and of the rope tensioning elements 18 on or in the wall 17 of the spherical hollow body 13 is, respectively, shown exemplary. FIG. 8 shows in a detailed representation the lugs of the rods 3 and of the guy ropes 6 at the node point 2. FIG. 9 shows in a detailed representation the rope construction of a rope game device with two hollow ball modules 11 and 12, which are retained via the connecting ropes 7 and the guy ropes 6 at an anchoring point 10. In FIG. 10 a frame element 4 is shown, which has a frame extension 21 connected to the node points 2 of the frame element 4. In this exemplary embodiment an additional node point 2 is provided as a tip of a triangular pyramid, which edges are connected as rods 3 to the node points 2 of the icosahedron. FIG. 11 shows a further embodiment according to the invention, in which the face within the frame element 4, an equilateral triangle, is provided with a face insert 20, especially from a fabric material, metal or plastic. The embodiments, shown in FIGS. 10 and 11, are especially suitable to give on the one hand playing children more security against falling out and on the other hand to achieve further design possibilities of the game device. REFERENCE NUMERALS LIST 1 outer frame 2 node point 3 rod 4 frame element 5 pentagon rope 6 guy rope 7 connecting rope 8 pentagon 9 hexagon 10 anchoring point 11 outer hollow ball module 12 inner hollow ball module 13 hollow body 14 threaded bolts 15 lid 16 tightening bolt 17 wall 18 rope tensioning element 19 opening 20 insert 21 frame extension

20070615

20110531

20071129

71420.0

A63B900

DONNELLY, JEROME W

ROPE GAME DEVICE

SMALL

ACCEPTED

A63B

ACCEPTED

Cinnamoyl derivatives and use thereof

The present invention relates to a cinnamoyl compound represented by the formula (I):

1. A I type collagen gene transcription suppressing composition, which comprises a cinnamoyl compound represented by the formula (I): [wherein I. A represents a benzene ring or a pyridine ring, in (Yα)q, Yα is a substituent on a carbon atom, and represents a substituent of the following X0 group or Y0 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yα's are the same or different and, when q is 2 or more, the adjacent two same or different Yα's constitute a group of a Z0 group, and may be fused with an A ring; (1) a X0 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a RbO—CO—NRe′—Rd-group (Rb, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re′″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—Re′″—Rd-group (Re, Re″, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group.]; (2) a Y0 group: a Mb0-Rd-group [Mb0 represents a Mc0-group (Mc0 represents a Md0-Rd′-group {Md0 represents a 6 to 10-membered aryl group optionally substituted with a Ma-group (Ma is as defined above), or 5 to 10-membered heteroaryl group optionally substituted with Ma group (Ma is as defined above), or a 3 to 10-membered hydrocarbon ring or heterocycle optionally substituted with a Ma-group (Ma is defined above) and optionally containing an unsaturated bond, or a (b0)-group (in (b0), G0 constitutes a saturated or unsaturated non-aromatic 5 to 14-membered hydrocarbon ring or heterocycle optionally having a substituent), a (c0)-group (in (C0), J0 may contain a nitrogen atom, and constitutes an aromatic 5 to 7-membered ring), a (d0)-group {d0 represents a 5 to 12-membered hydrocarbon ring substituted with carbonyl group or a thiocarbonyl group and, further, optionally substituted with an oxy group, a thio group, a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkenyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkenyl group), a sulfinyl group, or a sulfonyl group} or an (e0)-group {e0 constitutes a 5 to 12-membered hydrocarbon ring optionally substituted with a carbonyl group, a thiocarbonyl group, an oxy group, a thio group, a —NR1-group (R1 is as defined above), a sulfinyl group or a sulfonyl group), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc0-Ba-group (Mc0 and Ba are as defined above), a Mc0-CO-group (Mc0 is as defined above), a Mc0-CO—O group (Mc0 is as defined above), a Mc0O—CO-group (Mc0 is as defined above), a Mc0ReN-group (Mc0 and Re are as defined above), a Mc0-CO—NRe-group (Mc0 and Re are as defined above), a Mc0O—CO—NRe-group (Mc0 and Re are as defined above), a Mc0ReN—CO-group (Mc0 and Re are as defined above), a Mc0ReN—CO—NRe′-group (Mc0, Re and Re′ are as defined above) a Mc0ReN—C(═NRe′)—NRe″-group (Mc0, Re, Re′ and Re″ are as defined above), a Mc0-SO2—NRe-group (Mc0 and Re are as defined above) or Mc0ReN—SO2-group (Mc0 and Re are as defined above), and Rd is as defined above.]; (3) a Z0 group: a group which is a 5 to 12-membered hydrocarbon ring or heterocycle having a halogen atom, a C1-C10 alkoxy group, a C3-C10 alkenyloxy group, a C3-C10 alkynyloxy group, a carbonyl group, a thiocarbonyl group, an oxy group, a thio group, a sulfinyl group or a sulfonyl group, is an aromatic or non-aromatic monocyclic or fused ring, and is fused with an A ring; II. Qα represents an optionally substituted hydroxyl group, or an optionally substituted amino group; III. Wα represents an oxygen atom or a-NTα-group (Tα represents a hydrogen atom, or a substituent on a nitrogen atom.); IV. Kα and Lα are the same or different, and represent a hydrogen atom, or a substituent on a carbon atom, or Kα and Lα may form a C1-C10 alkylene group optionally having a substituent or a C1-C10 alkenylene group optionally having a substituent; provided that when an A ring is a benzene ring, Wα is an oxygen atom, Lα is a methyl group, Kα is a hydrogen atom, and Qα is a C1-C4 alkoxy group, a C3-C4 alkenyloxy group or a C3-C4 alkynyloxy group, then q is not 0 and, when an A ring is a benzene ring, Wα is an oxygen atom, Lα is a methyl group, Kα is a hydrogen atom, and Qα is a C1-C4 alkoxy group, a C3-C4 alkenyloxy group or a C3-C4 alkynyloxy group, then q is 1, and Yα is not a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a nitro group, or a C1-C4 alkoxy group, or a RB-group (R represents a C1-C4 haloalkyl group, and B represents an oxy group or a thio group) and, when A is a benzene ring, Wα is an oxygen atom, Lα and Kα form a 1,3-butadienylene group, and Qα is a methoxy group, then q is 1, and Yα is not a methoxy group or an ethoxy group and, when A is a benzene ring, Wα is an oxygen atom, Lα and Kα form a 1,3-butadienylene group, and Qα is a hydroxyl group, then q is 1, and Yα is not an ethoxy group; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or the different as far as they are selected in the range]; and an inert carrier; 2. A I type collagen gene transcription suppressing composition, which comprises a cinnamoyl compound represented by the formula (II): [wherein I. A represents a benzene ring or pyridine ring; II. In (YA0)q, YA0 is a substituent on a carbon atom, and represents a substituent of the following X0 group and Y0 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, YA0's are the same or different and, when q is 2 or more, the adjacent two same or different YA0's constitute a group of a Z0 group, and may be fused with an A ring; (1) a X0 group: a Ma-group [Ma represents a Rb group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxyl group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re′ has the same meaning as that of Re and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbC—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group.]; (2) a Y0 group: a Mb0-Rd-group [Mb0 represents a Mc0 group {Mc0 represents a Md0-Rd′-group {Md0 represents a 6 to 10-membered aryl group optionally substituted with a Ma-group (Ma is as defined above), or a 5 to 10-membered heteroaryl group optionally substituted with a Ma-group (Ma is as defined above), a 3 to 10-membered hydrocarbon ring or heterocycle optionally substituted with a Ma-group (Ma is as defined above) and optionally containing an unsaturated bond, or a (b0)-group (in (b0), G0 constitutes a saturated or unsaturated non-aromatic 5 to 14-membered hydrocarbon ring or heterocycle optionally having a substituent), a (c0)-group (in (c0), J0 may contain a nitrogen atom, and constitutes an aromatic 5 to 7-membered ring), a (d0)-group {d0 constitutes a 5 to 12-membered hydrocarbon ring substituted with a carbonyl group or a thiocarbonyl group and, further, optionally substituted with an oxy group, a thio group, a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and a B1 represents an oxy group, a thio group, a sulfinyl group or sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group), a sulfinyl group or a sulfonyl group) or an (e0)-group {e0 represents a 5 to 12-membered hydrocarbon ring optionally substituted with a carbonyl group, a thiocarbonyl group, an oxy group, a thio group, a —NR1-group (R1 is as defined above), a sulfinyl group or a sulfonyl group}, Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc0-Ba-group (Mc0 and Ba are as defined above), a Mc0-CO-group (Mc0 is as defined above), a Mc0-CO—O-group (Mc0 is as defined above), a Mc0O—CO-group (Mc0 is as defined above), a Mc0ReN-group (Mc0 and Re are as defined above), a Mc0-CO—NRe-group (Mc0 and Re are as defined above), a Mc0O—CO—NRe-group (Mc0 and Re are as defined above), a Mc0ReN—CO-group (Mc0 and Re are as defined above), a Mc0ReN—CO—NRe′-group (Mc0, Re and Re′ are as defined above), a Mc0ReN—C(═NRe′)—NRe″-group (Mc0, Re, Re′ and Re″ are as defined above), a Mc0-SO2—NRe-group (Mc0 and Re are as defined above) or Mc0ReN—SO2-group (Mc0 and Re are as defined above), and Rd is as defined above.]; (3) a Z0 group: a group which is a 5 to 12-membered hydrocarbon ring or heterocycle ring optionally having a halogen atom, a C1-C10 alkoxy group, a C3-C10 alkenyloxy group, a C3-C10 alkynyloxy group, a carbonyl group, a thiocarbonyl group, an oxy group, a thio group, a sulfinyl group or a sulfonyl group, is an aromatic or non-aromatic monocyclic or fused ring, and is fused with an A ring; III. QA0 represents a hydroxyl group, a (b0)-group ((b0) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1)-group {m represents 0 or 1, and R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ and R1 are the same or different, and has the same meaning as that of R1, and Bc is as defined above), a (b0)-SO2—Bc-group ((b0) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc0-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc0 and Bc are as defined above) or a Mc0-Bc-group (Mc0 and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1-group, and R4 is as defined above}, a (b0)-R4-group ((b0) is as defined above, and R4 is as defined above), a (c0)-R4-group ((c0) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b0)-group ((b0) is as defined above), a (c0)-group ((c0) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b0)-R4′-group ((b0) and R4′ are as defined above), a (c0)-R4′-group ((c0) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), (b0)-R4′-group ((b0) and R4′ are as defined above), a (c0)-R4′-group ((c0) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4-group: a hydroxy group or an A1-O-group [A1 represents a R3— (CHR0)m—(B2—B3)-m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′)-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, then m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b0)-R4-group ((b0) and R4 are as defined above), a ((c0)-R4-group ((c0) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an R4—SO2—R4-group {A4 is as defined above, and R4 is as defined above}; B4 represents an oxy group, a thio group or a —N((O)mR1) group (R1 and m are as defined above), provided that when B4 is a thio group, then A3 is not a hydrogen atom.]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, then R2 is not hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded; R1 is as defined above); 4) a (b0)-group ((b0) is as defined above); 5) a (c0)-group ((c0) is as defined above); or 6) a R1-A1N—NR1′-group (R1, A1 and R1 are as defined above); IV. WA0 represents an oxygen atom or a —NTA0-group [TA0 represents a hydrogen atom, an A9′ group (A9′ is as defined above), a D5-R4-group (D5 and R4 are as defined above) or a Mc0-group (Mc0 is as defined above)]; V. KA0 represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, LA0 represents a hydrogen atom, a C1-C10 alkyl group or a Mb0-group (Mb0 is as defined above), or KA0 and LA0 may form a C1-C10 alkylene group, or a C1-C10 alkenylene group optionally substituted with single or the same or different plural Ma groups, provided that when an A ring is a benzene ring, WA0 is an oxygen atom, LA0 is a methyl group, KA0 is a hydrogen atom, and QA0 is a C1-C4 alkoxy group, a C3-C4 alkenyloxy group or a C3-C4 alkynyloxy group, then q is not 0 and, when an A ring is a benzene ring, WA0 is an oxygen atom, LA0 is a methyl group, KA0 is a hydrogen atom, and QA0 is a C1-C4 alkoxy group, a C3-C4 alkenyloxy group or a C3-C4 alkynyloxy group, then q is 1, and YA0 is not a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a nitro group, or a C1-C4 alkoxy group, or a RB-group (R represents a C1-C4 haloalkyl group, and B represents an oxy group or a thio group) and, when A is a benzene ring, WA0 is an oxygen atom, LA0 and KA0 form a 1,3-butadienylene group, and QA0 is a methoxy group, q is 1, and YA0 is not a methoxy group or an ethoxy group and, when A is a benzene ring, WA0 is an oxygen atom, LA0 and KA0 form a 1,3-butadienylene group, and QA0 is a hydroxy group, then q is 1, and YA0 is not an ethoxy group; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of the substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or the different as far as they are selected in the range]; and an inert carrier; 3. A I type collagen gene transcription suppressing composition, which comprises a cinnamoyl compound represented by the formula (III): [wherein I. A represents a benzene ring or a pyridine ring; II. In (YA)q, YA is a substituent on a carbon atom, and represents a substituent of the following X group or Y group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, YA's are the same or the different and, when q is 2 or more, the adjacent two same or different YA's constitute a group of a Z group, and may be fused with an A ring; (1) a X group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′—Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different Re and Re″ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re″ and Re″ are as defined above, Re′″ has the same meaning as that of Re and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group]; (2) a Y group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a-NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and Bc represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group), or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methine group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd)}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); III. QA represents a hydroxyl group, a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group (D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a C2-C10haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxyl group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N(O)nR1′-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N(O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D group: a cyano group, a R1R1′NC′(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C(—O—) group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}; B4 represents an oxy group, a thio group or a —N((O)mR1)— group (R1 and m are as defined above) provided that when B4 is a thio group, A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, a R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above); 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above); or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); IV. WA represents an oxygen atom or a —NTA-group [TA represents a hydrogen atom, an A9′-group (A9' is as defined above), a D5-R4-group (D5 and R4 are as define above) or a Mc-group (Mc is as defined above)]; V. KA represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, LA represents a hydrogen atom, a C1-C10 alkyl group or a Mb-group (Mb is as defined above), or KA and LA may form a C1-C10 alkylene group or a —C(Ma′)=C(Ma″)—C(Ma′″)=C(Ma″″)-group (Ma′, Ma″, Ma′″ and Ma″″ are the same or different, are the same as or different from Ma, and represent a hydrogen atom or Ma); and provided that when an A ring is a benzene ring, WA is an oxygen atom, LA is a methyl group, KA is a hydrogen atom, and QA is a C1-C10 alkoxy group, a C3-10 alkenyloxy group or a C3-C10 alkynyloxy group, then q is not 0 and, when an A ring is a benzyl ring, WA is an oxygen atom, LA is a methyl group, KA is a hydrogen atom, and QA is a C1-C10 alkoxy group, a C3-C10 alkenyloxy group or a C3-C10 alkynyloxy group, then q is 1, and YA is not a halogen atom, or C1-C10 alkyl group optionally substituted with a halogen atom or a C1-C10 alkoxy group, or a nitro group, or a C1-C10 alkoxy group, or a RB-group (R represents a C1-C10haloalkyl group and B represents an oxy group or a thio group) and, when A is a benzene ring, WA is an oxygen atom, LA and KA form a 1,3-butadienylene group, and QA is a hydroxyl group or a C1-C10 alkoxy group, then q is 1, and YA is not a C1-C10 alkoxy group; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; and an inert carrier; 4. A I type collagen gene transcription suppressing composition, which comprises a 2H-pyran-2-one compound represented by the formula (IV): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xa)p, Xa is a substituent on a carbon atom, and represents a halogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a C1-C10 alkoxy group, or a nitro group, a C1-C10 alkoxy group, or a RB-group (R represents a C1-C10 haloalkyl group, and B represents an oxy group or a thio group), p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xa's are the same or different; III. In (Ya)q, Ya is a substituent on a carbon atom, and represents a substituent of the following X1 group or Y1 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Ya's are the same or different and, when q is 2 or more, the adjacent two same or different Ya's constitute a Z1 group, and may be fused with an A ring; (1) a X1 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxyl group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, a Xa-group (Xa is as defined above) is excluded; (2) a Y1 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above) or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C—C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group), or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group, or a thio group), or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re″ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z1 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); IV. QA represents a hydroxyl group, a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A9 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group {(b) is as defined above, and R4 is as defined above}, a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above}, a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above) or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxyl group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N(O)nR1′)-group (R1′ is as defined above, and n represents 0 or 1, B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, m is 0, and R3 is not a hydrogen atom)}]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)nR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A)-group (R1, R1′, n and N1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group. (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}; B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above), 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above); or 6) a R1A1N—NR1′-group (R1, R1 and R1′ are as defined above); V. Ka represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, La represents a hydrogen atom, a C1-C10 alkyl group or a Mb-group (Mb is as defined above), or Ka and La may form a C1-C10 alkylene group, provided that when Ka is a hydrogen atom, La is a methyl group and an A ring is a benzene ring, p is 2, 3 or 4 in the case that q is 0; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in a range]; and an inert carrier; 5. A 2H-pyran-2-one compound represented by the formula (V): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xb)p, Xb is a substituent on a carbon atom, and represents a halogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a C1-C10 alkoxy group, or a nitro group, or a C2-C10 alkoxy group, or a RB-group (R represents a C1-C10 haloalkyl group, and B represents an oxy group or a thio group), p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xb's are the same or different; III. In (Yb)q, Yb is a substituent on a carbon atom, and represents a substituent of the following X2 group or Y2 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yb's are the same or different and, when q is 2 or more, the adjacent two same or different Yb's constitutes a group of a Z2 group, and may be fused with an A ring; (1) a X2 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRd″—Rd-group (Re, Re′ and Re″ are the same or different, Re has the same meaning as that of Re′, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group), provided that, when A represents a benzene ring, then, a halogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a C1-C10 alkoxy group, or a nitro group, or a C1-C10 alkoxy group, or a RB-group (R and B are as described above) is excluded; (2) a Y2 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above) or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group, or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a NR1— group (R1 is as defined above)), a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d) group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Rd′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z2 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); III. QA′ represents a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1 and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above) or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a C2—B1—R4′-group (C2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8-group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″-group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxyl group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C1 alkynyl group, R0 represents a hydrogen atom, C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, and m′ represents 0 or 1 and, when B3 is a sulfonyl group, m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: O═C(R3) group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), an R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3) group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1-group (R1, R1′, n and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group. (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4 provided that when B4 is a thio group, R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above provided that a hydrogen atom is excluded, and R1 is as defined above), 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above); or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); IV. Ka represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, La represents a hydrogen atom, a C1-C10 alkyl group or a Mb-group (Mb is as defined above), or Ka and La may form a C1-C10 alkylene group, provided that when an A ring is a benzene ring, p is 2, 3 or 4 in the case that q is 0; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; 6. A 2H-pyran-2-one compound represented by the formula (VI): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xc)p, Xc is a substituent on a carbon atom, and represents a hydroxyl group, or a halogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a C1-C10 alkoxy group, or a C2-C10 alkenyl group, or a R′—S(O)l-group (R′ represents a C1-C10 alkyl group, and l represents 0, 1 or 2), or a cyano group, or a C1-C10 alkoxycarbonyl group, or an aminocarbonyl group, or a (R′)2N-group (R′ is as defined above), or a R′CO—NH-group (R′ is as defined above), or a nitro group, or a C1-C10 alkoxy group, or a RB-group (R represents a C1-C10 haloalkyl group, and B represents an oxy group or a thio group), p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xc's are the same or different; III. In (Yc)q, Yc is a substituent on a carbon atom, and represents a substituent of the following X3 group or Y3 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yc's are the same or different and, when q is 2 or more, the adjacent two same or different Yc's constitute a group of a Z3 group, and may be fused with an A ring; (1) a X3 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re″ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, then a hydroxy group, or a halogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a C1-C10 alkoxy group, or a C2-C10 alkenyl group, or a R′—S(O)l-group (R′ represents a C1-C10 alkyl group, and l represents 0, 1 or 2), or a cyano group, or a C1-C10 alkoxycarbonyl group, or an aminocarbonyl group, or a (R′)2N-group (R′ is as defined above), or a R′CO—NH-group (R′ is as defined above), or a nitro group or a C1-C10 alkoxy group is excluded; (2) a Y3 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group) or a C3-C10 alkenyl group, or a C3-C10 alkynyl group), or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above], provided that when P is 0, then a morpholino group, or a phenyl group, or a phenoxy group substituted with a trifluoromethyl group, or a phenoxy group substituted with single or plural halogen atoms is excluded; (3) a Z3 group: a —N═C(Ya) Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group), provided that when p is 0, then Yc is not fused with an A ring to form a benzo[1,3]dioxol ring; IV. Ka represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, La represents a hydrogen atom, a C1-C10 alkyl group or a Mb-group (Mb is as defined above), or Ka and La may form a C1-C10 alkylene group, provided that when an A ring is a benzene ring, then q is not 0 and, when an A ring is a benzene ring or a pyridine ring, then p and q are not 0 at the same time, in either case; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above, and between the plurality of substituents, a selection range of selected substituents is the same, while the selected range may be the same or different as far as they are selected in the range]; 7. A I type collagen gene transcription suppressing composition, which comprises a 2H-pyran-2-one compound represented by the formula (VII): [wherein XI represents a C2-C4 alkenyl group, a C2-C4 alkynyl group, a RI—S(O)l-group (RI represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), a cyano group, a carboxy group, a C1-C4 alkoxycarbonyl group, a (RI)2N-group (RI is as defined above), a RI—CO—NH-group (RI is as defined above), a RIO—CO—NH-group (RI is as defined above), a RINH—CO—NH-group (RI is as defined above) or a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group), X1′ represents a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a nitro group, or a C1-C4 alkoxy group, or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), k represents 0 or 1, k′ represents an integer of 0 to 4, when k is 0, k′ is an integer of 2 to 4 and, when k′ is 2 to 4, XI′'s may be different, and rI is a C1-C4 alkyl group, a C2-C4 alkenyl group or a C2-C4 alkynyl group], and a inert carrier; 8. A 2H-pyran-2-one compound represented by the formula (VIII): (wherein XI represents a C2-C4 alkenyl group, a C2-C4 alkynyl group, a RI—S(O)l-group (RI represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), a cyano group, a carboxy group, a C1-C4 alkoxycarbonyl group, a (RI)2N-group (RI is as defined above), a RI—CO—NH-group (RI is as defined above), a RIO—CO—NH-group (RI is as defined above), a RINH—CO—NH-group (RI is as defined above) or (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group), XI″ represents a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a nitro group, or a C2-C4 alkoxy group, or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), k represents 0 or 1, k′ represents an integer of 0 to 4, when k is 0, k′ is an integer of 2 to 4 and, when k′ is 2 to 4, XI″'s may be different, and rI is a C1-C4 alkyl group, a C2-C4 alkenyl group or a C2-C4 alkynyl group]; 9. A 2H-pyran-2-one compound represented by the formula (IX): [wherein XI′″ represents a C2-C4 alkenyl group, a C2-C4 alkynyl group, a carboxy group, a C2-C4 alkoxycarbonyl group or a (RII)2N-group (RII represents a C2-C4 alkyl group), XI″ represents a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a nitro group, or a C2-C4 alkoxy group, or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), k represents 0 or 1, k″ represents an integer of 0 to 2, when k is 0, k″ is 2 and, when k″ is 2, X″'s are different]; 10. A I type collagen gene transcription suppressing composition, which comprises a 2H-1-benzopyran-2-one compound represented by the formula (X): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xd)p, Xd is a substituent on a carbon atom, and represents a methoxy group or an ethoxy group, p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xd's are the same or different; III. In (Yd)q, Yd is a substituent on a carbon atom, and represents a substituent of the following X4 group or Y4 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yd's are the same or different and, q is 2 or more, the adjacent two same or different Yd's constitute a group of a Z4 group, and may be fused with an A ring; (1) a X4 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen, atom, a nitro group, a cyano group, a hydroxyl group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re″ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, then a methoxy group and an ethoxy group are excluded; (2) a Y4 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or C3-C10 alkynyl group, and Bc represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group} or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z4 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); IV. QA represents a hydroxyl group, a (b) group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as define above, and R4′ represents a C2-C4 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and D4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxy group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)mR1′)-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, then m is 0, and R3 is not a hydrogen atom)]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridinyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, then A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, then R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above), 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above) or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); V. Ma′ is the same as or different from Ma, and has the same meaning as that of Ma, and r represents 0, 1, 2, 3 or 4, provided that when an A ring is a benzene ring, in case that q and r are 0, then p is 2, 2, 3 or 4; and the “as defined above” in the same symbol between a plurality of substituent indicates that the plurality of the substituents independently represent the same meaning as that of described above and, between the plurality of substituents, a selection range of the selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; and an inert carrier; 11. A 2H-1-benzopyran-2-one compound represented by the formula (XI): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xd)p, Xd is a substituent on a carbon atom, and represents a methoxy group or an ethoxy group, p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xd's are the same or different; III. In (Yd)q, Yd is a substituent on a carbon atom, and represents a substituent of the following X4 group or Y4 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yd's are the same or different and, when q is 2 or more, the adjacent two same or different Yd's constitute a group of a Z4 group, and may be fused with an A ring; (1) a X4 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, then a methoxy group and an ethoxy group are excluded; (2) Y4 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2, and J3 are the same or different and, represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z4 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and a C1-C10 alkylene group); IV. QA′ represents a (b)-group ((b) is as defined above), an A9-B6—Bc-group (A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′ group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A9′ group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxy group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′)-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, then m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R)—(O)k)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C—(OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, R2 is not a hydrogen atom), or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above); 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above) or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); V. Ma′ is the same as or different from Ma, and has the same meaning as that of Ma, and r represents 0, 1, 2, 3 or 4, provided that when an A ring is a benzene ring, in case that q is 0, then p is 2, 3 or 4; and the “as defined above” between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; 12. A 2H-1-benzopyran-2-one compound represented by the formula (XII): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xe)p, Xe represents a hydroxy group, a halogen atom, a C1-C10 alkyl group, a R′—S(O)l- group (R′ represents a C1-C10 alkyl group, and l represents 0, 1 or 2), a cyano group, a HOCO—CH═CH-group, a (R′)2N-group (R′ is as defined above), a R′CO—NH-group (R′ is as defined above), a nitro group or a C1-C10 alkoxy group, p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xd's are the same or different; III. In (Ye)q, Ye is a substituent on a carbon atom, and represents a substituent of the following X5 group or Y5 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Ye's are the same or different and, when q is 2 or more, the adjacent two same or different Ye's constitute a group of a Z5 group, and may be fused with an A ring; (1) a X5 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxyl group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Rd represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re″ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, then a Xe-group (Xe is as defined above) is excluded; (2) a Y5 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z5 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group), provided that when p is 0, then Ye is not fused with an A ring to form a benzo[1,3]dioxol ring; IV. Ma′ is the same as or different from Ma, and has the same meaning as that of Ma, and r represents 0, 1, 2, 3 or 4, provided that when an A ring is a benzene ring, then q is not 0; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; 13. A 2H-1-benzopyran-2-one compound represented by the formula (XIII): [wherein XII represents a hydrogen atom, or a hydroxyl group, or a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a C2-C4 alkenyl group, or a C2-C4 alkynyl group, or a C3-C4 alkoxy group, or a RI—S(O)l-group (RI represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), or a nitro group, or a cyano group, or a carboxy group, or a C1-C4 alkoxycarbonyl group, or a (RI)2N-group (RI is as defined above), or a RI—CO—NI-group (RI is as defined above), or a RIO—CO—NH-group (RI is as defined above), or a RINH—CO—NH-group (RI is as defined above), or a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group), or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), k represents an integer of 1 to 4 and, when k is an integer of 2 to 4, XII's may be different, and rI represents a C1-C4 alkyl group, a C2-C4 alkenyl group or a C2-C4 alkynyl group]; 14. A 2H-1-benzopyran-2-one compound represented by the formula (XIV): [wherein XII′ represents a C1-C4 alkyl group substituted with a halogen atom or a C1-C4 alkoxy group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C3-C4 alkoxy group, a RII—S(O)l-group (RII represents a C2-C4 alkyl group, and l represents an integer of 0 to 2), a cyano group, a carboxy group, a C1-C4 alkoxycarbonyl group, a (RII)2N-group (RII is as defined above), a RI—CO—NH-group (RI represents a C1-C4 alkyl group), a RIO—CO—NH-group (RI is as defined above), a RINH—CO—NH-group (RI is as defined above), a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group) or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), XII″ represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group or a C3-C4 alkoxy group, m represents 1 or 2 and, when m is 2, XII″'s may be different]; 15. A I type collagen gene transcription suppressing composition, which comprises a 2(1H)-pyridinone compound represented by the formula (XV): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Yf)q, Yf is a substituent on a carbon atom, and represents a group of the following X group or Y group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yf's are the same or different and, when q is 2 or more, the adjacent two same or different Yf's constitutes a group of a Z group, and may be fused with an A ring; (1) a X group: a Ma-group (Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group]; (2) a Y group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group), or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an imino group optionally substituted with an oxy group, or a thio group, or a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4alkylene group optionally substituted with a halogen atom, or a C1-C4alkylene group optionally having an oxo group), or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); III. QA represents a hydroxyl group, a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc group (R1 is as defined above, R1′ is the same as or different of R1, and has the same meaning of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or a A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a 2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxy group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′)-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, then m is 0, and R3 is not a hydrogen atom)]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above)], a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group, or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, then A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from R4, and has the same meaning as that of B4, provided that when R4 is a thio group, then R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above); 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above) or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); IV. TA represents a hydrogen atom, an A9′-group (A9′ is as defined above), a D5-R4-group (D5 and R4 are as defined above) or a Mc-group (Mc is as defined above); V. Ka represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, La represents a hydrogen atom, a C1-C10 alkyl group or a Mb-group (Mb is as defined above) or a Ka and La may form a C1-C10 alkylene group; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; and an inert carrier; 16. A 2(1H)-pyridinone compound represented by the formula (XVI): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xg)p, Xg represents a hydroxyl group, a halogen atom, a (R′)2N-group (R′ represents a C1-C10 alkyl group), a nitro group or a C1-C10 alkoxy group, p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xg's are the same or different; III. In (Yg)q, Yg is a substituent on a carbon atom, and represents a group of the following X6 group or Y6 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yg's are the same or different and, when q is 2 or more, the adjacent two same or different Yg's constitutes a group of a Z6 group, and may be fused with an A ring; (1) a X6 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxyl group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of a Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and R′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, then a X9-group (Xg is as defined above) is excluded; (2) a Y6 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a Mc-O—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z6 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); IV. QA represents a hydroxyl group, a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, B1 is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1 is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above), or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a -(b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4 group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above), and an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxyl group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C1-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′)— group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, m is 0, and R3 is not a hydrogen atom)]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, then A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, then R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above); 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above) or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); V. TA represents a hydrogen atom, an A9′-group (A9′ is as defined above), a D5-R4-group (D5 and R4 are as defined above) or a Mc-group (mc is as defined above); VI. Ka represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, La represents a hydrogen atom, a C1-C10 alkyl group or a Mb-group (Mb is as defined above), or Ka and La may form a C1-C10 alkylene group, provided that when an A ring is a benzene ring, then q is not 0; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; 17. A I type collagen gene transcription suppressing composition, which comprises a 2(1H)-pyridinone compound represented by the formula (XVII): (wherein XIII represents a hydrogen atom, or a hydroxy group, or a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a C2-C4 alkenyl group, or a C2-C4 alkynyl group, or a C1-C4 alkoxy group, or a R1—S(O)l-group (R1 represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), or a nitro group, or a cyano group, or a carboxy group, or a C1-C4 alkoxycarbonyl group, or a (RI)2N-group (RI is as defined above), or a RI—CO—NH-group (RI is as defined above), or a RIO—CO—NH-group (RI is as defined above), or a RINH—CO—NH-group (RI is as defined above), or a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group) or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), K represents an integer of 1 to 4, when k is an integer of 2 to 4, XIII's may be different, rII and rII′ are the same or different, and represent a hydrogen atom or a C1-C4 alkyl group]; and an inert carrier; 18. A 2(1H)-pyridinone compound represented by the formula (XVIII): [wherein XIII′ represents a C2-C4 alkyl group, or a C1-C4 alkyl group substituted with a halogen atom or a C1-C4 alkoxy group, or a C2-C4 alkenyl group, or a C2-C4 alkynyl group, or a C2-C4 alkoxy group, or a RI—S(O)l-group (RI represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), or a cyano group, or a carboxy group, or a C1-C4 alkoxycarbonyl group, a (RII)2N-group (RII represents a C2-C4 alkyl group), or a RI—CO—NH-group (RI is as defined above), or a RIO—CO—NH-group (RI is as defined above), or a RINH—CO—NH-group (RI is as defined above), or a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group), or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), XIII″ represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group, or a C1-C4 alkoxy group, m represents 1 or 2, when m is 2, XIII″'s may be different, and rII and rII′ are the same or different, and represent a hydrogen atom or a C1-C4alkyl group]; 19. A I type collagen gene transcription suppressing composition, which comprises a 2(1H)-quinolinone compound represented by the formula (XIX): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Yf)q, Yf is a substituent on a carbon atom, and represents a group of the following X group or Y group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yf's are the same or different and, when q is 2 or more, the adjacent two same or different Yf's constitute a group of a Z group, and may be fused with an A ring; (1) a X group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxyl group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group]; (2) a Y group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group), or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′-Yb″-group (Yb and Yb′ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); III. QA represents a hydroxy group, a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A8 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group (D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above) or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxy group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′)-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, then m is 0, and R3 is not a hydrogen atom)]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, then A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, then R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above); 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above) or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); IV. TA represents a hydrogen atom, an A9′-group (A9′ is as defined above), a D5-R4-group (D5 and R4 are as defined above) or a Mc-group (Mc is as defined above); V. Ma′ is the same as or different from Ma, and has the same meaning as that of Ma, and r represents 0, 1, 2, 3 or 4; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; and an inert carrier; 20. A 2(1H)-pyridinone compound represented by the formula (XX): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xh)p, Xh represents a hydroxy group, a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxycarbonyl group, a (R′)2N-group (R′ represents a C1-C10 alkyl group), a nitro group or a C1-C10 alkoxy group, p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xh's are the same or different, provided that when p is 2 or more, and in case that Xh is selected from a hydroxy group, a halogen atom, a C1-C10 alkyl group and a C1-C10 alkoxy group, then Xh's do not represent the same group or atom at the same time; III. In (Yh)q, Yh is a substituent on a carbon atom, and represents a substituent of the following X7 group or Y7 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yh's are the same or different and, when q is 2 or more, the adjacent two same or different Yh's constitute a group of a Z7 group, and may be fused with an A ring; (1) a X7 group: a Ma-group (Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe″N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′, and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, then a Xh-group (Xh is as defined above) is excluded; (2) a Y7 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z7 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, or a C1-C10 alkylene group), provided that when p is 0, then Yh does not fused with an A ring to form a benzo[1,3]dioxol ring; IV. QA represents a hydroxy group, a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′—N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO2—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and Bc are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxy group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′)-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, then m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, N and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)nR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1-group (R1, R1′, N and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkynyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provide that when A4 is a thio group, then A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as B4, provided that when B4 is a thio group, then R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above); 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above) or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); V. TA represents a hydrogen atom, an A9′-group (A9′ is as defined above), a D5-R4-group (D5 and R4 are as defined above) or a Mc-group (Mc is as defined above); VI. Ma′ is the same as or different from Ma, and has the same meaning as that of Ma, and r represents 0, 1, 2, 3 or 4, provided that when an A ring is a benzene ring, then q is not 0 and, when an A ring is a benzene ring or a pyridine ring, then p and q are not 0 at the same time, in either case; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; 21. A I type collagen gene transcription suppressing composition, which comprises a 2(1H)-quinolinone compound represented by the formula (XXI): [wherein XIV represents a hydrogen atom, or a hydroxy group, or a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a C2-C4 alkenyl group, or a C2-C4 alkynyl group, or a C1-C4 alkoxy group, or a RI—S(O)l-group (RI represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), or a nitro group, or a cyano group, or a carboxy group, or a C1-C4 alkoxycarbonyl group, or a (RI)2N-group (RI is as defined above), or a RI—CO—NH-group (RI is as defined above), or a RI—O—CO—NH-group (RI is as defined above), or a RINH—CO—NH-group (RI is as defined above), or a (RI′)2N—CO-group (RI′represents a hydrogen atom or a C1-C4 alkyl group), or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), k represents an integer of 1 to 4 and, when k is an integer of 2 to 4, XIV's may be different, and rII and rII′ are the same or different, and represent a hydrogen atom or a C1-C4 alkyl group]; and an inert carrier; 22. A 2(1H)-quinolinone compound represented by the formula (XXII): [wherein XIV′ represents a C2-C4 alkyl group, or a C1-C4 alkyl group substituted with a halogen atom or a C1-C4 alkoxy group, or a C2-C4 alkenyl group, or a C2-C4 alkynyl group, or a C2-C4 alkoxy group, or a RI—S(O)l-group (RI represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), or a cyano group, or a carboxy group, or a C2-C4 alkoxycarbonyl group, or a (RII)2N-group (RII represents a C2-C4 alkyl group), or a RI—CO—NH-group (RI is as defined above), or a RIO—CO—NH-group (RI is as defined above), or a RINH—CO—NH-group (RI is as defined above), or a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group), or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), XIV″ represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group, m represents 1 or 2 and, when m is 2, XIV″'s may be different, and rII and rII′ are the same or different, and represent a hydrogen atom or a C1-C4alkyl group]; 23-24. (canceled) 25. A composition for improving tissue fibrosis, which comprises a compound according to claim 5, and an inert carrier; 26. A method for improving tissue fibrosis, which comprises administering an effective amount of a compound according to claim 5 to a mammal in need thereof; 27. (canceled) 28. A composition for suppressing the activity of TGF-β, which comprises a compound according to claim 5, and an inert carrier; 29. (canceled) 30. A composition for hair growth which comprises a compound according to claim 5, and an inert carrier; 31. A method for growing hair, which comprises administering an effective amount of a compound according to claim 5 to a mammal in need thereof; 32-33. (canceled) 34. A composition for improving tissue fibrosis, which comprises a compound according to claim 1, and an inert carrier; 35. A method for improving tissue fibrosis, which comprises administering an effective amount of a compound according to claim 1 to a mammal in need thereof; 36. (canceled) 37. A composition for suppressing the activity of TGF-β, which comprises a compound according to claim 1, and an inert carrier; 38. (canceled) 39. A composition for hair growth which comprises a compound according to claim 1, and an inert carrier; 40. A method for growing hair, which comprises administering an effective amount of a compound according to claim 1 to a mammal in need thereof; 41. A 2(1H)-pyridinone compound represented by the formula (XXIII): 42. A 2(1H)-pyridinone compound represented by the formula (XXIV):

TECHNICAL FIELD The present invention relates to cinnamoyl derivatives use thereof. BACKGROUND ART In diseases and disorders such as hepatic cirrhosis, interstitial pulmonary disease, chronic renal failure (or disease resulting in chronic renal failure), hyperplasia scar after inflammation, postoperative scars or burn scars, scleroderma, arteriosclerosis, hypertension and the like, excessive accumulation of an extracellular matrix, a representative of which is collagen, causes fibrosis and sclerosis of tissues, resulting in decreased functions, cicatrization and the like in the organs or tissues. Such excessive accumulation of an extracellular matrix is induced by increased production of collagen due to a breakdown of balance between biosynthesis and degradation of collagen and the like. In fact, it has been observed that expression of a collagen gene, in particular, a Type I collagen gene has been increased in a fibrotic tissue [e.g. J. Invest. Dermatol., 94, 365, (1990) and Proc. Natl. Acad. Sci. USA, 88, 6642, (1991)]. It has been also observed that the amount of TGF-β, which is a cytokine, has been increased in a fibrotic tissue [e.g. J. Invest. Dermatol., 94, 365, (1990) and Proc. Natl. Acad. Sci. USA, 88, 6642, (1991)]. It has been shown that TGF-β has increased expression of a Type I collagen gene and been involved in increased production of collagen and, consequently, fibrosis of a tissue [e.g. Lab. Invest., 63, 171, (1990) and J. Invest. Dermatol., 94, 365, (1990)]. It has been also shown that by administering an anti-TGF-β antibody or a soluble anti-TGF-β receptor to a model animal of tissue fibrosis, improvement of tissue fibrosis has been achieved and thereby the tissue function has been also improved [e.g. Diabetes, 45, 522-530, (1996), Proc. Natl. Acad. Sci. USA, 96, 12719-12724, (1999) and Proc. Natl. Acad. Sci. USA, 97, 8015-8020, (2000)]. It has been also known that by administering a compound which suppressively acts on intracellular signal transduction via TGF-β, improvement in fibrosis of a tissue has been achieved and thereby the tissue function has been also improved [e.g. Autoimmunity, 35, 277-282, (2002), J. Hepatol., 37, 331-339, (2002) and Life Sci., 71, 1559-1606, (2002)]. Thus, there is a need for development and provision of a drug which improves fibrosis of a tissue by decreasing expression of a Type I collagen gene in the tissue to reduce accumulation of collagen (i.e. a collagen accumulation-suppressing agent and a fibrosing disease-treating agent). DISCLOSURE OF THE INVENTION Under these circumstances, the present inventors have intensively studied and, as a result, found out that compounds represented by the following formulas (I) to (V), (VII), (VIII), (X), (XI), (XIII), and (XV) to (XIV) has the ability to suppress transcription of I type collagen gene. Thus, the present invention has been completed. That is, the present invention provides: 1. A I type collagen gene transcription suppressing composition, which comprises a cinnamoyl compound represented by the formula (I): [wherein I. A represents a benzene ring or a pyridine ring, in (Yα)q, Yα is a substituent on a carbon atom, and represents a substituent of the following X0 group or Y0 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yα's are the same or different and, when q is 2 or more, the adjacent two same or different Yα's constitute a group of a Z0 group, and may be fused with an A ring; (1) a X0 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a RbO—CO—NRe′—Rd-group (Rb, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—Re′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group.]; (2) a Y0 group: a Mb0-Rd-group [Mb0 represents a Mc0-group {Mc0 represents a Md0-Rd′-group {Md0 represents a 6 to 10-membered aryl group optionally substituted with a Ma-group (Ma is as defined above), or 5 to 10-membered heteroaryl group optionally substituted with Ma group (Ma is as defined above), or a 3 to 10-membered hydrocarbon ring or heterocycle optionally substituted with a Ma-group (Ma is defined above) and optionally containing an unsaturated bond, or a (b0)-group (in (b0), G0 constitutes a saturated or unsaturated non-aromatic 5 to 14-membered hydrocarbon ring or heterocycle optionally having a substituent), a (c0)-group (in (C0), J0 may contain a nitrogen atom, and constitutes an aromatic 5 to 7-membered ring), a (d0)-group {d0 represents a 5 to 12-membered hydrocarbon ring substituted with carbonyl group or a thiocarbonyl group and, further, optionally substituted with an oxy group, a thio group, a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkenyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkenyl group}, a sulfinyl group, or a sulfonyl group} or an (e0)-group {e0 constitutes a 5 to 12-membered hydrocarbon ring optionally substituted with a carbonyl group, a thiocarbonyl group, an oxy group, a thio group, a —NR1-group (R1 is as defined above), a sulfinyl group or a sulfonyl group}, Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc0-Ba-group (Mc0 and Ba are as defined above), a Mc0-CO-group (Mc0 is as defined above), a Mc0-CO—O group (Mc0 is as defined above), a Mc0O—CO-group (Mc0 is as defined above), a Mc0ReN-group (Mc0 and Re are as defined above), a Mc0-CO—NRe-group (Mc0 and Re are as defined above), a Mc0O—CO—NRe-group (Mc0 and Re are as defined above), a Mc0ReN—CO-group (Mc0 and Re are as defined above), a Mc0ReN—CO—NRe′-group (Mc0, Re and Re′ are as defined above), a Mc0ReN—C(═NRe′)—NRe″-group (Mc0, Re, Re′ and Re″ are as defined above), a Mc0-SO2—NRe-group (Mc0 and Re are as defined above) or Mc0ReN—SO2-group (Mc0 and Re are as defined above), and Rd is as defined above.]; (3) a Z0 group: a group which is a 5 to 12-membered hydrocarbon ring or heterocycle having a halogen atom, a C1-C10 alkoxy group, a C3-C10 alkenyloxy group, a C3-C10 alkynyloxy group, a carbonyl group, a thiocarbonyl group, an oxy group, a thio group, a sulfinyl group or a sulfonyl group, is an aromatic or non-aromatic monocyclic or fused ring, and is fused with an A ring; II. Qα represents an optionally substituted hydroxyl group, or an optionally substituted amino group; III. Wα represents an oxygen atom or a-NTα-group (Tα represents a hydrogen atom, or a substituent on a nitrogen atom.); IV. Kα and Lα are the same or different, and represent a hydrogen atom, or a substituent on a carbon atom, or Kα and Lα may form a C1-C10 alkylene group optionally having a substituent or a C1-C10 alkenylene group optionally having a substituent; provided that when an A ring is a benzene ring, Wα is an oxygen atom, La is a methyl group, Kα is a hydrogen atom, and Qα is a C1-C4 alkoxy group, a C3-C4 alkenyloxy group or a C3-C4 alkynyloxy group, then q is not 0 and, when an A ring is a benzene ring, Wα is an oxygen atom, Lα is a methyl group, Kα is a hydrogen atom, and Qα is a C1-C4 alkoxy group, a C3-C4 alkenyloxy group or a C3-C4 alkynyloxy group, then q is 1, and Yα is not a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a nitro group, or a C1-C4 alkoxy group, or a RB-group (R represents a C1-C4 haloalkyl group, and B represents an oxy group or a thio group) and, when A is a benzene ring, Wα is an oxygen atom, Lα and Kα form a 1,3-butadienylene group, and Qα is a methoxy group, then q is 1, and Yα is not a methoxy group or an ethoxy group and, when A is a benzene ring, Wα is an oxygen atom, Lα and Kα form a 1,3-butadienylene group, and Qα is a hydroxyl group, then q is 1, and Yα is not an ethoxy group; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or the different as far as they are selected in the range]; and an inert carrier; 2. A I type collagen gene transcription suppressing composition, which comprises a cinnamoyl compound represented by the formula (II): [wherein I. A represents a benzene ring or pyridine ring; II. In (YA0)q, YA0 is a substituent on a carbon atom, and represents a substituent of the following X0 group and Y0 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, YA0's are the same or different and, when q is 2 or more, the adjacent two same or different YA0's constitute a group of a Z0 group, and may be fused with an A ring; (1) a X0 group: a Ma-group [Ma represents a Rb group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxyl group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re′ has the same meaning as that of Re and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbC—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group.]; (2) a Y0 group: a Mb0-Rd-group [Mb0 represents a Mc0 group {Mc0 represents a Md0-Rd′-group {Md0 represents a 6 to 10-membered aryl group optionally substituted with a Ma-group (Ma is as defined above), or a 5 to 10-membered heteroaryl group optionally substituted with a Ma-group (Ma is as defined above), a 3 to 10-membered hydrocarbon ring or heterocycle optionally substituted with a Ma-group (Ma is as defined above) and optionally containing an unsaturated bond, or a (b0)-group (in (b0), G0 constitutes a saturated or unsaturated non-aromatic 5 to 14-membered hydrocarbon ring or heterocycle optionally having a substituent), a (c0)-group (in (c0), J0 may contain a nitrogen atom, and constitutes an aromatic 5 to 7-membered ring), a (d0)-group {d0 constitutes a 5 to 12-membered hydrocarbon ring substituted with a carbonyl group or a thiocarbonyl group and, further, optionally substituted with an oxy group, a thio group, a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and a B1 represents an oxy group, a thio group, a sulfinyl group or sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, a sulfinyl group or a sulfonyl group} or an (e0)-group {e0 represents a 5 to 12-membered hydrocarbon ring optionally substituted with a carbonyl group, a thiocarbonyl group, an oxy group, a thio group, a —NR1-group (R1 is as defined above), a sulfinyl group or a sulfonyl group}, Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc0-Ba-group (Mc0 and Ba are as defined above), a Mc0-CO-group (Mc0 is as defined above), a Mc0-CO—O-group (Mc0 is as defined above), a Mc0O—CO-group (Mc0 is as defined above), a Mc0ReN-group (Mc0 and Re are as defined above), a Mc0-CO—NRe-group (Mc0 and Re are as defined above), a Mc0O—CO—NRe-group (Mc0 and Re are as defined above), a Mc0ReN—CO-group (Mc0 and Re are as defined above), a Mc0ReN—CO—NRe′-group (Mc0, Re and Re′ are as defined above), a Mc0ReN—C(═NRe′)—NRe″-group (Mc0, Re, Re′ and Re″ are as defined above), a Mc0-SO2—NRe-group (Mc0 and Re are as defined above) or Mc0ReN—SO2-group (Mc0 and Re are as defined above), and Rd is as defined above.]; (3) a Z0 group: a group which is a 5 to 12-membered hydrocarbon ring or heterocycle ring optionally having a halogen atom, a C1-C10 alkoxy group, a C3-C10 alkenyloxy group, a C3-C10 alkynyloxy group, a carbonyl group, a thiocarbonyl group, an oxy group, a thio group, a sulfinyl group or a sulfonyl group, is an aromatic or non-aromatic monocyclic or fused ring, and is fused with an A ring; III. QA0 represents a hydroxyl group, a (b0)-group ((b0) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1)-group {m represents 0 or 1, and R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ and R1 are the same or different, and has the same meaning as that of R1, and Bc is as defined above), a (b0)—SO2—Bc-group ((b0) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc0-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc0 and Bc are as defined above) or a Mc0-Bc-group (Mc0 and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1-group, and R4 is as defined above}, a (b0)-R4-group ((b0) is as defined above, and R4 is as defined above), a (c0)-R4-group ((c0) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b0)-group ((b0) is as defined above), a (c0)-group ((c0) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b0)-R4′-group ((b0) and R4′ are as defined above), a (c0)-R4′-group ((c0) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), (b0)-R4′-group ((b0) and R4′ are as defined above), a (c0)-R4′-group ((c0) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4-group: a hydroxy group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)-m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′)-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, then m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b0)-R4-group ((b0) and R4 are as defined above), a ((c0)-R4-group ((c0) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an R4—SO2—R4-group {A4 is as defined above, and R4 is as defined above}; B4 represents an oxy group, a thio group or a —N((O)mR1) group (R1 and m are as defined above), provided that when B4 is a thio group, then A3 is not a hydrogen atom.]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, then R2 is not hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded; R1 is as defined above); 4) a (b0)-group ((b0) is as defined above); 5) a (c0)-group ((c0) is as defined above); or 6) a R1-A1N—NR1′-group (R1, A1 and R1′ are as defined above); IV. WA0 represents an oxygen atom or a —NTA0-group [TA0 represents a hydrogen atom, an A9′ group (A9′ is as defined above), a D5-R4-group (D5 and R4 are as defined above) or a Mc0-group (Mc0 is as defined above)]; V. KA0 represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, LA0 represents a hydrogen atom, a C1-C10 alkyl group or a Mb0-group (Mb0 is as defined above), or KA0 and LA0 may form a C1-C10 alkylene group, or a C1-C10 alkenylene group optionally substituted with single or the same or different plural Ma groups, provided that when an A ring is a benzene ring, WA0 is an oxygen atom, LA0 is a methyl group, KA0 is a hydrogen atom, and QA0 is a C1-C4 alkoxy group, a C3-C4 alkenyloxy group or a C3-C4 alkynyloxy group, then q is not 0 and, when an A ring is a benzene ring, WA0 is an oxygen atom, LA0 is a methyl group, KA0 is a hydrogen atom, and QA0 is a C1-C4 alkoxy group, a C3-C4 alkenyloxy group or a C3-C4 alkynyloxy group, then q is 1, and YA0 is not a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a nitro group, or a C1-C4 alkoxy group, or a RB-group (R represents a C1-C4 haloalkyl group, and B represents an oxy group or a thio group) and, when A is a benzene ring, WA0 is an oxygen atom, LA0 and KA0 form a 1,3-butadienylene group, and QA0 is a methoxy group, q is 1, and YA0 is not a methoxy group or an ethoxy group and, when A is a benzene ring, WA0 is an oxygen atom, LA0 and KA0 form a 1,3-butadienylene group, and QA0 is a hydroxy group, then q is 1, and YA0 is not an ethoxy group; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of the substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or the different as far as they are selected in the range]; and an inert carrier; 3. A I type collagen gene transcription suppressing composition, which comprises a cinnamoyl compound represented by the formula (III): [wherein I. A represents a benzene ring or a pyridine ring; II. In (YA)q, YA is a substituent on a carbon atom, and represents a substituent of the following X group or Y group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, YA's are the same or the different and, when q is 2 or more, the adjacent two same or different YA's constitute a group of a Z group, and may be fused with an A ring; (1) a X group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd— group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′—Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re″ and Re″ are the same or different Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), ReRe′N—SO2—Rd-group (Re, Re″ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group]; (2) a Y group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a-NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group), or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methine group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); III. QA represents a hydroxyl group, a (b)-group ((b) is as defined above), an A9-B6—Bc-group (A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a C2-C10haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxyl group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N(O)nR1′-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N(O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D group: a cyano group, a R1R1′NC′(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C(—O—) group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}; B4 represents an oxy group, a thio group or a —N((O)mR1)— group (R1 and m are as defined above) provided that when B4 is a thio group, A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, a R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above); 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above); or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); IV. WA represents an oxygen atom or a —NTA-group [TA represents a hydrogen atom, an A9′-group (A9′ is as defined above), a D5-R4-group (D5 and R4 are as define above) or a Mc-group (Mc is as defined above)]; V. KA represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, LA represents a hydrogen atom, a C1-C10 alkyl group or a Mb-group (Mb is as defined above), or KA and LA may form a C1-C10 alkylene group or a —C(Ma′)=C(Ma″)-C(Ma′″)=C(Ma″″)-group (Ma′, Ma″, Ma′″ and Ma″″ are the same or different, are the same as or different from Ma, and represent a hydrogen atom or Ma); and provided that when an A ring is a benzene ring, WA is an oxygen atom, LA is a methyl group, KA is a hydrogen atom, and QA is a C1-C10 alkoxy group, a C3-10 alkenyloxy group or a C3-C10 alkynyloxy group, then q is not 0 and, when an A ring is a benzyl ring, WA is an oxygen atom, LA is a methyl group, KA is a hydrogen atom, and QA is a C1-C10 alkoxy group, a C3-C10 alkenyloxy group or a C3-C10 alkynyloxy group, then q is 1, and YA is not a halogen atom, or C1-C10 alkyl group optionally substituted with a halogen atom or a C1-C10 alkoxy group, or a nitro group, or a C1-C10 alkoxy group, or a RB-group (R represents a C1-C10haloalkyl group and B represents an oxy group or a thio group) and, when A is a benzene ring, WA is an oxygen atom, LA and KA form a 1,3-butadienylene group, and QA is a hydroxyl group or a C1-C10 alkoxy group, then q is 1, and YA is not a C1-C10 alkoxy group; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; and an inert carrier; 4. A I type collagen gene transcription suppressing composition, which comprises a 2H-pyran-2-one compound represented by the formula (IV): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xa)p, Xa is a substituent on a carbon atom, and represents a halogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a C1-C10 alkoxy group, or a nitro group, a C1-C10 alkoxy group, or a RB-group (R represents a C1-C10 haloalkyl group, and B represents an oxy group or a thio group), p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xa's are the same or different; III. In (Ya)q, Ya is a substituent on a carbon atom, and represents a substituent of the following X1 group or Y1 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Ya's are the same or different and, when q is 2 or more, the adjacent two same or different Ya's constitute a Z1 group, and may be fused with an A ring; (1) a X1 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxyl group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re″ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, a Xa-group (Xa is as defined above) is excluded; (2) a Y1 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above) or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C—C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group, or a thio group), or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z1 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); IV. QA represents a hydroxyl group, a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group {(b) is as defined above, and R4 is as defined above}, a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxyl group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N(O)nR1′)-group (R1′ is as defined above, and n represents 0 or 1, B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, m is 0, and R3 is not a hydrogen atom)}]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A)-group (R1, R1′, n and N1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group. (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}; B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above), 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above); or 6) a R1A1N—NR1′-group (R1, R1 and R1′ are as defined above); V. Ka represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, La represents a hydrogen atom, a C1-C10 alkyl group or a Mb-group (Mb is as defined above), or Ka and La may form a C1-C10 alkylene group, provided that when Ka is a hydrogen atom, La is a methyl group and an A ring is a benzene ring, p is 2, 3 or 4 in the case that q is 0; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in a range]; and an inert carrier; 5. A 2H-pyran-2-one compound represented by the formula (V): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xb)p, Xb is a substituent on a carbon atom, and represents a halogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a C1-C10 alkoxy group, or a nitro group, or a C2-C10 alkoxy group, or a RB-group (R represents a C1-C10 haloalkyl group, and B represents an oxy group or a thio group), p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xb's are the same or different; III. In (Yb)q, Yb is a substituent on a carbon atom, and represents a substituent of the following X2 group or Y2 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yb's are the same or different and, when q is 2 or more, the adjacent two same or different Yb's constitutes a group of a Z2 group, and may be fused with an A ring; (1) a X2 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRd″—Rd-group (Re, Re′ and Re″ are the same or different, Re has the same meaning as that of Re′, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that, when A represents a benzene ring, then, a halogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a C1-C10 alkoxy group, or a nitro group, or a C1-C10 alkoxy group, or a RB-group (R and B are as described above) is excluded; (2) a Y2 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above) or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group, or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a NR1— group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d) group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Rd′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z2 group: a —N═C(Ya) Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); III. QA′ represents a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″—SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1 and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a C2—B1—R4′-group (C2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8-group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″-group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4″ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxyl group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C1 alkynyl group, R0 represents a hydrogen atom, C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, and m′ represents 0 or 1 and, when B3 is a sulfonyl group, m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: O═C(R3) group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), an R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4— (O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3) group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1-group (R1, R1′, n and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group. (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4 provided that when B4 is a thio group, R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above provided that a hydrogen atom is excluded, and R1 is as defined above), 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above); or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); IV. Ka represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, La represents a hydrogen atom, a C1-C10 alkyl group or a Mb-group (Mb is as defined above), or Ka and La may form a C1-C10 alkylene group, provided that when an A ring is a benzene ring, p is 2, 3 or 4 in the case that q is 0; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; 6. A 2H-pyran-2-one compound represented by the formula (VI): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xc)p, Xc is a substituent on a carbon atom, and represents a hydroxyl group, or a halogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a C1-C10 alkoxy group, or a C2-C10 alkenyl group, or a R′—S(O)l-group (R′ represents a C1-C10 alkyl group, and l represents 0, 1 or 2), or a cyano group, or a C1-C10 alkoxycarbonyl group, or an aminocarbonyl group, or a (R′)2N-group (R′ is as defined above), or a R′CO—NH-group (R′ is as defined above), or a nitro group, or a C1-C10 alkoxy group, or a RB-group (R represents a C1-C10 haloalkyl group, and B represents an oxy group or a thio group), p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xc's are the same or different; III. In (Yc)q, Yc is a substituent on a carbon atom, and represents a substituent of the following X3 group or Y3 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yc's are the same or different and, when q is 2 or more, the adjacent two same or different Yc's constitute a group of a Z3 group, and may be fused with an A ring; (1) a X3 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, then a hydroxy group, or a halogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a C1-C10 alkoxy group, or a C2-C10 alkenyl group, or a R′—S(O)l-group (R′ represents a C1-C10 alkyl group, and l represents 0, 1 or 2), or a cyano group, or a C1-C10 alkoxycarbonyl group, or an aminocarbonyl group, or a (R′)2N-group (R′ is as defined above), or a R′CO—NH-group (R′ is as defined above), or a nitro group or a C1-C10 alkoxy group is excluded; (2) a Y3 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group) or a C3-C10 alkenyl group, or a C3-C10 alkynyl group), or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above], provided that when P is 0, then a morpholino group, or a phenyl group, or a phenoxy group substituted with a trifluoromethyl group, or a phenoxy group substituted with single or plural halogen atoms is excluded; (3) a Z3 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group), provided that when p is 0, then Yc is not fused with an A ring to form a benzo[1,3]dioxol ring; IV. Ka represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, La represents a hydrogen atom, a C1-C10 alkyl group or a Mb-group (Mb is as defined above), or Ka and La may form a C1-C10 alkylene group, provided that when an A ring is a benzene ring, then q is not 0 and, when an A ring is a benzene ring or a pyridine ring, then p and q are not 0 at the same time, in either case; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above, and between the plurality of substituents, a selection range of selected substituents is the same, while the selected range may be the same or different as far as they are selected in the range]; 7. A I type collagen gene transcription suppressing composition, which comprises a 2H-pyran-2-one compound represented by the formula (VII): [wherein XI represents a C2-C4 alkenyl group, a C2-C4 alkynyl group, a RI—S(O)l-group (RI represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), a cyano group, a carboxy group, a C1-C4 alkoxycarbonyl group, a (RI)2N-group (RI is as defined above), a RI—CO—NH-group (RI is as defined above), a RIO—CO—NH-group (RI is as defined above), a RINH—CO—NH-group (RI is as defined above) or a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group), X1′ represents a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a nitro group, or a C1-C4 alkoxy group, or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), k represents 0 or 1, k′ represents an integer of 0 to 4, when k is 0, k′ is an integer of 2 to 4 and, when k′ is 2 to 4, XI′'s may be different, and rI is a C1-C4 alkyl group, a C2-C4 alkenyl group or a C2-C4 alkynyl group], and a inert carrier; 8. A 2H-pyran-2-one compound represented by the formula (VIII): [wherein XI represents a C2-C4 alkenyl group, a C2-C4 alkynyl group, a RI—S(O)l-group (RI represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), a cyano group, a carboxy group, a C1-C4 alkoxycarbonyl group, a (RI)2N-group (RI is as defined above), a RI—CO—NH-group (RI is as defined above), a RIO—CO—NH-group (RI is as defined above), a RINH—CO—NH-group (RI is as defined above) or (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group), XI″ represents a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a nitro group, or a C2-C4 alkoxy group, or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), k represents 0 or 1, k′ represents an integer of 0 to 4, when k is 0, k′ is an integer of 2 to 4 and, when k′ is 2 to 4, XI″'s may be different, and rI is a C1-C4 alkyl group, a C2-C4 alkenyl group or a C2-C4 alkynyl group]; 9. A 2H-pyran-2-one compound represented by the formula (IX): (wherein XI′″ represents a C2-C4 alkenyl group, a C2-C4 alkynyl group, a carboxy group, a C2-C4 alkoxycarbonyl group or a (RII)2N-group (RII represents a C2-C4 alkyl group), XI″ represents a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a nitro group, or a C2-C4 alkoxy group, or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), k represents 0 or 1, k″ represents an integer of 0 to 2, when k is 0, k″ is 2 and, when k″ is 2, X″'s are different]; 10. A I type collagen gene transcription suppressing composition, which comprises a 2H-1-benzopyran-2-one compound represented by the formula (X): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xd)p, Xd is a substituent on a carbon atom, and represents a methoxy group or an ethoxy group, p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xd's are the same or different; III. In (Yd)q, Yd is a substituent on a carbon atom, and represents a substituent of the following X4 group or Y4 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yd's are the same or different and, q is 2 or more, the adjacent two same or different Yd's constitute a group of a Z4 group, and may be fused with an A ring; (1) a X4 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen, atom, a nitro group, a cyano group, a hydroxyl group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re′″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, then a methoxy group and an ethoxy group are excluded; (2) a Y4 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group} or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z4 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); IV. QA represents a hydroxyl group, a (b) group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as define above, and R4′ represents a C2-C4 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and D4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxy group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)mR1′)-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, then m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridinyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, then A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, then R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above), 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above) or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); V. Ma′ is the same as or different from Ma, and has the same meaning as that of Ma, and r represents 0, 1, 2, 3 or 4, provided that when an A ring is a benzene ring, in case that q and r are 0, then p is 2, 2, 3 or 4; and the “as defined above” in the same symbol between a plurality of substituent indicates that the plurality of the substituents independently represent the same meaning as that of described above and, between the plurality of substituents, a selection range of the selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; and an inert carrier; 11. A 2H-1-benzopyran-2-one compound represented by the formula (XI): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xd)p, Xd is a substituent on a carbon atom, and represents a methoxy group or an ethoxy group, p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xd's are the same or different; III. In (Yd)q, Yd is a substituent on a carbon atom, and represents a substituent of the following X4 group or Y4 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yd's are the same or different and, when q is 2 or more, the adjacent two same or different Yd's constitute a group of a Z4 group, and may be fused with an A ring; (1) a X4 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, then a methoxy group and an ethoxy group are excluded; (2) Y4 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2, and J3 are the same or different and, represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z4 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′-Yb″-group (Yb and Yb′ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and a C1-C10 alkylene group); IV. QA′ represents a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′ group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A9′ group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxy group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′)-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, then m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R)—(O)k)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C—(OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, R2 is not a hydrogen atom), or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above); 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above) or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); V. Ma′ is the same as or different from Ma, and has the same meaning as that of Ma, and r represents 0, 1, 2, 3 or 4, provided that when an A ring is a benzene ring, in case that q is 0, then p is 2, 3 or 4; and the “as defined above” between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; 12. A 2H-1-benzopyran-2-one compound represented by the formula (XII): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xe)p, Xe represents a hydroxy group, a halogen atom, a C1-C10 alkyl group, a R′—S(O)l- group (R′ represents a C1-C10 alkyl group, and l represents 0, 1 or 2), a cyano group, a HOCO—CH═CH-group, a (R′)2N-group (R′ is as defined above), a R′CO—NH-group (R′ is as defined above), a nitro group or a C1-C10 alkoxy group, p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xd's are the same or different; III. In (Ye)q, Ye is a substituent on a carbon atom, and represents a substituent of the following X5 group or Y5 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Ye's are the same or different and, when q is 2 or more, the adjacent two same or different Ye's constitute a group of a Z5 group, and may be fused with an A ring; (1) a X5 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxyl group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Rd represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re″ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, then a Xe-group (Xe is as defined above) is excluded; (2) a Y5 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group fin (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z5 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group), provided that when p is 0, then Ye is not fused with an A ring to form a benzo[1,3]dioxol ring; IV. Ma′ is the same as or different from Ma, and has the same meaning as that of Ma, and r represents 0, 1, 2, 3 or 4, provided that when an A ring is a benzene ring, then q is not 0; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; 13. A 2H-1-benzopyran-2-one compound represented by the formula (XIII): [wherein XII represents a hydrogen atom, or a hydroxyl group, or a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a C2-C4 alkenyl group, or a C2-C4 alkynyl group, or a C3-C4 alkoxy group, or a RI—S(O)l-group (RI represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), or a nitro group, or a cyano group, or a carboxy group, or a C1-C4 alkoxycarbonyl group, or a (RI)2N-group (RI is as defined above), or a RI—CO—NI-group (RI is as defined above), or a RIO—CO—NH-group (RI is as defined above), or a RINH—CO—NH-group (RI is as defined above), or a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group), or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), k represents an integer of 1 to 4 and, when k is an integer of 2 to 4, XII's may be different, and rI represents a C1-C4 alkyl group, a C2-C4 alkenyl group or a C2-C4 alkynyl group]; 14. A 2H-1-benzopyran-2-one compound represented by the formula (XIV): [wherein XII′ represents a C1-C4 alkyl group substituted with a halogen atom or a C1-C4 alkoxy group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C3-C4 alkoxy group, a RI—S(O)l-group (RII represents a C2-C4 alkyl group, and l represents an integer of 0 to 2), a cyano group, a carboxy group, a C1-C4 alkoxycarbonyl group, a (RII)2N-group (RII is as defined above), a RI—CO—NH-group (RI represents a C1-C4 alkyl group), a RIO—CO—NH-group (RI is as defined above), a RINH—CO—NH-group (RI is as defined above), a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group) or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), XII″ represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group or a C3-C4 alkoxy group, m represents 1 or 2 and, when m is 2, XII″'s may be different]; 15. A I type collagen gene transcription suppressing composition, which comprises a 2(1H)-pyridinone compound represented by the formula (XV): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Yf)q, Yf is a substituent on a carbon atom, and represents a group of the following X group or Y group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yf's are the same or different and, when q is 2 or more, the adjacent two same or different Yf's constitutes a group of a Z group, and may be fused with an A ring; (1) a X group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group]; (2) a Y group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a is thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an imino group optionally substituted with an oxy group, or a thio group, or a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4alkylene group optionally substituted with a halogen atom, or a C1-C4alkylene group optionally having an oxo group), or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); III. QA represents a hydroxyl group, a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc group (R1 is as defined above, R1′ is the same as or different of R1, and has the same meaning of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or a A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a 2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxy group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′)-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, then m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4— (O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above)], a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group, or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, then A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from R4, and has the same meaning as that of B4, provided that when R4 is a thio group, then R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above); 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above) or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); IV. TA represents a hydrogen atom, an A9′-group (A9′ is as defined above), a D5-R4-group (D5 and R4 are as defined above) or a Mc-group (Mc is as defined above); V. Ka represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, La represents a hydrogen atom, a C1-C10 alkyl group or a Mb-group (Mb is as defined above) or a Ka and La may form a C1-C10 alkylene group; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; and an inert carrier; 16. A 2(1H)-pyridinone compound represented by the formula (XVI): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xg)p, Xg represents a hydroxyl group, a halogen atom, a (R′)2N-group (R′ represents a C1-C10 alkyl group), a nitro group or a C1-C10 alkoxy group, p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xg's are the same or different; III. In (Yg)q, Yg is a substituent on a carbon atom, and represents a group of the following X6 group or Y6 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yg's are the same or different and, when q is 2 or more, the adjacent two same or different Yg's constitutes a group of a Z6 group, and may be fused with an A ring; (1) a X6 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxyl group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of a Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and R′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, then a Xg-group (Xg is as defined above) is excluded; (2) a Y6 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z6 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); IV. QA represents a hydroxyl group, a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, B1 is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above), or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group (D2 represents a substituent of the following D2 group, and R4 is as defined above), a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a -(b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4 group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above), and an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxyl group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C1-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1)— group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, then A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, then R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above); 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above) or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); V. TA represents a hydrogen atom, an A9′-group (A9′ is as defined above), a D5-R4-group (D5 and R4 are as defined above) or a Mc-group (mc is as defined above); VI. Ka represents a hydrogen atom, a halogen atom or a C1-C10 alkyl group, La represents a hydrogen atom, a C1-C10 alkyl group or a Mb-group (Mb is as defined above), or Ka and La may form a C1-C10 alkylene group, provided that when an A ring is a benzene ring, then q is not 0; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; 17. A I type collagen gene transcription suppressing composition, which comprises a 2(1H)-pyridinone compound represented by the formula (XVII): [wherein XIII represents a hydrogen atom, or a hydroxy group, or a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a C2-C4 alkenyl group, or a C2-C4 alkynyl group, or a C1-C4 alkoxy group, or a R1—S(O)l-group (R1 represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), or a nitro group, or a cyano group, or a carboxy group, or a C1-C4 alkoxycarbonyl group, or a (RI)2N-group (RI is as defined above), or a RI—CO—NH-group (RI is as defined above), or a RIO—CO—NH-group (RI is as defined above), or a RINH—CO—NH-group (RI is as defined above), or a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group) or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), K represents an integer of 1 to 4, when k is an integer of 2 to 4, XIII's may be different, rII and rII′ are the same or different, and represent a hydrogen atom or a C1-C4 alkyl group]; and an inert carrier; 18. A 2(1H)-pyridinone compound represented by the formula (XVIII): [wherein XIII′ represents a C2-C4 alkyl group, or a C1-C4 alkyl group substituted with a halogen atom or a C1-C4 alkoxy group, or a C2-C4 alkenyl group, or a C2-C4 alkynyl group, or a C2-C4 alkoxy group, or a RI—S(O)l-group (RI represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), or a cyano group, or a carboxy group, or a C1-C4 alkoxycarbonyl group, a (RII)2N-group (RII represents a C2-C4 alkyl group), or a RI—CO—NH-group (RI is as defined above), or a RIO—CO—NH-group (RI is as defined above), or a RINH—CO—NH-group (RI is as defined above), or a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group), or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), XIII″ represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group, or a C1-C4 alkoxy group, m represents 1 or 2, when m is 2, XIII″'s may be different, and rII and rII′ are the same or different, and represent a hydrogen atom or a C1-C4alkyl group]; 19. A I type collagen gene transcription suppressing composition, which comprises a 2(1H)-quinolinone compound represented by the formula (XIX): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Yf)q, Yf is a substituent on a carbon atom, and represents a group of the following X group or Y group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yf's are the same or different and, when q is 2 or more, the adjacent two same or different Yf's constitute a group of a Z group, and may be fused with an A ring; (1) a X group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxyl group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′ —Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe′N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group]; (2) a Y group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group}, or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb′ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom, or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, and represent a C1-C10 alkylene group); III. QA represents a hydroxy group, a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1)-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′N-group (R1 and R1′ are as defined above), and R4 is as defined above} or an A2-CO—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxy group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′)-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, then m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, n and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—(O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1)-group (R1, R1′, n and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R10SO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkenyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group or a —N((O)nR1)-group (R1 and m are as defined above), provided that when B4 is a thio group, then A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as that of B4, provided that when B4 is a thio group, then R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above); 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above) or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); IV. TA represents a hydrogen atom, an A9′-group (A9′ is as defined above), a D5-R4-group (D5 and R4 are as defined above) or a Mc-group (Mc is as defined above); V. Ma′ is the same as or different from Ma, and has the same meaning as that of Ma, and r represents 0, 1, 2, 3 or 4; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; and an inert carrier; 20. A 2(1H)-pyridinone compound represented by the formula (XX): [wherein I. A represents a benzene ring or a pyridine ring; II. In (Xh)p, Xh represents a hydroxy group, a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxycarbonyl group, a (R′)2N-group (R′ represents a C1-C10 alkyl group), a nitro group or a C1-C10 alkoxy group, p represents 0, 1, 2, 3 or 4 and, when p is 2 or more, Xh's are the same or different, provided that when p is 2 or more, and in case that Xh is selected from a hydroxy group, a halogen atom, a C1-C10 alkyl group and a C1-C10 alkoxy group, then Xh's do not represent the same group or atom at the same time; III. In (Yh)q, Yh is a substituent on a carbon atom, and represents a substituent of the following X7 group or Y7 group, q represents 0, 1, 2, 3, 4 or 5, when q is 2 or more, Yh's are the same or different and, when q is 2 or more, the adjacent two same or different Yh's constitute a group of a Z7 group, and may be fused with an A ring; (1) a X7 group: a Ma-group [Ma represents a Rb-group (Rb represents a C1-C10 alkyl group optionally substituted with a halogen atom), a halogen atom, a nitro group, a cyano group, a hydroxy group, a Rc—Ba—Rd-group (Rc represents a C1-C10 alkyl group optionally substituted with a halogen atom, Ba represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group, and Rd represents a single bond or a C1-C10 alkylene group), a HORd-group (Rd is as defined above), a Re—CO—Rd-group (Re represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, and Rd is as defined above), a Re—CO—O—Rd-group (Re and Rd are as defined above), a ReO—CO—Rd-group (Re and Rd are as defined above), a HO—CO—CH═CH-group, a ReRe′N—Rd-group (Re and Re′ are the same or different, Re is as defined above, Re′ has the same meaning as that of Re, and Rd is as defined above), a Re—CO—NRe′—Rd-group (Re, Re′ and Rd are as defined above), a RbO—CO—N(Re)—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—CO—Rd-group (Re, Re′ and Rd are as defined above), a ReRe′N—CO—NRe″—Rd-group (Re, Re′ and Re″ are the same or different, Re and Re′ are as defined above, Re″ has the same meaning as that of Re, and Rd is as defined above), a ReRe″N—C(═NRe″)—NRe′″—Rd-group (Re, Re′, Re″ and Re′″ are the same or different, Re, Re′ and Re″ are as defined above, Re′″ has the same meaning as that of Re, and Rd is as defined above), a Rb—SO2—NRe—Rd-group (Rb, Re and Rd are as defined above), a ReRe′N—SO2—Rd-group (Re, Re′ and Rd are as defined above), a C2-C10 alkenyl group or a C2-C10 alkynyl group], provided that when A represents a benzene ring, then a Xh-group (Xh is as defined above) is excluded; (2) a Y7 group: a Mb-Rd-group [Mb represents a Mc-group {Mc represents a Md-Rd′-group {Md represents a phenyl group optionally substituted with a Ma-group (Ma is as defined above), or a pyridyl group optionally substituted with a Ma-group (Ma is as defined above), or a naphthyl group optionally substituted with a Ma-group (Ma is as defined above), or a (b)-group {in (b), G1, G2, G4 and G5 represent a methylene group which is connected to an adjacent atom with a single bond, and may be substituted with a methyl group, or a methine group which is connected to an adjacent atom with a double bond, and may be substituted with a methyl group, and G3 represents a single bond, or a double bond, or a C1-C10 alkylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group {R1 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 alkyl group substituted with a halogen atom or a R2—B1-group (R2 represents a C1-C10 alkyl group, a C3-C10 alkenyl group or a C3-C10 alkynyl group, and B1 represents an oxy group, a thio group, a sulfinyl group or a sulfonyl group), or a C3-C10 alkenyl group, or a C3-C10 alkynyl group), or a C2-C10 alkenylene group optionally substituted with a methyl group, an oxy group, a thio group, a sulfinyl group, a sulfonyl group or a —NR1-group (R1 is as defined above)}, a (c)-group (in (c), J1, J2 and J3 are the same or different, and represent a methine group optionally substituted with a methyl group, or a nitrogen atom), a (d)-group (l is 2, 3 or 4, and Bb represents an oxy group or a thio group) or an (e)-group (l and Bb are as defined above), Rd′ is the same as or different from Rd, and has the same meaning as that of Rd}}, a Mc-Ba-group (Mc and Ba are as defined above), a Mc-CO-group (Mc is as defined above), a Mc-CO—O-group (Mc is as defined above), a McO—CO-group (Mc is as defined above), a McReN-group (Mc and Re are as defined above), a Mc-CO—NRe-group (Mc and Re are as defined above), a McO—CO—NRe-group (Mc and Re are as defined above), a McReN—CO-group (Mc and Re are as defined above), a McReN—CO—NRe′-group (Mc, Re and Re′ are as defined above), a McReN—C(═NRe′)—NRe″-group (Mc, Re, Re′ and Re″ are as defined above), a Mc-SO2—NRe-group (Mc and Re are as defined above) or a McReN—SO2-group (Mc and Re are as defined above), and Rd is as defined above]; (3) a Z7 group: a —N═C(Ya)—Ya′-group (Ya represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom, or a C1-C10 alkoxy group, and Ya′ represents an oxy group, or a thio group, or an imino group optionally substituted with a C1-C10 alkyl group), a —Yb—Yb′—Yb″-group (Yb and Yb″ are the same or different, and represent a methylene group, or an oxy group, or a thio group, or a sulfinyl group, or an imino group optionally substituted with a C1-C10 alkyl group, and Yb′ represents a C1-C4 alkylene group optionally substituted with a halogen atom or a C1-C4 alkylene group optionally having an oxo group) or a —Yc—O—Yc′—O-group (Yc and Yc′ are the same or different, or a C1-C10 alkylene group), provided that when p is 0, then Yh does not fused with an A ring to form a benzo[1,3]dioxol ring; IV. QA represents a hydroxy group, a (b)-group ((b) is as defined above), an A9-B6—Bc-group [A9 represents a substituent of the following A7 group or A8 group, B6 represents a carbonyl group or a thiocarbonyl group, and Bc represents an oxy group or a —N((O)mR1-group (m represents 0 or 1, and R1 is as defined above), provided that when A9 is a hydrogen atom, then Bc is not a sulfonyl group], an A7″-SO2—Bc-group (A7″ represents a substituent of the following A7″ group, and Bc is as defined above), an A8-SO2—Bc-group (A8 represents a substituent of the following A8 group, and Bc is as defined above, provided that A8 is not a hydrogen atom), a R1R1′N—SO2—Bc-group (R1 is as defined above, R1′ is the same as or different from R1, and has the same meaning as that of R1, and Bc is as defined above), a (b)-SO2—Bc-group ((b) and Bc are as defined above), an A9′-Bc-group (A9′ represents a substituent of the following A7′ group or A8′ group, and Bc is as defined above), a D5-R4—Bc-group (D5 represents a substituent of the following D5 group, R4 represents a C1-C10 alkylene group, and Bc is as defined above), a Mc-B3—Bc-group (B3 represents a carbonyl group, a thiocarbonyl group or a sulfonyl group, and Mc and Bc are as defined above) or a Mc-Bc-group (Mc and Bc are as defined above); (1) an A7 group: a C2-C10 alkenyl group optionally substituted with a halogen atom, a C2-C10 alkynyl group, a C3-C10 haloalkynyl group, a R2—B1—R4-group (R2 and B1 are as defined above, and R4 is as defined above), a D4-R4-group (D4 represents a substituent of the following D4 group, and R4 is as defined above), a D5-R4-group (D5 represents a substituent of the following D5 group, and R4 is as defined above), a D1-R4-group {D1 represents a substituent of the following D1 group, and R4 is as defined above}, a (b)-R4-group ((b) is as defined above, and R4 is as defined above), a (c)-R4-group ((c) is as defined above, and R4 is as defined above), a D2-R4-group {D2 represents a substituent of the following D2 group, and R4 is as defined above}, a D3-R4-group {D3 represents a substituent of the following D3 group, and R4 is as defined above}, an A4-SO2—R4-group {A4 represents a (b)-group ((b) is as defined above), a (c)-group ((c) is as defined above) or a R1R1′-N-group (R1 and R1′ are as defined above), and R4 is as defined above) or an A2-CO2—R4-group (A2 represents a substituent of the following A2 group, and R4 is as defined above); (2) an A8 group: a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom; (3) an A7′ group: a C3-C10 alkenyl group optionally substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2 and B1 are as defined above, and R4′ represents a C2-C10 alkylene group), a D4-R4′-group (D4 and R4′ are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a D3-R4′-group (D3 and R4′ are as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (4) an A8′ group: a C1-C10 alkyl group or a C2-C10 haloalkyl group; (5) an A7″ group: a C2-C10 alkenyl group, a C3-C10 alkenyl group substituted with a halogen atom, a C3-C10 alkynyl group optionally substituted with a halogen atom, a R2—B1—R4′-group (R2, B1 and R4′ are as defined above), a D4-R4′-group (D4 and R4′ are as defined above), a D5-R4-group (D5 and R4 are as defined above), a D1-R4′-group (D1 and R4′ are as defined above), a (b)-R4′-group ((b) and R4′ are as defined above), a (c)-R4′-group ((c) and R4′ are as defined above), a D2-R4-group (D2 and R4 are as defined above), a NO2—R4-group (R4 is as defined above) or an A2-CO—R4-group (A2 and R4 are as defined above); (i) a D4 group: a hydroxy group or an A1-O-group [A1 represents a R3—(CHR0)m—(B2—B3)m′-group {R3 represents a hydrogen atom, or a C1-C10 alkyl group optionally substituted with a halogen atom or a R2—B1-group (R2 and B1 are as defined above), or a C2-C10 alkenyl group, or a C2-C10 alkynyl group, R0 represents a hydrogen atom, a C1-C10 alkyl group or a C2-C10 haloalkyl group, m is as defined above, B2 represents a single bond, an oxy group, a thio group or a —N((O)nR1′)-group (R1′ is as defined above, and n represents 0 or 1), B3 is as defined above, m′ represents 0 or 1 and, when B3 is a sulfonyl group, then m is 0, and R3 is not a hydrogen atom}]; (ii) a D5 group: an O═C(R3)-group (R3 is as defined above), an A1-(O)n—N═C(R3)-group (A1, N and R3 are as defined above), a R1—B0—CO—R4—(O)n—N═C(R3)-group [R1, R4, n and R3 are as defined above, and B0 represents an oxy group, a thio group or a —N((O)mR1′)-group (R1′ and m are as defined above)], a D2-R4—(O)n—N═C(R3)-group (D2, R4, n and R3 are as defined above) or a R1A1N—N═C(R3)-group (R1, A1 and R3 are as defined above); (iii) a D1 group: a (R1—O)k-)A1N—(O)k′-group (R1 and A1 are as defined above, and k and k′ are the same or different, and represent 0 or 1); (iv) a D2 group: a cyano group, a R1R1′NC(═N—(O)n-A1-group (R1, R1′, N and A1 are as defined above), an A1N═C(—OR2)-group (A1 and R2 are as defined above) or a NH2—CS-group; (v) a D3 group: a nitro group or a R1OSO2-group (R1 is as defined above); (vi) an A2 group: 1) an A3-B4-group [A3 represents a hydrogen atom, or a C1-C10 alkyl group, or a C2-C10 haloalkyl group, or a C2-C10 alkynyl group optionally substituted with a halogen atom, or a C3-C10 alkynyl group optionally substituted with a halogen atom, or a Ra—(R4)m-group (Ra represents a phenyl group, a pyridyl group, a furyl group or a thienyl group, optionally substituted with a halogen atom, a C1-C10 alkyl group, a C1-C10 alkoxy group or a nitro group, and R4 and m are as defined above), or a C1-C10 alkyl group substituted with a (b)-R4-group ((b) and R4 are as defined above), a (c)-R4-group ((c) and R4 are as defined above), a R2—B1—R4-group (R2, B1 and R4 are as defined above), a D4-R4-group (D4 and R4 are as defined above), a D5-group (D5 is as defined above), a D1-R4-group (D1 and R4 are as defined above), a D2-group (D2 is as defined above), a D3-R4-group (D3 and R4 are as defined above) or an A4-SO2—R4-group {A4 is as defined above, and R4 is as defined above}, B4 represents an oxy group, a thio group or a —N((O)mR1)-group (R1 and m are as defined above), provide that when A4 is a thio group, then A3 is not a hydrogen atom]; 2) a R1—B4—CO—R4—B4′-group (R1, B4 and R4 are as defined above, B4′ is the same as or different from B4, and has the same meaning as B4, provided that when B4 is a thio group, then R2 is not a hydrogen atom) or a D2-R4—B4-group (D2, R4 and B4 are as defined above); 3) a R2—SO2—NR1-group (R2 is as defined above, provided that a hydrogen atom is excluded, and R1 is as defined above); 4) a (b)-group ((b) is as defined above); 5) a (c)-group ((c) is as defined above) or 6) a R1A1N—NR1′-group (R1, A1 and R1′ are as defined above); V. TA represents a hydrogen atom, an A9′-group (A9′ is as defined above), a D5-R4-group (D5 and R4 are as defined above) or a Mc-group (Mc is as defined above); VI. Ma′ is the same as or different from Ma, and has the same meaning as that of Ma, and r represents 0, 1, 2, 3 or 4, provided that when an A ring is a benzene ring, then q is not 0 and, when an A ring is a benzene ring or a pyridine ring, then p and q are not 0 at the same time, in either case; and the “as defined above” in the same symbol between a plurality of substituents indicates that the plurality of substituents independently represent the same meaning as that described above and, between the plurality of substituents, a selection range of selected substituents is the same, while the selected substituents may be the same or different as far as they are selected in the range]; 21. A I type collagen gene transcription suppressing composition, which comprises a 2(1H)-quinolinone compound represented by the formula (XXI): [wherein XIV represents a hydrogen atom, or a hydroxy group, or a halogen atom, or a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C4 alkoxy group, or a C2-C4 alkenyl group, or a C2-C4 alkynyl group, or a C1-C4 alkoxy group, or a RI—S(O)l-group (RI represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), or a nitro group, or a cyano group, or a carboxy group, or a C1-C4 alkoxycarbonyl group, or a (RI)2N-group (RI is as defined above), or a RI—CO—NH-group (RI is as defined above), or a RI—O—CO—NH-group (R1 is as defined above), or a RINH—CO—NH-group (RI is as defined above), or a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group), or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), k represents an integer of 1 to 4 and, when k is an integer of 2 to 4, XIV's may be different, and rII and rII′ are the same or different, and represent a hydrogen atom or a C1-C4 alkyl group]; and an inert carrier; 22. A 2(1H)-quinolinone compound represented by the formula (XXII): [wherein XIV′ represents a C2-C4 alkyl group, or a C1-C4 alkyl group substituted with a halogen atom or a C1-C4 alkoxy group, or a C2-C4 alkenyl group, or a C2-C4 alkynyl group, or a C2-C4 alkoxy group, or a RI—S(O)l-group (RI represents a C1-C4 alkyl group, and l represents an integer of 0 to 2), or a cyano group, or a carboxy group, or a C2-C4 alkoxycarbonyl group, or a (RII)2N-group (RII represents a C2-C4 alkyl group), or a RI—CO—NH-group (RI is as defined above), or a RIO—CO—NH-group (RI is as defined above), or a RINH—CO—NH-group (RI is as defined above), or a (RI′)2N—CO-group (RI′ represents a hydrogen atom or a C1-C4 alkyl group), or a RB-group (B represents an oxygen atom or a sulfur atom, and R represents a C1-C4 alkyl group substituted with a halogen atom), XIV″ represents a hydrogen atom, a halogen atom, a C1-C4 alkyl group or a C1-C4 alkoxy group, m represents 1 or 2 and, when m is 2, XIV″'s may be different, and rII and rII′ are the same or different, and represent a hydrogen atom or a C1-C4alkyl group] 23. Use of a compound according to the above item 5, 6, 8, 9, 11, 12, 13, 14, 16, 18, 20 or 22, as an active ingredient for suppressing transcription of a Type I collagen gene; 24. Use of a compound according to the above item 5, 6, 8, 9, 11, 12, 13, 14, 16, 18, 20 or 22, as an active ingredient for decreasing expression of a Type I collagen gene to induce a reduction in accumulation of collagen and thereby improving tissue fibrosis; 25. A composition for improving tissue fibrosis, which comprises a compound according to the above item 5, 6, 8, 9, 11, 12, 13, 14, 16, 18, 20 or 22, and an inert carrier; 26. A method for improving tissue fibrosis, which comprises administering an effective amount of a compound according to the above item 5, 6, 8, 9, 11, 12, 13, 14, 16, 18, 20 or 22 to a mammal in need thereof; 27. Use of a compound according to the above item 5, 6, 8, 9, 11, 12, 13, 14, 16, 18, 20 or 22, as an active ingredient for suppressing the activity of TGF-β; 28. A composition for suppressing the activity of TGF-β, which comprises a compound according to the above item 5, 6, 8, 9, 11, 12, 13, 14, 16, 18, 20 or 22, and an inert carrier; 29. Use of a compound according to the above item 5, 6, 8, 9, 11, 12, 13, 14, 16, 18, 20 or 22, as an active ingredient for inhibiting a promoting effect of TGF-β on transition to a hair regression phase to induce extension of a hair growth phase and thereby providing hair-growing effect; 30. A composition for hair growth which comprises a compound according to the above item 5, 6, 8, 9, 11, 12, 13, 14, 16, 18, 20 or 22, and an inert carrier; 31. A method for growing hair, which comprises administering an effective amount of a compound according to the above item 5, 6, 8, 9, 11, 12, 13, 14, 16, 18, 20 or 22 to a mammal in need thereof; 32. Use of a compound according to the above item 1, 2, 3, 4, 7, 10, 15, 17, 19 or 21, as an active ingredient for suppressing transcription of a Type I collagen gene; 33. Use of a compound according to the above item 1, 2, 3, 4, 7, 10, 15, 17, 19 or 21, as an active ingredient for decreasing expression of a Type I collagen gene to induce a reduction in accumulation of collagen and thereby improving tissue fibrosis; 34. A composition for improving tissue fibrosis, which comprises a compound according to the above item 1, 2, 3, 4, 7, 10, 15, 17, 19 or 21, and an inert carrier; 35. A method for improving tissue fibrosis, which comprises administering an effective amount of a compound according to the above item 1, 2, 3, 4, 7, 10, 15, 17, 19 or 21 to a mammal in need thereof; 36. Use of a compound according to the above item 1, 2, 3, 4, 7, 10, 15, 17, 19 or 21, as an active ingredient for suppressing the activity of TGF-β; 37. A composition for suppressing the activity of TGF-β, which comprises a compound according to the above item 1, 2, 3, 4, 7, 10, 15, 17, 19 or 21, and an inert carrier; 38. Use of a compound according to the above item 1, 2, 3, 4, 7, 10, 15, 17, 19 or 21, as an active ingredient for inhibiting a promoting effect of TGF-β on transition to a hair regression phase to induce extension of a hair growth phase and thereby providing hair-growing effect; 39. A composition for hair growth which comprises a compound according to the above item 1, 2, 3, 4, 7, 10, 15, 17, 19 or 21, and an inert carrier; 40. A method for growing hair, which comprises administering an effective amount of a compound according to the above item 1, 2, 3, 4, 7, 10, 15, 17, 19 or 21 to a mammal in need thereof; 41. A 2(1H)-pyridinone compound represented by the formula (XXIII): 42. A 2(1H)-pyridinone compound represented by the formula (XXIV): ; and the like. BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be explained in detail below. In the present invention, a saturated hydrocarbon group in an alkyl group, a haloalkyl group, an alkoxy group, an alkoxycarbonyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group and an alkylene group may be branched, and a part or all of carbon atoms thereof may form a ring. An unsaturated hydrocarbon group in an alkenyl group, an alkenyloxy group, an alkynyl group, an alkynyloxy group and an alkenylene group may have a branch, and a part or all of carbon atoms thereof may form a ring, and the number of unsaturated bonds is singular or plural. In the present invention, examples of an alkyl group include a methyl group, an ethyl group, an isopropyl group, a cyclohexyl group, a cyclopropylmethyl group and the like, examples of a haloalkyl group include a 2,2,2-trifluoroethyl group and the like, examples of an alkoxy group include a methoxy group, an ethoxy group, a cyclopentyloxy group, a 2-cyclohexylethoxy group and the like, examples of an alkylthio group include a methylthio group and the like, examples of an alkylsulfinyl group include a methylsulfinyl group and the like, examples of an alkylsulfonyl group include a methylsulfonyl group and the like, examples of an alkylene group include a methylene group, an ethylethylene group, a 1,4-cyclohexylene group and the like, examples of an alkenyl group include a vinyl group, a 2-propenyl group, a 3-methyl-2-butenyl group, a 1,3-butadienyl group, a 3-cyclohexenyl group and the like, examples of an alkynyl group include an ethynyl group, a 2-propynyl group, a 2-penten-4-ynyl and the like, and examples of an alkenylene group include a vinylene group, a propenylene group, a 1,3-butadienylene group and the like. In the present invention, examples of a halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. In the present invention, a pyridyl group includes a 2-pyridyl group, a 3-pyridyl group and a 4-pyridyl group, a furyl group includes a 2-furyl group and a 3-furyl group, a thienyl group includes a 2-thienyl group and a 3-thienyl group, and a naphthyl group includes a 1-naphthyl group and a 2-naphthyl group. In the present invention, examples of a leaving group include an alkylsulfonyloxy group such as a mesyloxy group and the like, an arylsulfonyloxy group such as a tosyloxy group and the like, an alkoxysulfonyloxy group such as a methoxysulfonyloxy group and the like, and a halogen atom such as a bromine atom and the like. In a cinnamoyl compound represented by the formulas (I) to (III) (hereinafter, referred to as the present compounds (I) to (III), respectively, in some cases), a 2H-pyran-2-one compound represented by the formula (IV) and (V) (hereinafter, referred to as the present compound (IV) and (V), respectively, in some cases), a 2H-pyran-2-one compound represented by the formula (VI) (hereinafter, referred to as the present intermediate (VI) in some cases), a 2H-1-benzopyran-2-one compound represented by the formulas (X) and (XI) (hereinafter, referred to as the present compounds (X) and (XI), respectively, in some cases), a 2H-1-benzopyran-2-one compound represented by the formula (XII) (hereinafter, referred to as the present intermediate (XII) in some cases), a 2(1H)-pyridinone compound represented by the formulas (XV) and (XVI) (hereinafter, referred to as the present compounds (XV) and (XVI), respectively, in some cases) and a 2(1H)-quinolinone compound represented by the formulas (XIX) and (XX) (hereinafter, referred to as the present compounds (XIX) and (XX), respectively, in some cases), when an A ring is a pyridine ring, a N-oxide thereof is also included. The present compounds (I) to (V), (VII), (VIII), (X), (XI), (XIII), and (XV) to (XXII) (hereinafter, collectively referred to as the present compound in some cases) represents a pharmacologically acceptable salt thereof at the same time. A pharmacologically acceptable salt represents a salt with an inorganic acid, a salt with an organic acid, a salt with an inorganic base or a salt with an organic base, of the present compound. Examples of a salt with an inorganic acid include hydrochloride, hydrobromide and the like, examples of a salt with an organic acid include acetate, benzoate and the like, examples of a salt with an inorganic base include a potassium salt, a sodium salt and the like, and examples of a base with an organic base include a pyridine salt, a morpholine salt and the like. YA0, QA0, KA0, LA0 and TA0 in the present compound (II) are independently represented by groups represented by D1, D2, D3, D4, D5, R0, R1, R1′, R2, R3, R4, R4′, A1, A2, A3, A4, A7, A7′, A7″, A8, A8′, A9, A9′, B0, B1, B2, B3, B4, B4′, B6, (b0), (c0), (d0), (e0), Ma, Ma′, Ma″, Ma′″, Ma″″, Mb0, Mc0, Md0, Ra0, Rb, Rc, Rd, Rd′, Re, Re′, Re″, Re′″, Ba, Bb, Bc, Ya, Ya′, Yb, Yb′, Yb″, Yc and Yc′, and integers represented by k, k′, l, m, m′ and n. YA, QA, KA, LA and TA in the present compound (III) are independently represented by groups represented by D1, D2, D3, D4, D5, R0, R1, R1′, R2, R3, R4, R4′, A1, A2, A3, A4, A7, A7′, A7″, A8, A8′, A9, A9′, B0, B1, B2, B3, B4, B4′, B6, (b), (c), (d), (e), Ma, Ma′, Ma″, Ma′″, Ma″″, Mb, Mc, Md, Ra, Rb, Rc, Rd, Rd′, Re, Re′, Re″, Re′″, Ba, Bb, Bc, Ya, Ya′, Yb, Yb′, Yb″, Yc and Yc′, and integers represented by k, k′, l, m, m′ and n. Xa, Ya, Xb, Yb, Xc, Yc, QA, QA′ and La in the present compounds (IV) and (V), and the present intermediate (VI) are independently represented by groups represented by D1, D2, D3, D4, D5, R0, R1, R1′, R2, R3, R4, R4′, A1, A2, A3, A4, A7, A7′, A7″, A8, A8′, A9, A9′, B0, B1, B2, B3, B4, B4′, B6, (b), (c), (d), (e), Ma, Ma′, Ma″, Ma′″, Ma″″, Mb, Mc, Md, Ra, Rb, Rc, Rd, Rd′, Re, Re′, Re″, Re′″, Ba, Bb, Bc, Ya, Ya′, Yb, Yb′, Yb″, Yc and Yc′, and integers represented by k, k′, l, m, m′ and n. Xd, Yd, Xe, Ye, QA, QA′ and Ma′ in the present compounds (X) and (XI) and the present intermediate (XII) are independently represented by groups represented by D1, D2, D3, D4, D5, R0, R1, R1′, R2, R3, R4, R4′, A1, A2, A3, A4, A7, A7′, A7″, A8, A8′, A9, A9′, B0, B1, B2, B3, B4, B4′, B6, (b), (c), (d), (e), Ma, Ma′, Ma″, Ma′″, Ma″″, Mb, Mc, Md, Ra, Rb, Rc, Rd, Rd′, Re, Re′, Re″, Re′″, Ba, Bb, Bc, Ya, Ya′, Yb, Yb′, Yb″, Yc and Yc′, and integers represented by k, k′, l, m, m′ and n. Yf, Xg, Yg, QA, TA and La in the present compounds (XV) and (XVI) are independently represented by groups represented by D1, D2, D3, D4, D5, R0, R1, R1′, R2, R3, R4, R4′, A1, A2, A3, A4, A7, A7′, A7″, A8, A8′, A9, A9′, B0, B1, B2, B3, B4, B4′, B6, (b), (c), (d), (e), Ma, Ma′, Ma″, Ma′″, Ma″″, Mb, Mc, Md, Ra, Rb, Rc, Rd, Rd′, Re, Re′, Re″, Re′″, Ba, Bb, Bc, Ya, Ya′, Yb, Yb′, Yb″, Yc and Yc″, and integers represented by k, k′, l, m, m′ and n. Yf, Xh, Yh, QA, TA and Ma′ in the present compounds (XIX) and (XX) are independently represented by groups represented by D1, D2, D3, D4, D5, R0, R1, R1′, R2, R3, R4, R4′, A1, A2, A3, A4, A7, A7′, A7″, A8, A8′, A9, A9′, B0, B1, B2, B3, B4, B4′, B6, (b), (c), (d), (e), Ma, Ma′, Ma″, Ma′″, Ma″″, Mb, Mc, Md, Ra, Rb, Rc, Rd, Rd′, Re, Re′, Re″, R′″, Ba, Bb, Bc, Ya, Ya′, Yb, Yb′, Yb″, Yc and Yc′ and integers represented by k, k′, l, m, m′ and n. In the substituent Y0 group which can be taken by Ya of the present compound (I), the “6 to 10-membered aryl group” represents a groups constituting a monocyclic or fused aromatic hydrocarbon group, and examples include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 6-indanyl group and the like, the “5 to 10-membered heteroaryl group” represents a group constituting a monocyclic or fused aromatic heterocycle, and examples include a 2-furyl group, a 3-furyl group, a 2-thienyl group, a 3-thienyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 2-quinolyl group and the like, and “a group constituting 3 to 10-membered hydrocarbon ring or heterocycle optionally containing an unsaturated bond” includes a monocycle or a fused cycle, and examples include a 2-cyclohexenyl group, a 2-morpholinyl group, a 4-piperidyl group and the like, and these may be substituted with a single or same or different plural aforementioned Ma-groups. In the substituent Z0 group which can be taken by Ya of the present compound (I), “a group which is fused with an A ring” may have single or the same or different plural atoms or groups selected from a halogen atom, a C1-C10 alkoxy group, a C3-C10 alkenyloxy group, a C3-C10 alkynyloxy group, a carbonyl group, a thiocarbonyl group, an oxy group, a thio group, a sulfinyl group and a sulfonyl group. In (d0) of the substituent Y0 group which can be taken by Ya and Ya0, of the present compounds (I) and (II), the “5 to 12-membered hydrocarbon ring which is substituted with a carbonyl group or a thiocarbonyl group and, further, may be substituted with an oxy group, a thio group, a —NR1— group (R1 is as defined above), a sulfinyl group or a sulfonyl group” represents a 5 to 12-membered hydrocarbon ring in which one or plural of carbon atoms are substituted with a carbonyl group or a thiocarbonyl group and, further, one or plural of carbon atoms may be substituted with single or the same or different plural groups selected from an oxy group, a thio group, a —NR1-group (R1 is as defined above), a sulfinyl group or a sulfonyl group. In (e0) of the substituent Y0 group which can be taken by Ya and Ya0, of the present compounds (I) and (II), the “5 to 12-membered hydrocarbon ring optionally substituted with a carbonyl group, a thiocarbonyl group, an oxy group, a thio group, a —NR1-group (R1 is as defined above), a sulfinyl group or a sulfonyl group” represents a 5 to 12-membered hydrocarbon ring in which one or plural of carbon atoms may be substituted with single or the same or different plural groups selected from a carbonyl group, a thiocarbonyl group, an oxy group, a thio group, a —NR1-group (R1 is as defined above), a sulfinyl group and a sulfonyl group. The groups belonging to a X0 group, a Y0 group and a Z0 group which can be taken by Ya of the present compound (I) will be exemplified in the following Table X, Table Y and Table Z, respectively. The groups belonging to a X0 group, a Y0 group and a Z0 group which can be taken by YA0 of the present invention (II) are exemplified in the following Table X, Table Y and Table Z, respectively, and Q0 and T0 are exemplified in the following Table Q and Table T, respectively. The groups belonging to a X group, a Y group and a Z group which can be taken by YA of the present compound (III) are exemplified in the following Table X, Table Y and Table Z, respectively, and Q and T are exemplified in the following Table Q and Table T, respectively. The groups belonging to the aforementioned X0 group to Z0 group and X group to Z group will be exemplified in the following Table X to Table Z and, when geometrical isomerism is possible, all geometrical isomers thereof are meant and, when tautomerism is possible, all tautomers thereof are meant. The groups belonging to a X0 group and a X group will be exemplified in Table X. TABLE X No. Group X-1 —CH3 X-2 —C2H5 X-3 —CF3 X-4 —CH═CHCH3 X-5 —CH2CH═CH2 X-6 —C≡CH X-7 —F X-8 —Cl X-9 —Br X-10 —NO2 X-11 —CN X-12 —OCH3 X-13 —SCH3 X-14 —SOC4H9 X-15 —SO2C4H9 X-16 —OCHF2 X-17 —OCF3 X-18 —OCF2CHF2 X-19 —SCF3 X-20 —CH2OCH3 X-21 —COCH3 X-22 —OCOCH3 X-23 —COOH X-24 —COOCH3 X-25 —CH═CHCOOH X-26 —N(CH3)2 X-27 —NHCOCH3 X-28 —NHCOOCH3 X-29 —CONH2 X-30 —CON(CH3)2 X-31 —NHCON(CH3)2 X-32 —NHC(═NH)NH2 X-33 —NHSO2CF3 X-34 —SO2N(CH3)2 The groups belonging to a Y0 group and a Y group will be exemplified in Table Y. TABLE Y No. Group Y-1 Y-2 Y-3 Y-4 Y-5 Y-6 Y-7 Y-8 Y-9 Y-10 An A ring fused with a Z0 group or a Z group will be exemplified in Table Z. TABLE Z No. Group Z-1 Z-2 Z-3 Z-4 Z-5 Z-6 Z-7 Z-8 Z-9 Z-10 QA0 and QA will be exemplified in Table Q. TABLE Q No. Group Q-1 —OH Q-2 Q-3 Q-4 Q-5 —OCOCH3 Q-6 —OSO2N(CH3)2 Q-7 —NHCH2CH═CH2 Q-8 —NHCH2C≡CH Q-9 —NHCH2CH2OCH3 Q-10 —OCH3 Q-11 —OCH2CH2 (c) C6H11 Q-12 —OCH2CH═CH2 Q-13 —OCH2C≡CH Q-14 —OCH2COOH Q-15 —OCH2COOCH3 Q-16 —OCH2CONH2 Q-17 —OCH2CN Q-18 —OCH2CH2OH Q-19 —OCH2CH2OCH3 Q-20 —OCH2CH2N(CH3)2 Q-21 —OCH2COCH3 Q-22 —OCOC6H5 Q-23 —OCH2C6H5 Q-24 Q-25 Q-26 TA0 and TA will be exemplified in Table T. TABLE T No. Group T-1 —H T-2 —CH3 T-3 —CH2CH2 (c) C6H11 T-4 —CH2CH═CH2 T-5 —CH2C≡CH T-6 —CH2C6H5 T-7 —CH2COOH T-8 —CH2COOCH3 T-9 —CH2CONH2 T-10 —CH2CN T-11 —CH2CH2OH T-12 —CH2CH2OCH3 T-13 —CH2CH2N(CH3)2 T-14 —CH2COCH3 T-15 —CH2CF3 T-16 —Ph T-17 Examples of the present compound (I) include the compound wherein Qα is a hydroxy group, a (b)-group ((b0) is as defined above) or an A9′-O-group (A9′ is as defined above) and, at the same time, Ka is a hydrogen atom and La is a methyl group, or Ka and La form a 1,3-butadienylene group. Examples of the present compound (II) include the compound wherein QA0 is a hydroxy group, a (b0)-group ((b0) is as defined above) or an (A9′-O-group (A9′ is as defined above) and, at the same time, KA0 is a hydrogen atom and LA0 is a methyl group, or KA0 and LA0 form a 1,3-butadienylene group. Examples of the present compound (III) include the compound wherein QA is a hydroxy group, a (b)-group ((b) is as defined above) or an Q9′-O-group (A9′ is as defined above) and, at the same time, KA is a hydrogen atom and LA is a methyl group, or KA and LA form a 1,3-butadienylene group. Examples of the present compound (IV) include the compound wherein QA is a hydroxy group, a (b)-group ((b) is as defined above) or an A9′-O-group (A9′ is as defined above) and, at the same time, Ka is a hydrogen atom and La is a methyl group. Examples of the present compound (X) include the compound wherein QA is a hydroxy group, a (b)-group ((b) is as defined above) or an A9′-O-group (A9′ is as defined above) and, at the same time, r is 0. Examples of the present compound (XV) include the compound wherein QA is a hydroxy group, a (b)-group ((b) is as defined above) or an A9′-O-group (A9′ is as defined above) and, at the same time, Ka is a hydrogen atom and La is a methyl group. Examples of the present compound (XIX) include the case where QA is a hydroxy group, a (b)-group ((b) is as defined above) or an A9′-O-group (A9′ is as defined above) and, at the same time, r is 0. Some of the present compounds are described in documents such as Tetrahedron (1973), 29, 1083, WO 01/79187, Zhurnal Prikladnoi Spektroskopii (1967), 7,638), Khimiya Geterotsiklicheskikh Soedinenii (1967), 4, 682, Chemical Papers (1997), 51, 33 and Synthetic Communications (2000), 30, 2735, and is known. However, in these publications, there is no description about the effect of suppressing transcription of I type collagen gene in a tissue, in its turn, the effect of suppressing an accumulated amount of collagen. The present compounds (V), (VI), (XI), (XII), (XVI) and (XX) are novel compounds. Although WO 97/35565, JP09227547, WO 00/20371, JP2002371078, WO 01/79187 and WO 92/18483 disclose compounds having a certain conceptional skeleton, there is no specific description of a compound having a similar structure as that of the present compound. In addition, in the publications, there is no description regarding the effect of suppressing transcription of I type collagen gene in a tissue, in its turn, the effect of suppressing an accumulated amount of collagen. The present compound (I) can be produced by reacting a compound represented by the formula (α) (wherein A, Ya and q are as defined above) and a compound represented by the formula (α′) (wherein Qa, Wa, Ka and La are as defined above) (see Russian J. General Chem. (2001), 71, 1257, Indian J. Chem. (1974), 12, 956 and JP50046666). The present compound (II) can be produced by reacting a compound represented by the formula (A0) (wherein A, YA0 and q are as defined above) and a compound represented by the formula (A0′) (wherein QA0, WA0, KA0 and LA0 are as defined above), as described above. Among the present compounds, a cinnamoyl compound represented by the formula (II-1): [wherein A, YA0, q, KA0 and LA0 are as defined above, r represents an A9′-group (A9′ is as defined above), WA0′ represents an oxygen atom or a —NTA′-group {TA′ represents an A9′-group (A9′ is as defined above), a D5-R4-group (D5 and R4 are as defined above) or a Mc-group (Mc is as defined above)}] can be produced by reacting a cinnamoyl compound represented by the formula (II-2): [wherein A, YA0, q, KA0, LA0 and WA0′ are as defined above] (hereinafter, referred to as the present intermediate (II-2) in some cases) with a compound represented by the formula (II-3): r-V (II-3) [r is as defined above, and V represents a leaving group.] Examples of the reaction method include a method wherein the present intermediate (II-2) is reacted with a compound (II-3) in the presence of a base. The reaction of the present intermediate (II-2) and a compound (II-3) in the presence of a base is performed usually in a solvent. Examples of the solvent used in the reaction include acid amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like, sulfoxides such as dimethyl sulfoxide and the like, phosphoric acid amide compounds such as hexamethylphosphoramide and the like, and ketones such as acetone, methyl ethyl ketone and the like. Examples of the base used in the reaction include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, and carbonates of an alkali metal such as sodium carbonate, potassium carbonate and the like. Examples of the compound (II-3) include alkylsulfonic acid esters such as methyl methanesulfonate and the like, arylsulfonic acid esters such as p-toluenesulfonic acid methyl ester, p-toluenesulfonic acid 2-methoxyethyl ester and the like, sulfate esters such as dimethyl sulfate and the like, and halides such as methyl iodide, 2-chloroethyldimethylamine, allyl bromide, propargyl bromide, methyl bromoacetate, bromoacetonitrile, 2-bromoethanol, benzyl bromide, bromoacetone and the like. The amount of the reagent used in the reaction is such a ratio that a base is usually 1 mole to 2 moles, and a compound (II-3) is usually 1 mole to 2 moles per 1 mole of the present intermediate (II-2). The reaction temperature is usually in a range of 0° C. to 100° C., and a reaction time is usually in a range of 1 hour to 20 hours. After completion of the reaction, the reaction mixture is extracted with an organic solvent, and the organic layer is subjected to a post-treatment procedure such as drying, concentration and the like, thereby, a cinnamoyl compound (II-1) can be isolated. The isolated cinnamoyl compound (II-1) can be also further purified by chromatography, recrystallization or the like. The present intermediate (VI) can be produced by reacting a compound represented by the formula (VI-1) (wherein A, Xc, Yc, p and q are as defined above) and a compound represented by the formula (VI-2) (wherein Ka and La are as defined above) as in the reaction of the compound (A0) and the compound (A0′). The present intermediate (XII) can be produced by reacting a compound represented by the formula (XII-1) (wherein A, Xe, Ye, p and q are as defined above) and a compound represented by the formula (XII-2) (wherein Ma′ and r are as defined above) as in the reaction of a compound (A0) and a compound (A0′). Among the present compounds, a 2H-pyran-2-one compound represented by the formula (VI-3) can be produced by reacting the present intermediate (VI) and the compound (II-3). The reaction can be performed as in the reaction of the present intermediate (II-2) and the compound (II-3). Among the present compounds, a 2H-1-benzopyran-3-one compound represented by the formula (XII-3) can be produced by reacting the present intermediate (XII) and the compound (II-3). The reaction can be performed as in the reaction of the present intermediate (II-2) and the compound (II-3). The present intermediates (VI) and (XII) are novel compounds. Although WO 97/35565, JP09227547, WO 00/20371, JP2002371078, WO 01/79187 and WO 92/18483 disclose compounds having a certain conceptional skeleton, there is no specific description of a compound having a similar structure as that of the present intermediates (VI) and (XII). Among the present intermediate (II-2), the present intermediate (II-2a) represented by compound numbers (1a-1) to (1a-12) will be exemplified in Table 1a. TABLE 1a The present intermediate (II-2a) (II-2a) Compound No. (YA0)q (1a-1) 3-CH═CHCH3 (1a-2) 3-C≡CH (1a-3) 3-CON(CH3)2 (1a-4) 3-CH3, 4-OCH3 (1a-5) 3-CF3, 4-Cl (1a-6) 3-Cl, 4-OCF3 (1a-7) 3-F, 4,5-(OCH3)2 (1a-8) 3-COOCH3 Compound No. (1a-9) (1a-10) (1a-11) (1a-12) Among the present intermediate (II-2), the present intermediate (II-2b) represented by a compound number (1b-1) to (1b-4) will be exemplified in Table 1b. TABLE 1b The present intermediate (II-2b) (II-2b) Com- pound No. The present intermediate (II-2b) (1b-1) (1b-2) (1b-3) (1b-4) Among the present intermediate (II-2), the present intermediate (II-2c) represented by a compound number (1c-1) to (1c-12) will be exemplified in Table 1c. TABLE 1c The present intermediate (II-2c) (II-2c) Compound No. (YA0)q (1c-1) 3-CH═CHCH3 (1c-2) 3-C≡CH (1c-3) 3-CON(CH3)2 (1c-4) 3-CH3, 4-OCH3 (1c-5) 3-CF3, 4-Cl (1c-6) 3-Cl, 4-OCF3 (1c-7) 3-F, 4,5-(OCH3)2 (1c-8) 3-COOCH3 Compound No. (1c-9) (1c-10) (1c-11) (1c-12) Among the present compound (II), the present compound (IIa) represented by a compound number (2a-1) to (2a-28) will be exemplified in Table 2a. TABLE 2a The present compound (IIa) (IIa) Compound No. (YAO)q r (2a-1) 3-CH═CHCH3 CH3 (2a-2) 3-C≡CH C2H5 (2a-3) 4-SCH3 CH3 (2a-4) 4-S(O)CH3 CH3 (2a-5) 4-S(O)2CH3 CH3 (2a-6) 3-CN CH3 (2a-7) 4-COOH CH2CH═CH2 (2a-8) 4-COOCH3 CH3 (2a-9) 4-N(CH3)2 CH3 (2a-10) 3-NHCOCH3 CH2C≡CH (2a-11) 3-NHCON(CH3)2 CH3 (2a-12) 3-CONH2 CH3 (2a-13) 3-CON(CH3)2 CH3 (2a-14) 3, 4-Cl2 CH3 (2a-15) 3-CH3, 4-OCH3 CH3 (2a-16) 3-CF3, 4-Cl CH3 (2a-17) 3-Cl, 4-OCF3 CH3 (2a-18) 3-F ,4,5-(OCH3)2 CH3 (2a-19) 3-COOCH3 CH3 Compound No. r (2a-20) CH3 (2a-21) CH3 (2a-22) CH3 (2a-23) CH3 (2a-24) 3-CH3 CH2CH2OCH3 (2a-25) 3-CH3 CH2COOCH3 (2a-26) 3-CH3 CH2CH2CH2COCH3 (2a-27) 3-CH3 CH2CH2OH (2a-28) 3-CH3 CH2CH2S(O)2CH3 Among the present compound (II), the present compound (IIb) represented by a compound number (2b-1) to (2b-3) will be exemplified in Table 2b. TABLE 2b The present compound (IIb) (IIb) Compound No. The present compound (IIb) (2b-1) (2b-2) (2b-3) Among the present compound (II), the present compound (IIc) represented by a compound number (2c-1) to (2c-23) will be exemplified in Table 2c. TABLE 2c The present compound (IIc) (IIc) Com- pound No. (YA0)q r (2c-1) 3-CH═CHCH3 CH3 (2c-2) 3-C≡CH C2H5 (2c-3) 4-SCH3 CH3 (2c-4) 4-S(O)CH3 CH3 (2c-5) 4-S(O)2CH3 CH3 (2c-6) 3-CN CH3 (2c-7) 4-COOH CH2CH═CH2 (2c-8) 4-COOCH3 CH3 (2c-9) 4-N(CH3)2 CH3 (2c-10) 3-NHCOCH3 CH2C≡CH (2c-11) 3-NHCON(CH3)2 CH3 (2c-12) 3-CONH2 CH3 (2c-13) 3-CON(CH3)2 CH3 (2c-14) 3, 4-Cl2 CH3 (2c-15) 3-CH3, 4-OCH3 CH3 (2c-16) 3-CF3, 4-Cl CH3 (2c-17) 3-Cl, 4-OCF3 CH3 (2c-18) 3-F, 4,5-(OCH3)2 CH3 (2c-19) 3-COOCH3 CH3 Com- pound No. r (2c-20) CH3 (2c-21) CH3 (2c-22) CH3 (2c-23) CH3 Among the present compound (II), the present compound (IIa′) represented by a compound number (3a-1) to (3a-40) will be exemplified in Table 3a. TABLE 3a The present compound (IIa′) (IIa′) Compound No. (YA0)q r r′ (3a-1) H H H (3a-2) H H CH3 (3a-3) H CH3 CH3 (3a-4) 3-Cl H H (3a-5) 3-HC3 H H (3a-6) 4-CF3 H H (3a-7) 3-CH2OCH3 H H (3a-8) 3-CH═CHCH3 H H (3a-9) 3-C≡CH H H (3a-10) 3-OC2H5 H H (3a-11) 4-SCH3 H H (3a-12) 4-S(O)CH3 H H (3a-13) 4-S(O)2CH3 H H (3a-14) 4-NO2 H H (3a-15) 3-CN H H (3a-16) 4-COOH H H (3a-17) 4-COOCH3 H H (3a-18) 4-N(CH3)2 H H (3a-19) 3-NHCOCH3 H H (3a-20) 3-NHCON(CH3)2 H H (3a-21) 3-CONH2 H H (3a-22) 3-CON(CH3)2 H H (3a-23) 3-OCHF2 H H (3a-24) 4-OCF3 H H (3a-25) 4-OCF2CHF2 H H (3a-26) 2-SCF3 H H (3a-27) 3,4-Cl2 H H (3a-28) 2,4-(OCH3)2 H H (3a-29) 3-CH3, 4-OCH3 H H (3a-30) 3-OC2H5, 4-OH H H (3a-31) 3-CF3, 4-Cl H H (3a-32) 3-Cl, 4-OCF3 H H (3a-33) 3-F, 4,5-(OCH3)2 H H (3a-34) 3-COOCH3 H CH3 Compound No. r r′ (3a-35) H CH3 (3a-36) H CH3 (3a-37) H H (3a-38) H CH3 (3a-39) H H (3a-40) H CH3 Among the present compound (II), the present compound (IIb′) represented by a compound number (3b-1) to (3b-3) will be exemplified in Table 3b. TABLE 3b The present compound (IIb′) (IIb′) Compound No. The present compound (IIb′) (3b-1) (3b-2) (3b-3) Among the present compound (II), the present compound (IIc′) represented by a compound number (3c-1) to (3c-40) will be exemplified in Table 3c. TABLE 3c The present compound (IIc′) (IIc′) Compound No. (YA0)q r r′ (3c-1) H H H (3c-2) H H CH3 (3c-3) H CH3 CH3 (3c-4) 3-Cl H H (3c-5) 3-CH3 H H (3c-6) 4-CF3 H H (3c-7) 3-CH2OCH3 H H (3c-8) 3-CH═CHCH3 H H (3c-9) 3-C≡CH H H (3c-10) 3-OC2H5 H H (3c-11) 4-SCH3 H H (3c-12) 4-S(O)CH3 H H (3c-13) 4-S(O)2CH3 H H (3c-14) 4-NO2 H H (3c-15) 3-CN H H (3c-16) 4-COOH H H (3c-17) 4-COOCH3 H H (3c-18) 4-N(CH3)2 H H (3c-19) 3-NHCOCH3 H H (3c-20) 3-NHCON(CH3)2 H H (3c-21) 3-CONH2 H H (3c-22) 3-CON(CH3)2 H H (3c-23) 3-OCHF2 H H (3c-24) 4-OCF3 H H (3c-25) 3-OCF2CHF2 H H (3c-26) 2-SCF3 H H (3c-27) 3,4-Cl2 H H (3c-28) 2,4-(OCH3)2 H H (3c-29) 3-CH3, 4-OCH3 H H (3c-30) 3-OC2H5, 44-OH H H (3c-31) 3-CF3, 4-Cl H H (3c-32) 3-Cl, 4-OCF3 H H (3c-33) 3-F, 4,5-(OCH3)2 H H (3c-34) 3-COOCH3 H CH3 Compound No. r r′ (3c-35) H CH3 (3c-36) H CH3 (3c-37) H H (3c-38) H CH3 (3c-39) H H (3c-40) H CH3 The present compound has the ability to suppress transcription of a Type I collagen gene. The ability is important in improving tissue fibrosis because it decreases expression of a Type I collagen gene to induce a reduction in accumulation of collagen. Therefore, the present compound can be utilized as an active ingredient of a composition (medicament, cosmetic, food additive etc.) which can improve tissue fibrosis by decreasing expression of a Type I collagen gene to induce a reduction in accumulation of collagen. A disease to which the transcription-suppressing composition of the present invention and the fibrosis-improving composition of the present invention can be applied includes, for example, a disease in which excessive accumulation of collagen causes fibrosis and then sclerosis of tissues, resulting in decreased function, cicatrization and the like in the tissues such as organs (i.e. fibrosing disease etc.). Specifically, the disease includes diseases and disorders such as hepatic cirrhosis, interstitial pulmonary disease, chronic renal failure (or disease resulting in chronic renal failure), hyperplasia scar after inflammation, postoperative scars or burn scars, scleroderma, arteriosclerosis, hypertension and the like. Incidentally, as an example of hepatic cirrhosis, it has been already known that C type or B type hepatitis virus induces chronic inflammation and then increased production of TGF-β, and thereby, hepatic fibrosis (particularly, accumulation of type I and type III collagen) is induced to cause hepatic cirrhosis (e.g. see Clin. Liver Dis., 7, 195-210 (2003)). As an example of interstitial pulmonary disease, it has been thought that pneumonia caused by mites, viruses, tubercle bacilli or the like induces increased production of TGF-β and then pulmonary fibrosis, and thereby interstitial pulmonary disease is caused. For chronic renal failure such as diabetic nephropathy and IgA nephropathy, it has been already suggested that diabetic nephropathy is caused by increased level of TGF-β in renal glomeruli due to hyperglycemia and thereby induction of renal fibrosis (particularly accumulation of Type I and Type IV collagen), and IgA nephropathy is caused by induction of nephritis due to accumulation of IgA in renal glomeruli followed by increased level of TGF-β, and thereby induction of renal fibrosis (particularly accumulation of Type I and Type IV collagen) (e.g. see Am. J. Physiol. Renal Phsiol., 278, F830-F838 (2000), Kidney Int. 64.149-159 (2003)). A db/db mouse, a diabetic nephropathy model animal, develops hyperglycemia by overeating because it has a mutation in a leptin receptor for suppressing ingestion, and then spontaneously develops diabetes. In the db/db mouse, the blood glucose concentration is about 4 times higher than a normal mouse, and fibrosis of renal glomeruli and increased level of TGF-β are found (e.g. see Am. J. Pathol., 158, 1653-1663 (2001)). An anti-Thy-1 rat, an IgA nephropathy model animal, is produced by administering an anti-Thy-1 antibody to a normal rat to artificially cause renal fibrosis. It has been shown that renal fibrosis is suppressed by administering an anti-TGF-β receptor antibody to the model animal (e.g. see Kidney Int., 60, 1745-1755 (2001)). Although the cause of scleroderma is unknown, it has been found that skin fibrosis is improved by administering a TGF-β inhibitor to a Tsk mouse, which is a model animal therefor (e.g. see J. Invest. Dermatol., 118.461-470 (2001)). Thus, a compound which suppresses the activity of TGF-β can be utilized as an active ingredient of a composition (medicament, cosmetic, food additive etc.) for inhibiting the collagen synthesis-promoting activity of TGF-β to suppress tissue fibrosis and thereby providing a fibrosing disease therapeutic effect. Such transcription-suppressing composition and fibrosis-improving composition of the present invention comprise the present compound and an inert carrier. Such composition usually comprises 0.01% by weight to 99.99% by weight of the present compound and 99.99% by weight to 0.01% by weight of an inert carrier. The inert carrier is a pharmaceutically acceptable carrier or excipient. The transcription-suppressing composition and fibrosis-improving composition of the present invention may further comprise pharmaceutical additives, cosmetic additives, food additives and the like. The present compound also inhibits the ability of TGF-β to promote transcription of a Type I collagen gene, as shown in Example 22 below. That is, the present compound is a TGF-β antagonist having the ability to suppress the activity of TGF-β. Therefore, the present compound can be also utilized as an active ingredient of a composition for suppressing the activity of TGF-β. It has been known that TGF-β has the ability to promote transition from a growth phase (hereinafter, also referred to as hair growth phase in some cases) to a regression phase (hereinafter, also referred to as a hair regression phase in some cases) in the hair life cycle [J. Invest. Dermatol., 111, 948-954 (1998), FASEB J., 16, 1967-1969 (2002)]. Further, it has been reported that an anti-TGF-β antibody, Fetuin, which is a TGF-β inhibitor, and the like antagonize the suppressing-activity of TGF-β on hair extension and exhibit a promoting-effect on hair extension [J. Invest. Dermaton., 118, 993-997 (2002), JP-A 2000-342296]. Therefore, the present compound (and a TGF-β activity-suppressing composition containing the present compound as an active ingredient) may be utilized for inhibiting a promoting effect of TGF-β on transition to a hair regression phase to induce extension of a hair growth phase and thereby providing a hair-growing effect. Such TGF-β suppressing composition and hair-growing composition of the present invention comprise the present compound and an inert carrier. Such composition usually comprises 0.01% by weight to 99.99% by weight of the present compound and 99.99% by weight to 0.01% by weight of an inert carrier. The inert carrier is a pharmaceutically acceptable carrier or excipient. The TGF-β suppressing composition and hair-growing composition of the present invention may further comprise pharmaceutical additives, cosmetic additives, food additives and the like. A pharmaceutically acceptable carrier, excipient, pharmaceutical additive, food additive, cosmetic additive, a medicament additive, and the like contained in the above-described composition can be appropriately selected depending on the specific use thereof. In addition, the composition may be in a form of various solids, liquids and the like depending on the specific use thereof. For example, when the present compound is used as an active ingredient of a medicament, specific examples of the medicament include oral preparations such as powders, fine granules, granules, tablets, syrups, capsules, suspensions, emulsions, extracts and pills; and parenteral preparations such as injections, transdermal absorbing agents such as external liquids and ointments, suppositories and local preparations. Oral preparations can be prepared using carriers or excipients, and pharmaceutical additives such as binders, disintegrants, surfactants, lubricants, glidants, diluents, preservatives, coloring agents, flavors, stabilizers, humectants, antiseptics, antioxidants and the like, for example, gelatin, sodium alginate, starch, corn starch, white sugar, lactose, glucose, mannit, carboxymethylcellulose, dextrin, polyvinylpyrrolidone, crystalline cellulose, soybean lecithin, sucrose, fatty acid ester, talc, magnesium stearate, polyethylene glycol, magnesium silicate, anhydrous silicic acid and the like, according to a conventional method. A dose of the oral preparation varies depending on the age, sex and weight of a mammal to be administered, the severity of disease, the kind and dosage form of the composition of the present invention, and the like. Usually, in the case of oral administration, about 1 mg to about 2 g per day, preferably about 5 mg to about 1 g per day of the active ingredient may be administered to an adult human. The daily dose may be also administered at one time or in several divided doses. Among parenteral preparations, an injection can be prepared using such as a water-soluble solvent such as physiological saline or sterilized water Ringer solution, a water-insoluble solvent such as vegetable oil or fatty acid ester, an isotonic agent such as glucose or sodium chloride, pharmaceutical additives such as a solubilizer, a stabilizer, an antiseptic, a suspending agent and an emulsifying agent, and the like, according to a conventional method. A transdermal absorbing agent such as external liquid or a gel-like ointment, a suppository for rectal administration and the like can be also prepared according to a conventional method. For administering such parenteral preparations, they may be administered by injection (subcutaneously, intravenously etc.), transdermally, or rectally. A local preparation can be prepared, for example, by incorporating the present compound into a pellet of a sustained-release polymer such as ethylene vinyl acetate polymer. The pellet may be surgically transplanted into a tissue to be treated. A dose of the parenteral preparation varies depending on the age, sex and weight of a mammal to be administered, the severity of disease, the kind and dosage form of the composition of the present invention, and the like. Usually, in the case of administration by injection, about 0.1 mg to about 500 mg of the active ingredient may be administered to an adult human. The daily dose may be also administered at one time or in several divided doses. When the present compound is used by adding to cosmetics, specific examples of the form of a cosmetic with comprises the present compound include liquid, emulsion, cream, lotion, ointment, gel, aerosol, mousse and the like. Lotion can be prepared using cosmetic additives such as a suspending agent, an emulsifier, a preservative and the like, according to a conventional method. A dose of the cosmetic varies depending on the age, sex and weight of a mammal to be administered, the severity of disease, the kind and dosage form of the composition of the present invention, and the like. Usually, about 0.01 mg to about 50 mg of the active ingredient may be administered to an adult human. The daily dose may be also administered at one time or in several divided doses. When the present compound is used as a food additive, specific examples of the form of a food which comprises the additive include powder, a tablet, a beverage, an edible gel or a mixed liquid of the gel and syrup, for example, general beverage and food and luxury food and beverage such as seasonings, Japanese confectioneries, western confectioneries, ice confectioneries, beverage, spreads, pastes, pickles, bottled or canned products, processed domestic animal meats, processed fish meats or marine product, processed dairy or egg products, processed vegetables, processed fruits, processed cereals and the like. Alternatively, the present compound can be also added to feeds or provenders for rearing animals such as livestocks, poultry, honey bee, silkworm, fish and the like. A dose of the food varies depending on the age, sex and weight of a mammal to be administered, the severity of disease, the kind and dosage form of the composition of the present invention, and the like. Usually, about 0.1 mg to about 500 mg of the active ingredient may be administered to an adult human. The daily dose may be also administered at one time or in several divided doses. EXAMPLES The present invention will be further specifically explained below by way of Examples. Example 1 Synthesis of the Present Intermediate (II-2a) [Compound No. (1a-6)] A mixture of 1.85 g of 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one, 2.25 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 20 ml of chloroform and 0.7 ml of piperidine was heated under refluxing for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography. Resulting crystals were washed with 40 ml of t-butyl methyl ether to obtain 0.40 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (1a-6]) as a yellow crystal. 1H-NMR (300 MHz, CDCl3) δ (ppm): 2.31 (s, 3H), 5.70 (s, 1H), 7.38 (d, 1H), 7.61 (d, 1H), 7.78 (s, 1H), 7.80 (d, 1H, J=15.0 Hz), 8.27 (d, 1H, J=15.0 Hz) Example 2 Synthesis of the Present Intermediate (II-2a) [Compound No. (1a-9)] According to the same manner as that of Example 1 except that 2.57 g of 3-([1,3]dioxolan-2-yl)benzaldehyde was used in place of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 0.38 g of 4-hydroxy-3-[3-[3-([1,3]dioxolan-2-yl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (1a-9)] was obtained as a pale yellow crystal. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.29 (s, 3H), 4.04-4.17 (m, 4H), 5.84 (s, 1H), 5.96 (s, 1H), 7.44 (t, 1H, J=7.7 Hz), 7.54 (d, 1H, J=7.6 Hz), 7.70 (d, 1H, J=7.8 Hz), 7.78 (s, 1H), 7.97 (d, 1H, J=15.9 Hz), 8.32 (d, 1H, J=15.9 Hz) Example 3 Synthesis of the Present Intermediate (II-2a) [Compound No. (1a-10)] According to the same manner as that of Example 1 except that 4.97 g of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde was used in place of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 0.50 g of 4-hydroxy-3-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (1a-10)] was obtained as a pale yellow crystal. 1H-NMR (300 MHz, CDCl3) δ (ppm): 2.27 (s, 3H), 4.28-4.31 (m, 4H), 5.94 (s, 1H), 6.90 (d, 1H, J=8.1 Hz), 7.21-7.24 (m, 2H), 7.88 (d, 1H, J=15.6 Hz), 8.17 (d, 1H, J=15.6 Hz), 12.19 (s, 1H) Example 4 Synthesis of the Present Intermediate (II-2b) [Compound No. (1b-1)] According to the same manner as that of Example 1 except that n-tolualdehyde was used in place of 3-chloro-4-(trifluoromethoxy)benzaldehyde, and 3-acetyl-5-bromo-4-hydroxy-6-methyl-2H-pyran-2-one was used in place of 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one, 5-bromo-4-hydroxy-3-[3-(3-methylphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (1b-1)] was obtained as a pale yellow crystal. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.40 (s, 3H), 2.50 (s, 3H), 7.25-7.34 (m, 2H), 7.49-7.51 (m, 2H), 8.05 (d, 1H, J=15.9 Hz), 8.30 (d, 1H, J=15.9 Hz) Example 5 Synthesis of the Present Intermediate (II-2b) [Compound No. (1b-4)] According to the same manner as that of Example 1 except that 3-acetyl-4-hydroxy-6-phenyl-2H-pyran-2-one was used in place of 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one, 4-hydroxy-3-[3-(3-methylphenyl)-1-oxo-2-propenyl]-6-phenyl-2H-pyran-2-one [Compound No. (1b-4)] was obtained. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.40 (s, 3H), 6.59 (s, 1H), 7.22-7.28 (1H), 7.32 (t, 1H, J=7.6 Hz), 7.48-7.58 (m, 5H), 7.86-7.93 (m, 2H), 7.97 (d, 1H, J=15.6 Hz), 8.35 (d, 1H, J=15.8 Hz), 12.06 (s, 1H) Example 6 Synthesis of the Present Intermediate (II-2c) [Compound No. (1c-6)] A mixture of 2.25 g of 3-acetyl-4-hydroxy-2H-1-benzopyran-2-one, 2.25 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 20 ml of chloroform and 0.7 ml of piperidine was heated under refluxing for 2 hours and 30 minutes. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography. Resulting crystals were washed with 40 ml of t-butyl methyl ether to obtain 1.49 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (1c-6)] was obtained as a yellow crystal. 1H-NMR (270 MHz, CDCl3) δ (ppm): 7.30-7.40 (3H), 7.63 (dd, 1H, J=2.2, 8.6 Hz), 7.72 (t, 1H, J=7.8 Hz), 7.81 (d, 1H, J=2.2 Hz), 7.91 (d, 1H, J=15.4 Hz), 8.10 (dd, 1H, J=1.6, 7.6 Hz), 8.41 (d, 1H, J=15.9 Hz), 18.64 (s, 1H) Example 7 Synthesis of the Present Compound (IIa) [Compound No. (2a-17)] In 4 ml of hexamethylphosphoramide was dissolved 0.33 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one, to this solution was added 50 mg of sodium hydride (60% oily), and the mixture was stirred at room temperature for 30 minutes. Then, 0.2 ml of dimethyl sulfate was added, and the mixture was stirred at 65° C. for 1 hour, and at room temperature overnight. Thereafter, the reaction mixture was added to ice water, and this was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.13 g of 4-methoxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran [Compound No. (2a-17)] as a pale yellow crystal. 1H-NMR (270 MHz, CDCl3) δ (ppm): 2.31 (s, 3H), 3.95 (s, 3H), 5.99 (s, 1H), 7.16 (d, 1H, J=15.9 Hz), 7.32 (d, 1H, J=7.6 Hz), 7.47 (d, 1H, J=6.5 Hz), 7.53 (d, 1H, J=15.9 Hz), 7.68 (d, 1H, J=1.9 Hz) Example 8 Synthesis of the Present Compound (IIa) [Compound No. (2a-20)] According to the same manner as that of Example 7 except that 0.35 g of 4-hydroxy-3-[3-[3-([1,3]dioxolan-2-yl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one was used in place of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one, 0.18 g of 4-methoxy-3-[3-[3-([1,3]dioxolan-2-yl)phenyl]-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (2a-20)] was obtained as a pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.35 (s, 3H), 3.93 (s, 3H), 4.03-4.18 (m, 4H), 5.82 (s, 1H), 6.12 (s, 1H), 7.15 (d, 1H, J=16.0 Hz), 7.39 (t, 1H, J=7.7 Hz), 7.49 (d, 1H, J=7.6 Hz), 7.57 (d, 1H, J=7.6 Hz), 7.62 (d, 1H, J=16.0 Hz), 7.68 (s, 1H) Example 9 Synthesis of the Present Compound (II-a) [Compound No. (2a-24)] To a mixture of 0.81 g of 4-hydroxy-3-[3-(3-methylphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one, 10 ml of tetrahydrofuran, 0.25 ml of 2-methoxyethanol, and 0.87 g of triphenylphosphine was added dropwise a solution of 0.57 g of diethyl azodicarboxylate in 6 ml of tetrahydrofuran, and this was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 389 mg of 4-(2-methoxyethoxy)-3-[3-(3-methylphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (2a-24)] as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.32 (s, 3H), 2.36 (s, 3H), 3.33 (s, 3H), 3.66 (t, 2H, J=4.6 Hz), 4.25 (t, 2H, J=4.6 Hz), 6.12 (s, 1H), 7.09 (d, 1H, J=15.9 Hz), 7.15-7.40 (4H), 7.56 (d, 1H, J=15.9 Hz) Example 10 Synthesis of the Present Compound (IIa) [Compound No. (2a-25)] According to the same manner as that of Example 9 except that 0.25 ml of methyl glycolate was used in place of 2-methoxyethanol, 470 mg of 4-methoxycarbonylmethoxy-3-[3-(3-methylphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (2a-25)] was obtained. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.30 (s, 3H), 2.35 (s, 3H), 3.79 (s, 3H), 4.75 (s, 2H), 5.95 (s, 1H), 7.06 (d, 1H, J=16.2 Hz), 7.20-7.80 (5H) Example 11 Synthesis of the Present Compound (IIa) [Compound No. (2a-26)] According to the same manner as that of Example 9 except that 0.34 ml of 3-acetyl-1-propanol was used in place of 2-methoxyethanol, 98 mg of 4-(3-acetylpropoxy)-3-[3-(3-methylphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (2a-26)] was obtained. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.95-2.05 (m, 2H), 2.07 (s, 3H), 2.33 (s, 3H), 2.36 (s, 3H), 2.61 (t, 2H, J=6.6 Hz), 4.15 (t, 2H, J=6.1 Hz), 6.12 (s, 1H), 7.09 (d, 1H, J=16.2 Hz), 7.15-7.40(4H), 7.54 (d, 1H, J=16.2 Hz) Example 12 Synthesis of the Present Compound (IIa) [Compound No. (2a-27)] According to the same manner as that of Example 9 except that 0.52 ml of ethylene glycol monoacetate was used in place of 2-methoxyethanol, 40 mg of 4-(2-hydroxyethoxy)-3-[3-(3-methylphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (2a-27)] was obtained. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.34 (s, 3H), 2.36 (s, 3H), 3.34 (t, 2H, J=6.4 Hz), 3.88-3.92 (m, 2H), 4.26 (t, 2H, J=4.6 Hz), 6.09 (s, 1H), 7.15-7.45 (m, 5H), 7.64 (d, 1H, J=16.1 Hz) Example 13 Synthesis of the Present Compound (IIa) [Compound No. (2a-28)] According to the same manner as that of Example 9 except that 0.32 ml of 2-(methylsulfonyl)ethanol was used in place of 2-methoxyethanol, 137 mg of 4-(2-methylsulfonylethoxy)-3-[3-(3-methylphenyl)-1-oxo-2-propenyl]-6-methyl-2H-pyran-2-one [Compound No. (2a-28)] was obtained. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.38 (s, 6H), 3.05 (s, 3H), 3.42 (t, 2H, J=5.6 Hz), 4.56 (t, 2H, J=5.2 Hz), 6.12 (s, 1H), 7.13 (d, 1H, J=16.1 Hz), 7.15-7.40 (4H), 7.55 (d, 1H, J=15.9 Hz) Example 14 Synthesis of the Present Compound (IIc) [Compound No. (2c-17)] In 15 ml of hexamethylphosphoramide was dissolved 1.37 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]1-oxo-2-propenyl]-2H-1-benzopyran-2-one, to this solution was added 0.17 g of sodium hydride (60% oily), and this was stirred at room temperature for 30 minutes. Then, 0.8 ml of dimethyl sulfate, and this was stirred at 65° C. for 2 hours. Thereafter, the reaction mixture was added to ice water, and this was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was washed with t-butyl methyl ether to obtain 0.38 g of 4-methoxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (2c-17)] as a pale yellow crystal. 1H-NMR (270 MHz, CDCl3) δ (ppm): 3.97 (s, 3H), 7.16 (d, 1H, J=15.9 Hz), 7.30-7.40 (2H), 7.48-7.55 (1H), 7.54 (d, 1H, J=15.9 Hz), 7.55-7.65 (2H), 7.71 (d, 1H, J=1.9 Hz), 7.92 (dd, 1H, J=1.4, 7.8 Hz) Example 15 Synthesis of the Present Compound (IIa′) [Compound No. (3a-32)] A mixture of 0.50 g of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone, 0.74 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 6 mg of pyridine and 0.1 ml of piperidine was heated under refluxing for 4 hours. After cooled to room temperature, 40 ml of water was added to the reaction mixture, precipitated crystals were filtered, and this was washed with tetrahydrofuran, then with ethyl acetate to obtain 0.41 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (3a-32)] as a yellow crystal. 1H-NMR (270 MHz, DMSO-d6) δ (ppm): 2.22 (s, 3H), 5.90 (s, 1H), 7.60-7.70 (2H), 7.76 (d, 1H, J=16.2 Hz), 8.01 (s, 1H), 8.49 (d, 1H, J=15.9 Hz), 11.62 (s, 1H), 16.14 (s, 1H) Example 16 Synthesis of the Present Compound (IIa′) [Compound No. (3a-34)] In a mixture of 2 ml of pyridine and 0.05 ml of piperidine were dissolved 0.23 g of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone and 0.23 g of 3-(methoxycarbonyl)benazldehyde, and the solution was heated under refluxing for 2 hours. After cooled to room temperature, this was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 0.06 g of 4-hydroxy-3-[3-[3-(methoxycarbonyl)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (3a-34)] as a yellow crystal. 1H-NMR (270 MHz, DMSO-d6) δ (ppm): 2.41 (s, 3H), 3.41 (s, 3H), 3.89 (s, 3H), 6.07 (s, 1H), 7.63 (t, 1H, J=7.8 Hz), 7.85 (d, 1H, J=15.8 Hz), 7.96-8.03 (m, 2H), 8.25 (s, 1H), 8.54 (d, 1H, J=15.8 Hz), 15.92 (broads, 1H) Example 17 Synthesis of the Present Compound (IIa′) [Compound No. (3a-37)] To a solution of 2.93 g of 3-[N-(t-butoxycarbonyl)amino]benzaldehyde in 20 ml of dimethylformamide was added 0.58 g of sodium hydride (60% oily) under ice-cooling. After stirring at room temperature for 1 hour, a solution of 0.93 ml of 2-bromoethanol in 5 ml of dimethylformamide was added dropwise under ice-cooling. After stirring at room temperature for 14 hours, the mixture was heated to stir at 115° C. for 6 hours. Ethyl acetate was added, and this was washed successively with water and an aqueous saturated sedum chloride solution, dried with anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.75 g of oily 3-(2-oxo-oxazolidin-3-yl)benzaldehyde. 1H-NMR (270 MHz, DMSO-d6) δ (ppm): 4.10-4.16 (m, 2H), 4.44-4.51 (m, 2H), 7.61-7.71 (m, 2H), 7.86-7.91 (m, 1H), 8.10-8.12 (m, 1H), 10.03 (s, 1H) According to the same manner as that of Example 16 except that 0.33 g of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone, and 0.30 g of 3-(2-oxo-oxazolidin-3-yl)benzaldehyde was used in place of 3-(methoxycarbonyl)benzaldehyde, 0.22 g of 4-hydroxy-3-[3-[3-(2-oxo-oxazolidin-3-yl)phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (3a-37)] was obtained as a yellow crystal. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 2.21 (s, 3H), 4.11 (t, 2H, J=7.5 Hz), 4.47 (t, 2H, J=7.5 Hz), 5.89 (s, 1H), 7.38-7.53 (m, 2H), 7.65-7.69 (m, 1H), 7.81 (d, 1H, J=15.0 Hz), 7.89 (s, 1H), 8.53 (d, 1H, J=15.0 Hz), 11.57 (broads, 1H) Example 18 Synthesis of the Present Compound (IIa′) [Compound No. (3a-38)] According to the same manner as that of Example 16 except that 0.42 g of 3-(2-oxo-oxazolidin-3-yl)benzaldehyde was used in place of 3-(methoxycarbonyl)benzaldehyde, 0.25 g of 4-hydroxy-3-[3-[3-(2-oxo-oxazolidin-3-yl)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (3a-38)] was obtained as a yellow crystal. 1H-NMR (270 MHz, DMSO-d6) δ (ppm): 2.41 (s, 3H), 3.40 (s, 3H), 4.09-4.15 (m, 2H), 4.44-4.50 (m, 2H), 6.06 (s, 1H), 7.48-7.53 (m, 2H), 7.65-7.69 (m, 1H), 7.80 (d, 1H, J=16.1 Hz), 7.89 (s, 1H), 8.50 (d, 1H, J=16.1 Hz), 16.03 (broads, 1H) Example 19 Synthesis of the Present Compound (IIa′) [Compound No. (3a-39)] According to the same manner as that of Example 16 except that 1.09 g of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone, and 1.68 g of 3-(2-morpholinoethoxy)benzaldehyde was used in place of 3-(methoxycarbonyl)benzaldehyde, 0.27 g of 4-hydroxy-3-[3-[3-(2-morpholinoethoxy)phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (3a-39)] was obtained as a yellow crystal. 1H-NMR (270 MHz, DMSO-d6) δ (ppm): 2.21 (s, 3H), 2.47-2.50 (m, 4H), 2.71 (t, 2H, J=5.4 Hz), 3.58 (t, 4H, J=4.6 Hz), 4.14 (t, 2H, J=5.4 Hz), 5.88 (s, 1H), 7.05 (d, 1H, J=8.4 Hz), 7.24-7.41 (m, 3H), 7.77 (d, 1H, J=16.2 Hz), 8.50 (d, 1H, J=16.2 Hz), 11.56 (s, 1H), 16.42 (s, 1H) Example 20 Synthesis of the Present Compound (IIa′) [Compound No. (3a-40)] According to the same manner as that of Example 16 except that 4.87 g of 3-(2-morpholinoethoxy)benzaldehyde was used in place of 3-(methoxycarbonyl)benzaldehyde, 0.86 g of 4-hydroxy-3-[3-[3-(2-morpholinoethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (3a-40)] was obtained as a yellow crystal. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 2.38 (s, 3H), 2.41-2.50 (m, 4H), 2.71 (t, 2H, J=5.4 Hz), 3.32 (s, 3H), 3.57-3.60 (m, 4H), 4.14 (t, 2H, J=5.4 Hz), 6.06 (s, 1H), 7.03-7.07 (m, 1H), 7.25-7.54 (m, 3H), 7.77 (d, 1H, J=13.5 Hz), 8.46 (d, 1H, J=16.2 Hz) Example 21 Synthesis of the Present Compound (IIc′) [Compound No. (3c-32)] A mixture of 0.60 g of 3-acetyl-4-hydroxy-2(1H)-quinolinone, 1.99 g of 3-chloro-4-(trifluoromethoxy)benzaldehyde, 10 ml of pyridine and 88 μl of piperidine was heated under refluxing overnight. After cooling to room temperature, 50 ml of water was added to the reaction mixture, and precipitated crystals were filtered, and washed with 40 ml of tetrahydrofuran, and 60 ml of hexane to obtain 0.92 g of 4-hydroxy-3-[3-[3-chloro-4-(trifluoromethoxy)phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone [Compound No. (3c-32)] as a yellow crystal. 1H-NMR (270 MHz, DMSO-d6) δ (ppm): 7.26 (t, 1H, J=7.8 Hz), 7.32 (d, 1H, J=8.4 Hz), 7.65-7.75 (2H), 7.87 (d, 1H, J=8.4 Hz), 7.87 (d, 1H, J=17.0 Hz), 8.03 (d, 1H, J=7.8 Hz), 8.07 (s, 1H), 8.60 (d, 1H, J=15.9 Hz), 11.56 (s, 1H), 17.71 (s, 1H) Example 22 Preparation of a Plasmid Having a Reporter Gene Linked to a Transcription Regulatory Region for a Type I Collagen Gene 1×108 cells of a normal human fetal skin fibroblast (Clontech, catalogue No. CC-2509) were cultured at 37° C. overnight under 5% CO2 atmosphere. After the cultured cells were washed with a sodium phosphate buffer (hereinafter, referred to as PBS) twice, 3 ml of PBS was added thereto and the cells were scraped away the wall of a vessel using a cell scraper (Nalgen, catalogue No. 179693). The scraped cells were collected by centrifugation (1,500 rpm, 4° C., 15 min), and these were suspended in 20 ml of PBS and centrifuged again. To the resulting precipitates were added 11 ml of Solution 2 and 4.8 μl of pronase of DNA Extraction Kit (Stratagene, catalogue No. 200600). After shaken at 60° C. for 1 hour, the resulting mixture was allowed to stand in ice for 10 minutes. Then, 4 ml of Solution 3 of the kit was added to the mixture. After mixed, the mixture was allowed to stand in ice for 5 minutes and then centrifuged (3,000 rpm, 4° C., 15 min) to recover a supernatant. To the recovered supernatant was added 2 μl of RNase per 1 ml of the supernatant and the mixture was allowed to stand at 37° C. for 15 minutes. To the mixture was added 2-fold volume of ethanol. After mixed, a white thread-like substance (genomic DNA) appeared and the substance was recovered. The recovered genomic DNA was washed with 70% ethanol and then air-dried. The air-dried genomic DNA was dissolved in 500 μl of 10 mM Tris-HCl, 1 mM EDTA (pH 8.0) (hereinafter, referred to as TE). The resulting genomic DNA solution (the amount equivalent to 1 μg of genomic DNA), each 1 μl (10 μmol/μl) of an oligonucleotide consisting of the nucleotide sequence represented by SEQ ID No:1 and an oligonucleotide consisting of the nucleotide sequence represented by SEQ ID No: 2, 29 μL of distilled water, 5 μl of the buffer attached to TaKaRa LA Taq (TAKARA SHUZO, catalogue No. RR002A), 5 μL of a Mg2+ solution, 5 μL of a dNTP mixture and 0.5 μl of TaKaRa LA Taq (TAKARA SHUZO, catalogue No. RR002A) were mixed. After the resulting mixed solution was incubated at 94° C. for 5 minutes, the mixed solution was subjected to 30 cycles, in which one cycle consists of incubation at 94° C. for 1 minute, at 60° C. for 1 minute and then at 72° C. for 1 minute. The mixed solution was electrophoresed on a 2% agarose gel to recover about 0.5 kb of a DNA. The recovered DNA was treated with phenol/chloroform and then precipitated with ethanol to recover the DNA. The resulting DNA was dissolved in ultrapure water. To this solution were added 2.5 μl of NheI and 2.5 μl of HindIII, and then incubated at 37° C. for 3 hours. Then, the solution was electrophoresed on a 2% agarose gel to recover about 3.5 kb of a DNA. The recovered DNA was precipitated with ethanol to recover again the DNA (hereinafter, referred to as the collagen promoter DNA). On the other hand, the vector pGL3 (Promega, catalogue No. E1751) having the nucleotide sequence encoding firefly luciferase was digested with NheI and HindIII, and then subjected to agarose gel electrophoresis as described above to recover about 5 kb of a DNA. The recovered DNA was precipitated with ethanol to recover the DNA again. To the recovered DNA were added 44 μl of distilled water, 5 μl of Buffer attached to Alkaline Phosphatase (TAKARA SHUZO, catalogue No. 2120A) and 1 μl of Alkaline Phosphatase (TAKARA SHUZO, catalogue No. 2120A). The mixed solution was incubated at 65° C. for 30 minutes. Then, the mixed solution was treated with phenol/chloroform twice, and precipitated with ethanol to recover the DNA (hereinafter referred to as the Luc vector DNA). Then, after about 20 ng of the collagen promoter DNA and about 20 ng of the Luc vector DNA were mixed, the same amount of a DNA Ligation kit Ver2 enzyme solution was added and this was incubated overnight at 16° C. To the mixed solution was added Escherichia coli 5Hdα (TOYOBO, catalogue No. DNA-903), this was allowed to stand in ice for 30 minutes, and then incubated at 42° C. for 45 seconds. The resulting Escherichia coli was seeded on a LB plate containing 50 μg/ml ampicillin sodium (Nacalai, catalogue No. 027-39), and this was allowed to stand at 37° C. for 1 day. A single colony appeared and the colony was cultured in 2 ml of a LB medium containing 50 μg/ml ampicillin at 37° C. for 12 hours. From the resulting culture solution, a plasmid DNA was prepared using AUTOMATIC DNA ISOLATION SYSTEM PI-50 (KURABO). The nucleotide sequence of the prepared plasmid DNA was analyzed with a DNA sequencer. As a result, it was confirmed that the plasmid (hereinafter, referred to as COL-Luc) had a nucleotide sequence comprising a nucleotide sequence encoding the amino acid sequence of firefly luciferase as a reporter gene linked downstream of the nucleotide sequence −3500 to +57 (the transcription initiation point is +1) of a transcription regulatory region for a human-derived Type I collagen α2 chain gene. Example 23 Measurement of the Ability of a Test Compound to Regulate Transcription of a Type I Collagen Gene Using the Expression Level of a Report Gene as an Index 1×106 cells of a normal human fetal skin fibroblast were seeded on a 100 mm dish and cultured at 37° C. overnight under 5% CO2 atmosphere in a Dulbecco's-MEM (Nissui Seiyaku, catalogue No. 05919) medium containing 10 (v/v) % heat-inactivated bovine fetal serum (hereinafter, referred to as FBS; Gibco, catalogue No. 21140-079) (hereinafter, this medium is referred to as D-MEM(+)). Then, the medium was replaced with a Dulbecco's-MEM medium not containing FBS (hereinafter, this medium is referred to as D-MEM(−)). To 300 μl of D-MEM(−) were added 5 μg of COL-Luc and 5 μg of pCMV-β-gal (Invitrogen, catalogue No. 10586-014), and the resulting mixed solution was allowed to stand at room temperature for 5 minutes (solution 1). To 300 μl of D-MEM(−) was added 20 μl of Lipofectine (Gibco, catalogue No. 18292-011), and the resulting mixed solution was allowed to stand at room temperature for 45 minutes (solution 2). Then, the solution 1 and the solution 2 were mixed. After the mixture was allowed to stand at room temperature for 10 minutes, 5.4 ml of D-MEM(−) was added to thereto, followed by mixing. The mixed solution was added to the normal human fetal skin fibroblasts, and the cells were cultured at 37° C. under 5% CO2 atmosphere. After 6 hours, the culture supernatant was removed from the dish, and the cells were washed with PBS twice. To the dish was added 1 ml of PBS containing 0.25% trypsin, and the cells were scraped off the dish. To the scraped cells was added D-MEM(+), and these were mixed well. The mixture was dispensed into a 12-well plate at 1 ml per well, and the plate was incubated at 37° C. overnight under 5% CO2 atmosphere. On the next day, each well was washed with D-MEM(−) twice, and this was replaced with 1 ml of a Dulbecco's-MEM medium containing 0.1% FBS (hereinafter, this medium is referred to as D-MEM (0.1%)). To the thus cultured cells was added 10 μl of a 100 μM solution of the present compound represented by the compound number (2a-17), (2c-17), (3a-32) or (3c-32) in dimethyl sulfoxide (hereinafter, DMSO) (final concentration 1 μM). As a control, only 10 μl of DMSO was added. After one hour, 10 μl of a 0.5 μg/ml aqueous solution of TGF-β (Pepro Tech) or distilled water was added to the well, and the plate was further incubated at 37° C. for 40 hours under 5% CO2 atmosphere. After the incubated cells were washed with PBS twice, 200 μl of a cell lysing agent (Toyo Inc., catalogue No. PD10) was added thereto and the cells were scraped. The scraped cells were recovered as a cell suspension, and the suspension was centrifuged (15,000 rpm, 4° C., 5 min) to recover a supernatant. The recovered supernatant was transferred to a 96-well plate at 50 μl per well, and then 50 μl of a Luc assay solution (20 mM Tricine (pH 7.8), 2.67 mM MgSO4, 0.1 mM EDTA, 33.3 mM DTT, 270 μM Coenzyme A, 530 μM ATP, 470 μM Luciferin) was automatically dispensed into the plate using MICROLUMAT LB96P (manufactured by EG&G BERTHOLD). Luminescence in each well was measured (Delay: 1.6 second, Meas. Interval: 20 second). On the other hand, 50 μl of the recovered supernatant or the cell lysing agent was added to 50 μl of a β-gal substrate solution (5.8 mM o-nitrophenyl-beta-D-galactopyranoside, 1 mM MgCl2, 45 mM 2-mercaptoethanol) which had been dispensed into a 96-well plate in advance, and the plate was incubated at 37° C. for 2 hours. Then, an absorbance in each well was measured using a microplate reader at 420 nm. Based on the resulting value, the transcription activity was calculated according to the following equation: Transcription activity=[luminescence amount (supernatant-added section)−luminescence amount (cell lysing agent-added section)]/[420 nm absorbance (supernatant-added section)−420 nm absorbance (cell lysing agent-added section)] Then, based on the calculated transcription activity, an inhibitory effect of a test compound on the ability of TGF-β to promote transcription of a Type I collagen gene was calculated as an inhibition percentage according to the following equation: Inhibition percentage=[transcription activity (DMSO and TGF-β-added test section)−transcription activity (compound and TGF-β-added test section)]/[transcription activity (DMSO and TGF-β-added test section)−transcription activity (DMSO and TGF-β non-added test section)]×100 The inhibition percentages of the present compounds represented by the compound number (2a-17), (2c-17), (3a-32) and (3c-32) were 70 or more. It was found that these compounds can inhibit the ability of TGF-β to promote transcription of a Type I collagen gene, and then can suppress transcription of a Type I collagen gene. INDUSTRIAL APPLICABILITY According to the present invention, it is possible to develop and provide a composition which decreases expression of a Type I collage gene in a tissue to induce a reduction in accumulation of collagen and thereby improves tissue fibrosis (i.e. a collagen accumulation-suppressing agent and a fibrosing disease-treating agent). Sequence Listing Free Text SEQ ID NO: 1 Oligonucleotide primer designed for amplifying a collagen promoter DNA SEQ ID NO: 2 Oligonucleotide primer designed for amplifying a collagen promoter DNA SEQ ID NO: 3 Oligonucleotide primer designed for detecting a collagen DNA SEQ ID NO: 4 Oligonucleotide primer designed for detecting a collagen DNA SEQ ID NO: 5 Oligonucleotide probe designed for detecting a collagen DNA

<SOH> BACKGROUND ART <EOH>In diseases and disorders such as hepatic cirrhosis, interstitial pulmonary disease, chronic renal failure (or disease resulting in chronic renal failure), hyperplasia scar after inflammation, postoperative scars or burn scars, scleroderma, arteriosclerosis, hypertension and the like, excessive accumulation of an extracellular matrix, a representative of which is collagen, causes fibrosis and sclerosis of tissues, resulting in decreased functions, cicatrization and the like in the organs or tissues. Such excessive accumulation of an extracellular matrix is induced by increased production of collagen due to a breakdown of balance between biosynthesis and degradation of collagen and the like. In fact, it has been observed that expression of a collagen gene, in particular, a Type I collagen gene has been increased in a fibrotic tissue [e.g. J. Invest. Dermatol., 94, 365, (1990) and Proc. Natl. Acad. Sci. USA, 88, 6642, (1991)]. It has been also observed that the amount of TGF-β, which is a cytokine, has been increased in a fibrotic tissue [e.g. J. Invest. Dermatol., 94, 365, (1990) and Proc. Natl. Acad. Sci. USA, 88, 6642, (1991)]. It has been shown that TGF-β has increased expression of a Type I collagen gene and been involved in increased production of collagen and, consequently, fibrosis of a tissue [e.g. Lab. Invest., 63, 171, (1990) and J. Invest. Dermatol., 94, 365, (1990)]. It has been also shown that by administering an anti-TGF-β antibody or a soluble anti-TGF-β receptor to a model animal of tissue fibrosis, improvement of tissue fibrosis has been achieved and thereby the tissue function has been also improved [e.g. Diabetes, 45, 522-530, (1996), Proc. Natl. Acad. Sci. USA, 96, 12719-12724, (1999) and Proc. Natl. Acad. Sci. USA, 97, 8015-8020, (2000)]. It has been also known that by administering a compound which suppressively acts on intracellular signal transduction via TGF-β, improvement in fibrosis of a tissue has been achieved and thereby the tissue function has been also improved [e.g. Autoimmunity, 35, 277-282, (2002), J. Hepatol., 37, 331-339, (2002) and Life Sci., 71, 1559-1606, (2002)]. Thus, there is a need for development and provision of a drug which improves fibrosis of a tissue by decreasing expression of a Type I collagen gene in the tissue to reduce accumulation of collagen (i.e. a collagen accumulation-suppressing agent and a fibrosing disease-treating agent).

20060317

20130903

20070531

94416.0

A61K31541

ANDERSON, REBECCA L

Cinnamoyl derivatives and use thereof

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Hand power tool

A hand power tool, having a housing (12) and a tool bit (15), in particular a metal-cutting tool bit, as well as having a guard means (22), which embraces the tool bit (15) and is coupleable to the housing (12) and axially adjustable relative to it, is made easy to manipulate in setting the cutting depth by providing that the housing (12) and the guard means (22), in a first adjusting position, are positionable axially freely and in a second adjusting position, in particular guided by adjusting means, are positionable axially finely adjustably to one another, in particular lockably.

1. A hand power tool, having a housing (12) and a tool bit (15), in particular a metal-cutting tool bit, as well as having a guard means (22), which embraces the tool bit (15) and is coupleable to the housing (12) and axially adjustable relative to it, characterized in that the housing (12) and the guard means (22), in a first adjusting position, are positionable axially freely and in a second adjusting position, in particular guided by adjusting means, are positionable axially finely adjustably to one another, in particular lockably. 2. The hand power tool in accordance with claim 1, characterized in that the adjusting positions are rapidly changeable by means of a relative motion between the guard means (22) and the housing (12). 3. The hand power tool in accordance with claim 2, characterized in that the relative motion is a rotary motion between the guard means and the housing (12), in particular limited by a short rotational course. 4. The hand power tool in accordance with claim 1, characterized in that the guard means (22) is designed as a supporting foot, which annularly embraces the housing (12) and can be put into two predetermined rotary positions, which define one fine adjustment stage and one coarse adjustment stage for varying the axial position of the housing (12) relative to the supporting foot (22). 5. The hand power tool in accordance with claim 3, characterized in that the two rotary positions are limited in overlooking fashion, in particular directly next to one another, with a minimal rotational course of the housing (12) relative to the supporting foot (22). 6. The hand power tool in accordance with claim 3, characterized in that overlooking means (36, 37) that secure every adjustment stage against unintentional change are located between the housing (12) and the supporting foot (22). 7. The hand power tool in accordance with claim 1, characterized in that the housing (12) has a collar, onto which the supporting foot (22) can be slipped in telescoping fashion, and the outer contour of the housing (12) merges flush with that of the completely slipped-on supporting foot (22), and in this position of the housing (12) relative to the supporting foot (22), the minimal telescoping extension position and hence a maximum cutting depth for the tool bit (15) are set. 8. The hand power tool in accordance with claim 1, characterized in that located between the housing (12) and the supporting foot (22) is a depth stop (34), which in the first adjustment stage does not and in the second adjustment stage does lockingly engage the inside of the housing (12) and the supporting foot (22). 9. The hand power tool in accordance with claim 8, characterized in that the depth stop (34) is designed as a screw bolt, on one end of which a control wheel (28) is seated in a manner fixed against relative rotation, with which control wheel the depth stop (34) is located rotatably and axially secured in the supporting foot (22). 10. The hand power tool in accordance with claim 9, characterized in that the control wheel (28) reaches outward, in particular in a manually operable way, through the supporting foot (22), and in particular its sleevelike wall (23), and the screw bolt (35) rests in form-locking fashion over approximately half its length in a longitudinally parallel groove (33) in the inside of the wall (23) of the supporting foot (22) and with its radially protruding lengthwise region rests on the diametrically opposite side in an outer longitudinal housing groove (38) that is parallel to the groove (33). 11. The hand power tool in accordance with claim 10, characterized in that a further longitudinal housing groove (40), in particular with the same radius of curvature, is located next to the one longitudinal housing groove (38), and the screw bolt (35) can be longitudinally placed in this further longitudinal housing groove. 12. The hand power tool in accordance with claim 11, characterized in that the longitudinal housing grooves (38, 40) are directly next to each other and can be put into a parallel overlooking engagement with the screw bolt (35) selectively by rotating the supporting foot (22) relative to the housing (12). 13. The hand power tool in accordance with claim 12, characterized in that the center spacing of the longitudinal housing grooves (38, 40) is less than twice their radius of curvature. 14. The hand power tool in accordance with claim 13, characterized in that overlooking means are located between the longitudinal housing grooves (38, 40) and seek to keep the screw bolt (35) positionally secure in prestressed fashion in its respective longitudinal housing groove (38, 40). 15. The hand power tool in accordance with claim 14, characterized in that one of the longitudinal housing grooves (38, 40) has fitting threaded means (50) or the like that are capable of engaging the inside of the screw bolt (35). 16. The hand power tool in accordance with claim 15, characterized in that the other of the longitudinal housing grooves (38, 40) embraces the screw bolt (34) with little contact, and in particular with radial play. 17. The hand power tool in accordance with claim 16, characterized in that between the longitudinal housing grooves (38, 40), as overlooking means a bolt (36) is braceable, radially spring-prestressed outward, longitudinally against the screw bolt (35), and in particular is retained in captive fashion in a slot in the housing wall (13). 18. The hand power tool in accordance with claim 17, characterized in that the collar (20) of the housing (12) and/or the upper edge (21), braceable thereon, of the sleevelike shaft of the supporting foot (22) extends obliquely. 19. The hand power tool in accordance with claim 1, characterized in that the adjusting positions are axially and radially fixable and releasable, in particular by clamping means (25, 30). 20. The hand power tool in accordance with claim 1, characterized in that it is capable of being be set down, in freestanding fashion, on a horizontal, level surface, with the aid of the supporting foot (22). 21. The hand power tool in accordance with claim 1, characterized in that the housing (12) and the supporting foot (22) are secured against unintentional release from one another, in particular by a bayonet mount or stop means. 22. The hand power tool in accordance with claim 1, characterized in that scale means (53) are located between the housing (12) and the supporting foot (22) for indicating the cutting depth. 23. The hand power tool in accordance with claim 1, characterized in that it is designed as a top spindle molder, and the adjusting positions can be associated with a predetermined cutting depth. 24. Adjusting means for varying or fixing two parts relatively to one another that are located in telescoping fashion relative to one another, characterized in that they are designed in accordance with claim 1. 25. The hand power tool in accordance with claim 1, characterized in that the supporting foot (22), particularly on the top side of its foot plate (26), has at least one indentation with an upward-protruding edge and with a nonslip surface structure which in particular is provided with rectangular impressions and which serves as a finger rest with a touch guard protecting the finger against the tool bit (15) when the supporting foot (22) is guided and held by hand in milling work. 26. The hand power tool in accordance with claim 1, characterized in that a power cord (16) emerges from the housing (12) radially, to the rear, and angled upward.

PRIOR ART The present invention is based on a hand power tool as generically defined by the preambles to claims 1 and 4 and adjusting means as generically defined by the preamble to claim 27. From German Patent DE 196 37 690 C2, a hand power tool designed as a top spindle molder with cutting depth adjustment is known that permits relatively safe and convenient adjustment of the cutting depth, but a continuously variable rapid adjustment by hand is not possible. ADVANTAGES OF THE INVENTION The present invention having the characteristics of claim 1 has the advantage that with it, rapid and precise adjustment of the cutting depth can be done in a safely monitorable way, and the means provided for it can be produced and installed simply and economically and are sturdy and easy to operate. Because the adjusting positions between the housing and the guard means can be quickly changed, it is possible to finely adjust the cutting depth position safely and precisely immediately after a rapid coarse adjustment. Because the adjusting positions can be changed between coarse and fine adjustment by means of a relative motion between the housing and the guard means, the cutting depth adjustment can be done especially simply and quickly. Because the guard means is designed as a supporting foot which annularly embraces the housing and can be switched over into two predetermined rotary positions that define one fine adjustment stage and one coarse adjustment stage for varying the axial position of the housing relative to the supporting foot, it is possible to switch over the hand power tool in adjusting the cutting depth safely and simply. Because the two rotary positions are limited in overlooking fashion, directly next to one another, with a minimal rotational course of the housing relative to the supporting foot, the rotational position can be adjusted in a quickly variable way. Because overlooking means between the housing and the supporting foot make any change in the adjustment stage audible and feelable, these means secure the housing and the supporting foot against unintentional change. Because the housing has a steplike collar onto which the supporting foot can be slipped, and the outer contour of the housing merges smoothly with that of the completely slipped-on supporting foot, and the minimal telescoping extension position and hence a maximum cutting depth for the tool bit are set in this position of the housing relative to the supporting foot, it is possible for the mutual rotation of the supporting foot and the housing in the switchover operation to be safely felt and monitored by the user's hand in the transition region between the supporting foot and the housing. Because a depth stop is located between the housing and the supporting foot and this depth stop in the first adjustment stage does not but in the second adjustment stage does adjustably engage between the housing and the supporting foot, it is possible to make an axial coarse adjustment of the housing relative to the supporting foot in the first adjustment stage, from which, after a switchover to the second adjustment stage, the final cutting depth can be finely adjusted by rotating the depth stop. Because the depth stop is designed as a screw bolt, on one end of which a control wheel is seated in a manner fixed against relative rotation, with which control wheel the depth stop is located rotationally drivably and axially secured in the supporting foot, it can axially finely adjust the housing relative to the supporting foot in the fine adjustment stage by rotation by hand, and in the first adjustment stage it remains disengaged from the inside of the housing, and furthermore, upon release of the housing from the supporting foot, it can remain secured in captive fashion in the supporting foot. Because the control wheel passes through the supporting foot to the outside in a manually operable way, and the screw bolt, over nearly half its length, rests longitudinally parallel in a groove in an inside of the wall of the supporting foot in form-locking fashion and with its protruding longitudinal region on the diametrically opposite side is associated with a parallel outer longitudinal housing groove, the depth stop can be adjusted from outside especially safely - without the risk of injury to the user's hand by the tool bit. Because next to the one longitudinal housing groove there is a further longitudinal housing groove, particularly with a female thread that fits the thread of the depth stop and into which female thread the screw bolt can be placed longitudinally, a fine adjustment of the housing relative to the supporting foot can be done upon placement of this bolt in the one longitudinal housing groove, and upon its placement in the other longitudinal housing groove, a free axial adjustment of the housing relative to the supporting foot can be done by hand. Because the center spacing of the longitudinal housing grooves is less than the groove diameter, the switchover travel for changing the adjustment stages is especially short. Because overlooking means are located between the longitudinal housing grooves at the transition from one to the other and positionally secure the screw bolt in overlooking fashion in its applicable longitudinal housing groove, an unintentional change of the adjustment stages is precluded. Because one of the longitudinal housing grooves has fitting threaded means that can engage the inside of the screw bolt upon rotation of the screw bolt, via actuation of the control wheel, replicable fine adjustment of the housing relative to the supporting foot is possible. Because the other of the longitudinal housing grooves embraces the screw bolt with radial play without engaging it, the housing can be easily adjusted easily relative to the supporting foot axially between the two end points of the axial position in the second adjustment stage, as it were by free axial displacement. Because a parallel bolt, as the overlooking means between the longitudinal housing grooves, seeks to brace itself in spring prestressed fashion radially movably outward longitudinally, that is, toward the supporting foot, counter to the screw bolt of the depth stop, the result is the creation of a large-area, securely effective overlooking means between the supporting foot and the housing. Because the collar of the housing and/or the upper edge, braceable thereon, of the sleevelike shaft of the supporting foot extends obliquely, the correct reinsertion of the housing into the supporting foot after separate manipulation is safe to operate. Because the adjusting positions, particularly by clamping means, are detachably lockable and thus axially and radially fixable, the cutting depth of the hand power tool is adjustable in a secured way. Because the supporting foot is dimensioned such that with its aid the hand power tool can be set down, in freestanding fashion, on a horizontal, level surface, working with the hand power tool can be done especially precisely and without tilting. Because the housing is limited relative to the supporting foot in its axial end positions upon longitudinal displacement by stops, and in particular by a bayonet mount, unintentional release or loss of the supporting foot from the housing or vice versa is precluded. Because scale means for monitoring the cutting depth are located between the housing and the supporting foot, the cutting depth position can be adjusted in a securely monitorable and replicable way, particularly in the fine adjustment stage. Because it is designed as a top spindle molder, and the adjusting positions can be associated with a respective predetermined cutting depth, it can be adjusted in an especially time-saving way and can be manipulated safely. Because the adjusting means, described above in terms of their advantages, serve to alter or fix two parts, which are arranged in telescoping fashion with respect to one another, relative to one another, they can also be employed especially advantageously—with their own inventive value—not only in hand power tools but also in other areas of use, where both rapid and especially precise adjustment of the relative position is necessary. DRAWING The invention is described below in further detail in terms of an exemplary embodiment in conjunction with the drawings. Shown are FIG. 1, the hand power tool from the front; FIG. 2, the hand power tool from the left; FIG. 3, the supporting foot and the hand power tool, shown in an exploded view, taken apart axially; FIG. 4, the hand power tool without the supporting foot and the depth stop; FIG. 5, the supporting foot from above with the depth stop; FIG. 6, an enlarged cross section between the supporting foot and the housing with the depth stop in the fine adjustment stage; FIG. 7, the view of FIG. 6 in the coarse adjustment stage; and FIG. 8, a further side view of the housing. DESCRIPTION OF THE EXEMPLARY EMBODIMENT A hand power tool 10 shown from the front in FIG. 1 is designed as an electrically operable top spindle molder, which comprises a housing 12 that at the front has a toggle switch 14 for switching it on and off, and from whose lower free end 11 a rotating tool bit 15 for metal-cutting machining of workpieces protrudes. The cylindrical housing 12, in the uppermost quarter of its length, has a waist 17, which can easily be grasped with one hand and which with its radial protrusion fits, axially bracingly, into the hand holding it. The lower half of the housing 12 has a slightly smaller outer diameter than the upper region and with the smaller diameter forms a collar 20 (FIG. 3), which can be inserted in telescoping fashion into a hollow-cylindrical supporting foot 22. The transition between the collar 20 and the upper region of the housing 12 forms a protrusion or feelable edge 200. This edge 200, located between the collar 20 and the region above it having the larger diameter of the housing 12, extends obliquely downward toward the rear—like the upper edge of the supporting foot 22. An electrical connection cord 16 emerges from the upper housing region at the rear, with a slight slant upward. Because of the direction in which it emerges and its inclination, it is reliably kept spaced apart from the engagement point of the tool bit 15 and a workpiece, without being a hindrance to the work as cables that emerge vertically upward are. The hollow-cylindrical supporting foot 22 has a vertical, tubular supporting foot wall 23, which is longitudinally slotted at the front, and at the slot 27, two lateral, forward-protruding, perforated clamping tabs 24 are formed. A clamping screw 25 (FIG. 2) can be inserted through these tabs, transversely to the longitudinal axis of the supporting foot 22. If the clamping screw is tightened, the two clamping tabs 24 move toward one another and in the process seek to close the slot 27. In so doing, they clamp the collar 20 of the housing 12, seated in the supporting foot 22, firmly-securing it against rotation and axial displacement. Thus a cutting depth of the tool bit 15, once set, is securely fixed against unintentional change. The clamping screw 25 is a fast-clamping screw with a pivot lever 30 with an eccentric region, not identified by reference numeral, of the kind known for instance for adjusting the saddle height of bicycles, and can be released and tightened by means of the pivot lever 30. The pivot lever 30 of the clamping screw 25 is pivoted against the supporting foot 22 in the clamped state and is largely pulled inside the contour of the supporting foot. As a result, when the top spindle molder 10 is being used, and for instance when it meets edges of a workpiece, an unintentional upward pivoting of the pivot lever 30 is precluded. Below the clamping tabs 24, the supporting foot wall 23 opens, over its full width, downward as far as the foot plate 26, to form a windowlike front recess 31. The foot plate 26 on the lower end of the supporting foot 22 is essentially square and protrudes past the outer contour of the cylindrical supporting foot 22 to the side, the rear, and the front. Its area is dimensioned such that the top spindle molder 10 can be set down with the supporting foot 22, in freestanding fashion, securely and stably on a level support. The cutting depth for the tool bit 15 is monitorably adjustable by means of a scale 53 on the lower edge of the housing 12; the scale position can be read off relative to the adjacent upper edge 310 of the windowlike front recess 31 as a reference edge. The foot plate 26 has a vertical opening 29, designed as a circular hole, for the passage through it of the tool bit 15 downward into a workpiece to be machined. By axial adjustment of the top spindle molder 10 or housing 12 relative to supporting foot 22, the depth to which the tool bit 15 plunges into a tool to be machined is adjustable. On the outside, at the back and side, the housing 12 and the supporting foot are provided, in the grip region 18, with regularly distributed, hemispherical indentations 19, which have a diameter of approximately 2 to 3 mm and which improve the grip and thus the safety of using the top spindle molder 10. A grip region with an especially nonslip fluting 260 made up of rectangular impressions is also formed on the top side of the foot plate 26. FIG. 2 shows the left-hand side of the top spindle molder 10, in which in particular—going beyond FIG. 1—the a power cord 16 extending obliquely upward at the rear, can be seen along with the housing 12, ribbed transversely at the top, and the clamping tabs 24 protruding from the front with the pivot lever 30. The grip region 18 is furthermore visible, with the hemispherical indentations 19 and the edge 21, descending obliquely to the rear, of the supporting foot 22 or correspondingly the protruding edge 200 at the collar 20, as well as the shape of the front recess 31 with the archlike edge and the transition to the relatively far forward-protruding foot plate 26. Laterally at the back,a control wheel 28 can be seen in the lower region of the supporting foot 22; it emerges from a transverse slot 32 in the supporting foot wall and—although not visible here—has a threaded bolt 35 (FIG. 3), which extends in the interior between the housing 12 and the supporting foot wall 23 and serves as a depth stop 34 (FIG. 3). FIG. 3 is an exploded view with the top spindle molder 10 positioned above the supporting foot 22; of the top spindle molder, only the lower region with the collar 20, the lower free end 11, and the tool bit 15 can be seen. The edge 200 between the upper region of the housing 12 and the collar 20 is clearly visible. At the supporting foot 22, the clamping screw 25 has been removed, making the design of the perforated clamping tabs 24 visible along with the slot 27 between the two clamping tabs. Also visible is the upper edge 21 of the supporting foot 22 and the transverse slot 32 for the control wheel 28 in the lower region of the supporting foot 22 above the base plate 26. The depth stop 34 with the control wheel 28 has been removed from its inserted position in the inside face of the supporting foot wall 23. For removing it, a retaining screw, not shown, that engages the control wheel in the middle must be removed; in the installed position, it secures the depth stop 34 on the supporting foot 22 against unintentional loosening. The depth stop 34 is designed in its upper region as a screw bolt 35 with a thread 50. The screw bolt 35 is intended for selective entry into a first or second longitudinal housing groove 38, 40 in the outer wall of the housing 12 in the region of the collar 20. The two longitudinal housing grooves 38, 40 extend parallel to the screw bolt 35, or to its longitudinal groove 33 (FIG. 5) in the inside face of the supporting foot wall 23. Approximately centrally between and parallel to the longitudinal housing grooves 38, 40, an overlooking bolt 36 is placed in a slot 42 in the housing wall 13 in the region of the collar 20 in such a way that it cannot fall out radially outward through the suitably narrowly dimensioned slot 42; it is held in prestressed fashion from behind by a leaf spring 37 radially outward in the slot 42. If the housing 12 has been inserted axially in telescoping fashion as intended into the supporting foot 22, the screw bolt 35 rests in one of the longitudinal grooves 38, 40. If the housing 12 is rotated slightly relative to the supporting foot 22 such that the screw bolt 35 is supposed to emerge laterally outward from the pair of longitudinal housing grooves 38, 40, this direction of rotation is blocked. Conversely, however, the housing 12 can be rotated counter to the force of the leaf spring 37 and of the overlooking bolt 36; after a suitable rotational course, the threaded bolt 35 snaps audibly into whichever is the adjacent longitudinal housing groove 38, 40. Before the housing 12 is rotated relative to the supporting foot 22, the pivot lever 30 of the clamping screw 25 must be put into its release position, so that the slot 27 between the clamping tabs 24 opens and the force lock between the supporting foot 22 and the housing 12, or collar 20, is released. The first longitudinal housing groove 38 has a thread 39, which fits the thread 50 of the screw bolt 35. If the longitudinal housing groove 38 is in engagement with the screw bolt 35, then upon its rotation, or the rotation of the control wheel 28, the housing 12 is axially adjusted relative to the supporting foot 22. If the second longitudinal housing groove 40 is in overlooking engagement with the screw bolt 35, no form or force lock becomes operative between it and the housing 12. As a result, in this position, the housing 12 can easily be displaced back and forth axially by hand relative to the supporting foot 22 between two defined axial end positions. In this position, a coarse preselection of the cutting depth can be done simply and quickly by axial sliding. Once the cutting depth position has been coarsely adjusted, the housing 12 should be rotated relative to the supporting foot 22 such that the screw bolt 35 enters overlockingly into the first longitudinal housing groove 38, so that in this position, by rotation of the control wheel 28, the threads 39, 50 engaging one another bring about an axial force transfer with finely meterable longitudinal adjustment. Once the desired cutting depth position has been reached, the housing 12 is locked relative to the supporting foot 22 by pivoting of the pivot lever 30 into its clamping position, so that neither a rotary nor an axial motion between these two parts is possible. Thus the cutting depth position of the housing 12 relative to the supporting foot 22 is set. Depending on the cutting depth selected, the tool bit 15 protrudes outward more or less far past the lower edge of the foot plate 26, with a corresponding cutting depth into the workpiece to be machined, onto which workpiece the foot plate 26 is to be set. To the right in the viewing direction below the control wheel 28, a radially inward-protruding cam 57 seated on the inside of the supporting foot wall 23 can be seen, which is intended for secure engagement with a bayonet groove 55 (FIG. 8) of the housing 12. FIG. 4 shows a side view of the top spindle molder 10 in the region of the collar 20, with a depth stop 34—put in place for the sake of demonstration—which had previously been removed from its installed position in the supporting foot 22. This depth stop 24 is placed in the second longitudinal housing groove without a thread 40 and axially freely displaceably therein and cannot take on any locking or force transfer function between the supporting foot 22 and the housing 12. This demonstrates the coarse adjustment position, in which the housing 12 is limitedly freely displaceable relative to the supporting foot 22. In the first longitudinal housing groove 38, which is parallel to the second longitudinal housing groove 40, the thread 39 can be seen, which upon engagement of the depth stop 34 prevents an axial displacement between the housing 12 and the supporting foot 22 by means of forces from outside exerted against these two parts and permits such displacement only by means of rotation of the control wheel 28. The other details mentioned in connection with the preceding drawings will not be repeated here again; it will be mentioned that the reference numerals are the same. FIG. 5 shows the detail of the supporting foot 22; going beyond the preceding drawing figures, the depth stop 34 is shown in its inserted position on the inside face of the supporting foot wall 23, and the screw bolt 35 rests axially nondisplaceably with radial play and freely rotatably in the longitudinal groove 33 of the supporting foot wall 23. Moreover, the slot 27 between the clamping tabs 24 in the supporting foot 22 is also clearly visible. The other details described in conjunction with the preceding figures will not be repeated again here. FIG. 6 shows an enlarged detail of the cross section between the supporting foot wall 23 and the housing wall 13 in the region of the longitudinal housing grooves 38, 40 with the threaded bolt 35 in place, and on the opposite side, the longitudinal groove 33 in the supporting foot wall 23. This makes the overlooking and action position of the screw bolt 35 clear. FIG. 7 shows the same details as FIG. 6, but with the housing 12 rotated relative to the supporting foot 22; the threaded bolt 35 rests in the second longitudinal housing groove 40 and makes a free displacement of the housing 12 possible relative to the supporting foot 22. FIG. 8 shows a further sectional view of the housing 12 with its collar 20, looking toward an L-shaped bayonet groove 55. This groove is composed of an upper, wide region 56, which extends vertically, and merges toward the bottom with a narrow, angled region 58. The bayonet groove 55 is engaged by a cam 57 as a locking or stop element, which is seated on the inside of the hollow-cylindrical supporting foot wall 23 (FIG. 9) and protrudes radially inward. The cam 57 is put into engagement with the bayonet groove 55 in the following way: First, the housing 12 should be placed axially on the supporting foot 22. In the process, the region 58, opening laterally downward, of the bayonet groove 55 is slipped over the cam 57, until a further axial displacement of the housing 12 relative to the supporting foot 22 is stopped, because the cam 57 strikes the upper groove wall 60 of the region 58. By corresponding rotation of the housing 12 relative to the supporting foot 22, the cam 57 is guided along the groove wall 60 until it reaches the upper region 56. Once this position of the cam 57 is reached, the housing 12 is longitudinally freely displaceable relative to the supporting foot 22, as long as the threaded bolt 35 is simultaneously resting in the second longitudinal housing groove 40. So that the cam 57 will not hinder the adjustment of the rotary positions of the housing 12 relative to the supporting foot 22 and is axially freely movable in every rotary position, the upper region 56 of the bayonet groove 55 is designed as suitably wide. For limiting the axial motion between the supporting foot 22 and the housing 12, an upper groove end 64 and the lower side wall 62 of the region 58 of the bayonet groove 55 are used, which simultaneously determine the outermost axial end positions, and on which the cam 57 rests in its respective end position. This prevents an unintentional release of the supporting foot 22 from the housing 12 when the clamping screw 25 is open. To facilitate the assembly of the supporting foot 22 with the housing 12, arrow-shaped symbols, not identified by reference numerals, are impressed into the housing 12 and/or the supporting foot 22; these symbols mark housing regions that belong to one another or are to be aligned with one another as such, and at the same time they describe a preconditional assembly motion.

20060321

20081125

20070322

79331.0

B23C120

ROSS, DANA

HAND POWER TOOL

UNDISCOUNTED

ACCEPTED

B23C

ACCEPTED

Ventilator mask and system

A continuous positive air pressure (“CPAP”) or ventilator system includes a mask (60) and an air flow generator (20). The air flow generator is mounted or provided to the mask's wearer. In one embodiment, air flow generator is mounted on the mask.

1. A ventilator system comprising: a mask to be placed over a wearer's face, said mask having a shell; a cushion provided to the shell to sealingly connect the mask to the wearer's face and thereby form a chamber between the shell and the wearer's face; and an inlet port in said shell to receive a flow of breathable gas; and an air flow generator, said air flow generator being mounted on said mask and being capable of creating a pressure of about 2-40 cm H20 in said chamber. 2. The system of claim 1, wherein the mask is structured to cover the wearer's nasal and oral region. 3. The system of claim 1, wherein the mask is constructed to avoid obstruction of the wearer's vision or field of view. 4. The system of claim 1, wherein said mask is absent a dust filter. 5. The system of claim 1, wherein the mask is designed to have said inlet port located in front of the wearer's oral region. 6. The system of claim 1, wherein said air flow generator has an air intake opening and an air outlet, said air outlet being positioned in proximity to said air inlet port of the mask. 7. The system of claim 6, wherein a perforated screen positioned between said air outlet and said inlet port. 8. The system of claim 1, wherein said cushion comprises a silicone elastomer. 9. The system of claim 1, wherein said air flow generator comprises a housing including an impeller and a motor to drive the impeller, said housing forming a contiguous surface with the shell. 10. The system of claim 9, the ventilator system further comprising a power cord and a power source, said power cord connecting said power source to said motor. 11. The system of claim 10, wherein said power source is a battery pack. 12. The system of claim 11, wherein said battery pack comprises at least one fastener to mount the battery pack to said wearer's body. 13. The system of claim 1, further comprising a self-contained power source. 14. A ventilator system comprising: a mask having a shell; a cushion provided to the shell to sealingly connect the mask to a wearer's face and thereby form a chamber between said shell and said wearer's face; an inlet port in said shell to receive a flow of breathable gas; an air flow generator; and an air delivery tube not exceeding 1.5 meters in length, said air delivery tube being functionally connected to said inlet port and said air flow generator to create a pressure of about 2-40 cm H20 in said chamber by delivery of breathable gas from said air flow generator to said inlet port. 15. The system of claim 14, wherein said air delivery tube does not exceed 1 meter in length. 16. The system of claim 14, wherein the air delivery tube is low in profile and is kink resistant. 17. The system of claim 14, wherein the mask is structured to cover the wearer's nasal and oral region. 18. The system of claim 14, wherein the mask is constructed to avoid obstruction of the wearer's vision. 19. The system of claim 14, wherein said mask is absent a dust filter. 20. The system of claim 14, wherein said air flow generator is absent a dust filter. 21. The system of claim 14, wherein the mask is designed to have said inlet port located in proximity to a wearer's oral region. 22. The system of claim 14, wherein said cushion comprises a silicone elastomer. 23. The system of claim 14, wherein said air flow generator comprises a housing with an impeller and a motor for driving the impeller. 24. The system of claim 23, wherein said ventilator system further comprises a power cord and a power source, said power cord connecting said power source to said motor. 25. The system of claim 24, wherein said power source is a battery pack. 26. The system of claim 14, wherein said air flow generator comprises one or more straps or clips for mounting the air flow generator to the wearer's body. 27. The system of claim 1, wherein said air flow generator is selectively detachable from the shell. 28. The system of claim 27, wherein the air flow generator and shell are coupled with a quick release clip. 29. The system of claim 1, further comprising at least one sensor provided to the mask. 30. The system of claim 29, wherein the sensor is structured to provide a signal indicative of the fit of the mask. 31. The system of claim 29, wherein the sensor is structured to provide a signal indicative of leak on the basis of which the flow generator is adapted to be controlled.

CROSS-REFERENCE TO PRIORITY APPLICATION This application claims the benefit of U.S. Provisional Application No. 60/505,718, filed Sep. 25, 2003, the content of which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to ventilators, e.g., continuous positive air pressure (“CPAP”) systems comprising a mask and an air flow generator, wherein the air flow generator is mountable to the mask's wearer. In one embodiment, the present invention provides CPAP systems wherein an air flow generator is mounted on the mask. In other embodiments, the air flow generator may be provided to the body of the wearer, e.g., the arm, leg, chest or waist, and a short air delivery tube can be used to connect the mask with the air flow generator. 2. Description of Related Art CPAP administration is commonly used to treat respiratory conditions such as obstructive sleep apnea. The procedure for CPAP administration typically involves sealingly engaging a mask over a patient's nasal and/or oral region and supplying pressurized air to a chamber formed by the interior of the mask. In conventional systems, the air is supplied to the mask by an air flow generator typically placed in proximity to the patient's bed. An air delivery tube is thus needed to deliver air generated by the air flow generator to the mask. There are two main sources of instability of a mask system during use or sleep. Normal patient movement can create instability, for example, a patient rolling on his or her side, which may cause the mask to interfere with the bedding material. Another concern of using an air delivery tube that is connected to an apparatus away from the patient is so-called “tubing drag”, which refers to a drag force on the air delivery tube which is draped over the back or side of the bed. Tubing drag can be created or complicated by movement of the wearer. Tubing drag may cause relative movement between the mask seal and the patient's face during the CPAP administration and produce leaks and/or discomfort. Another concern involving the air delivery tube is the length thereof (often about 2 meters or more), which may impart a lag in the response and rise times in delivering pressured air from the air flow generator to the mask. Increased flow impedance and/or pressure drop due to diameter and length of tubing may also necessitate a larger blower motor to compensate for the pressure drop along the air delivery tube. U.S. Pat. Nos. 4,590,951; 5,372,130; and 6,435,184 describe masks for safety applications. SUMMARY OF THE INVENTION Aspects of the present invention include addressing the concerns in the art, e.g., by reducing or eliminating the risk of tubing drag during CPAP administration. A further aspect of the present invention is to provide the wearer with a greater freedom of movement in bed without compromising seal and/or comfort. Another aspect of the present invention includes reducing or eliminating the lag in response/rise times in delivering pressured air from the generator to the mask. In one embodiment, a ventilator or CPAP system comprises a mask and an air flow generator, wherein both the mask and the air flow generator are provided to or on the wearer. In one embodiment, the mask is configured to be fitted to the patient's face and the air flow generator is mountable to the wearer's body. The air flow generator may be provided directly to the mask. According to one embodiment a CPAP system comprises a face mask and an air flow generator, wherein the air flow generator is mounted on the face mask. In a further embodiment, a ventilator or CPAP system comprises: (i) a face mask configured to be placed over an area of a wearer's face, the face mask having: (1) a shell; (2) a cushion provided to a perimeter of the shell to sealingly connect the face mask to the area of a wearer's face and thereby form a chamber between the shell and the wearer's face; and (3) an inlet port in the shell to receive a flow of breathable gas; (ii) an air flow generator, said air flow generator being mounted on said mask and being capable of creating a pressure of about 2-40 cm H2O in the chamber. In embodiments, a ventilator or CPAP system includes an air flow generator able to be located sufficiently close to a wearer so that an air delivery tube may be less than 1.5 meters in length. In one embodiment, a ventilator or CPAP system comprises: a face mask having an inlet port, an air flow generator having an outlet, and at least one air delivery tube for delivering breathable gas from the gas outlet to the inlet port, wherein the at least one air delivery tube does not exceed about 1.5 meters in length. The at least one air delivery tube may include two or more air delivery tubes having a combined overall length of not more than about 1.5 meters. In a further embodiment, a ventilator or CPAP system comprises: (i) a face mask having (1) a shell; (2) a cushion provided to the shell to sealingly connect the face mask to a wearer's face and thereby form a chamber between the shell and the wearer's face, and; (3) an air inlet port in the shell to receive a flow of breathable gas; (ii) an air flow generator; and (iii) an air delivery tube not exceeding 1.5 meters in length, the air delivery tube being functionally connected to the air inlet port and the air flow generator to create a pressure of about 2-40 cm H2O in the chamber by delivery of breathable gas from the air flow generator to the air inlet port. Additional aspects, advantages and features of the present invention are set forth in this specification, and in part will become apparent to those skilled in the art on examination of the following, or may be learned by practice of the invention. The inventions disclosed in this application are not limited to any particular set of or combination of aspects, advantages and features. It is contemplated that various combinations of the stated aspects, advantages and features make up the inventions disclosed in this application. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a perspective view of a CPAP system according to one embodiment of the invention; FIG. 2 is an exploded view of the CPAP system of FIG. 1; FIG. 3 is a front view taken from an interior of the CPAP system of FIG. 1; FIG. 4 is a rear view taken from an exterior of the CPAP system of FIG. 1; FIG. 5 is a right side view of the CPAP system of FIG. 4; FIG. 6 is a top view of the CPAP system of FIG. 4; FIG. 7 is a bottom view of the CPAP system of FIG. 4; FIG. 8 is a bottom view of a CPAP system according to a further embodiment of the invention; FIG. 9A illustrates a person wearing the CPAP system of FIG. 1; FIG. 9B illustrates an alternative embodiment of the present invention; FIG. 10A illustrates a person wearing a CPAP system according to a further embodiment of the invention; FIG. 10B is a schematic view of an air flow generator and battery pack for a CPAP system according to an embodiment of the invention; FIG. 11A represents a person wearing a person wearing a CPAP system according to a further embodiment of the invention; and FIG. 11B represents a battery pack and strap for a CPAP system according to an embodiment of the invention. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS A CPAP system includes a mask and an air flow generator, wherein the air flow generator is provided to a wearer of the mask. In one embodiment, the air flow generator is mountable to a wearer's body (including a wearer's clothing). In another embodiment, the air flow generator is mounted on or provided to the mask. Figures 1-11B show several embodiments of CPAP systems according to the present invention. Referring to FIG. 1, a CPAP system 10 includes a mask 60 provided with a cushion 30 and a shell 46 to form an air chamber in communication with the airways of a wearer. In this example, the mask 60 covers at least the oral and nasal region of a wearer. However, the mask 60 could also be a nasal mask and cover, for instance, only the nasal region or only the mouth region. In either case, it is preferable that the mask does not cover or interfere with the wearer's eyes or vision. The mask may include a vent opening 61 for CO2 gas washout, and one or more inlet ports 47 for use in introducing supplemental gas, e.g., oxygen, into the air chamber. The vent opening 61 can be covered with a suitable insert 63 or the like to controllably exhaust CO2. The insert is described in ResMed's U.S. Pat. Nos. 6,561,190 and 6,561,191, each incorporated herein by reference in its entirety. Mask cushion 30 is preferably made of a soft material (e.g. a rubber material, such as a silicone elastomer) and sealingly connects to the wearer's face to form the air chamber between the wearer's face and the mask 60. The shell can be made of a relatively hard plastic, although the shell can be made of the same material as the cushion 30, in some applications. Examples of cushions 30 are described in, for instance, U.S. Pat. No. 6,513,526, assigned to ResMed Limited, which is hereby incorporated in its entirety by reference. Commercial examples of mask 60 include, for instance, the Mirage® Full Face Mask Series II from ResMed Limited (not taking into account adjustments described below in more detail). Headgear connectors 50 are provided to the shell 46. Headgear connectors are designed to receive headgear straps for securing CPAP system 10 to a wearer's head (securing straps 55 are shown in FIGS. 9 and 10A). Attached to shell 46 is an extension 72 which will generally be provided with a resilient pad (not shown) to engage the forehead of the wearer, to provide additional stability. A strap may be provided to each connector 50 of the extension 72 for contact with the wearer's crown. Alternatively, or in addition, a strap connector 50a may be provided to the extension 72 such that the strap extends over the top of the wearer's head, as shown in FIGS. 9 and 10A. The air chamber formed between a wearer's face and the interior of mask 60 receives breathable gas (e.g. air) through air inlet port 56 (see FIG. 2), which is designed to be placed in close proximity to (e.g. over) the wearer's oral/nasal region. The breathable gas is supplied by air flow generator 20. In one embodiment, the air flow supplied by air flow generator 20 creates single or variable pressures within the air chamber in the range of 2-40 cm H2O, for instance 10-28 cm H2O or 15-20 cm H2O; or relatively constant 10 cm H2O etc. Referring to FIG. 2, air flow generator 20 includes, for example, a first part 90 and a second part 80 that are joined, e.g., by screws 130 through bores 134 and 136 to form a housing for impeller 120 and motor 100. The parts 80 and 90 may be made from a variety of materials, for instance from cured resinous materials, from metal (e.g. aluminum), or from polymers, e.g. from polyolefins (such as polyethylene or polypropylene), polycarbonates, or acrylonitrile-butadiene-styrene polymers (“ABS”). Motor 100 drives impeller 120. Power is supplied to motor 100 via power cord 110 and the motor is fixedly secured within the impeller housing by tightening screw 132. Examples of electrical motors include, for instance, miniature bullet motors commercially available from, e.g., Servo Magnetics Inc., of California. However, various types of motors may be used, including for instance pneumatic air powered motors in which case the energy source would be a tiny air line instead of an electrical pulse. The motor assembly may include multiple motors or single motors with multiple impellers, double ended impellers, etc. Other possibilities include separate systems which can deliver prescribed air pressure. In another variant, another motor impeller assembly can be utilized to modify, for instance, if an inflatable cuff is provided to react to stimulus or sensed parameters like leak problems. A separate motor impeller can be used to control positioning of the mask relative to the face or the profile of the cushion seal. Examples of impellers include, for instance, the S6 CPAP impeller from ResMed Limited. Various impellers may be used, however, such as axial fans, radial fans, centrifugal fans, etc. or any new technology able to deliver the required flow of gas such as air. The power cord 110 may receive power from any suitable power source, e.g., a wall power outlet, wall mounted transformers, a battery pack or other power storage medium. In one embodiment, power cord 110 includes sensor cables to register and/or adjust to data received from sensors that may be provided in the mask (e.g. CO2, O2, humidity, pressure, flow, and/or temperature sensors). In one embodiment, the monitoring of sensors occurs via infrared technology or radio waves. A control box may be provided to adjust, e.g., the motor speed, e.g., for bi-level treatment, or other parameters relative to the information received through the sensors. Other embodiments may be to sense leak and adjust motor speed and thus delivery pressure or flow accordingly. The power cord 110 can be connected to a small controller chip (not shown) integrated with an electrical transformer plugged into a power outlet. This provides greater flexibility, freedom of movement of the wearer, increased versatility during traveling, etc. Also, there are less components at the mask interface, less overall size of the system and potentially greater stability. The system may be used for bi-level treatment or general ventilatory applications, e.g., where the magnitude of the pressurized air varies. The system may also provide faster response and rise times and eliminate or at least reduce lag associated with air delivery tubes typically having a length of 2 m or more. The system may be easier to use from the perspective of a physician, a dealer or clinician, in that only one rather than numerous components need to be fitted for the wearer. Another embodiment provides the ability to change the strap adjusting points; the ability to modify the fit of the mask relative to the face through the integrated sensing. For example, if there is a leak generated by the mask and a sensor, e.g., a pressure transducer 67 (FIG. 4), produces a signal indicative of leaking in the mask, the flow generator pressure could be modified. There is also an embodiment where bladders or cuffs or sections of the mask seal could be modified so that the seal profile is modified in certain regions until the leak is resolved and the sensors would provide feedback to the control box that the leak is gone and the motor can be controlled to react to the feedback. See, e.g., U.S. patent application Ser. No. 10/332,578 filed Dec. 19, 2002, to ResMed, incorporated herein by reference in its entirety. Sensing flow or pressure of the mask system will increase reaction time and having a motor and an impeller assembly mounted directly into a mask system would mean that reaction times to pressure and flow changes would be very rapid; therefore there is improved synchrony of delivered gas to the wearer. Presently, flow generators essentially need to predict when a patient is about to breathe in or have some delay or lag, for example, by pressure sensors mounted to the flow generator. By contrast, one aspect of the present embodiment allows the mask system to react very quickly, which provides excellent synchrony of the flow to a patient and this is key to treat patients especially those with respiratory insufficiency who require very good synchrony of flow generator flow pattern to a breathing patient. Air flow generator 20, e.g., second part 80, is mounted on mask 60, e.g., with four screws 140 (only two are shown in FIG. 2) which extend through holes 70 (also, only two shown) into bores 136 (at the opposite side of screws 130). Of course, a variety of other methods for mounting the air flow generator 20 on full face mask 60 are feasible, such as using adhesives, using melt-welding, or integrally forming the shell 46 and second part 80 through injection molding. Still another embodiment includes the ability to easily remove the generator 20 from the mask, e.g., to facilitate cleaning, etc. One or more quick release clips could be used for this purpose. In one embodiment, such as the embodiment shown in FIG. 2, a perforated screen 40 (e.g. a perforated metal screen, for instance a perforated aluminum screen) is placed between inlet port 56 and air flow generator 20. The screen separates the outlet 85 (FIG. 3) from air flow generator 20 and prevents foreign matter that might enter the air flow generator from reaching the wearer's oral and facial region (air outlet 85 is visible in FIG. 3 through screen 40). Perforated screen 40 also ensures that a wearer's tongue or other body parts larger than perforation size cannot contact the impeller 120. Examples of perforated screen 40 include, for instance, a mesh structure or a thin plate with a plurality of small bores. This arrangement also prevents any motor or impeller failure such as breakage from harming the wearer. FIGS. 3-7 show various views for the CPAP mask 10 in FIGS. 1 and 2. A further embodiment is depicted in FIG. 8, where a filter 128 is provided in front of air intake opening 125 (See FIG. 7 for air intake opening 125). The filter 128 may be, for instance, a filter to prevent dust from entering the impeller system (i.e. a dust filter) or a perforated screen. Although a perforated screen does not prevent dust from entering the impeller system, it is helpful in avoiding, for instance, the wearer's fingers from being able to come into contact with the impeller 120. In addition, a perforated screen prevents larger particles from entering the impeller system. In one embodiment, the CPAP system and/or the air flow generator has a dust or antimicrobial filter. In a further embodiment, the CPAP system and/or air flow generator is absent a dust or antimicrobial filter. Referring to FIG. 9A, the CPAP system of FIG. 1 is mounted on the face of a wearer 1 by means of strap 55. The power is provided to the air flow generator 20 by battery pack 150 via power cord 110. Battery pack 150 is attached to the wearer's body via strap 160. Advantages of using a battery pack as the power source include, for instance, the increased mobility of the wearer. In yet another embodiment illustrated in FIG. 9B, power to the air flow generator may be provided via a transformer power pack 150′ plugged into a wall outlet 163. FIG. 10A shows an embodiment where impeller system 20A is not directly mounted on mask 60A but instead on a wearer's body via strap 160. The air outlet of air flow generator 20A is attached to air delivery tube 65, which is connected to the air inlet port of full face mask 60A via socket 64 and coupling tube 62. In one embodiment, air delivery tube 65 is shorter than 1.5 meter, for instance 1.0 meter or 0.5 meter. The air delivery tube may be of any diameter or include multiple air tubes that are low profile and/or kink resistant, as described in ResMed's U.S. Patent Application No. 60/494,119 filed Aug. 12, 2003, incorporated by reference in its entirety. Power is supplied to air flow generator 20A by battery pack 150 via power cord 110A. Power pack or flow generator may also be integrated into one assembly. In one embodiment, air flow generator 20A and battery pack 150 are attached to strap 160 using clips 162A and 162B (see FIG. 10B). Of course, this embodiment is not limited to such an attachment system and the air flow generator and/or battery pack may be attached to any suitable part of a wearer's body (including clothing) by any suitable means. For instance, as depicted in FIGS. 11A and 11B, air flow generator 20A may also be attached to a wearer's arm using, e.g., a Velcro® strap 160A. The motor assembly, including the impeller, may also be attached to other portions of the wearer's body, e.g., the chest via a strap, the shoulder, etc. In yet another variant (not shown), the motor assembly may be mounted or provided or combined to a headgear system, with short tubing running to the mask. The headgear system could act as form a of vibration damping. Motors invariably vibrate due to imbalances or during motion. Isolating this vibration from the wearer will reduce irritation and noise. As the head is sensitive to vibration, some form of motor and/or impeller isolation is preferable. A damping system may be used; for example a visco-elastic/soft foam “cushion” between the head and flow generator would provide some benefit. In another aspect, a motor can provide a heat sink to provide ability to warm patient breathing air temperature to improve breathing comfort. An additional aspect is to be able to control the temperature based on ambient conditions, e.g., using a feedback loop. These aspects may be incorporated as part of any of the above embodiments. While the invention has been described by way of illustrative embodiments, it is understood that the words which have been used herein are words of description, rather than words of limitation. Changes may be made without departing from the scope and spirit of the embodiments. For example, while embodiments have been described as relation to CPAP application, it is to be understood that the features described herein may also have application in the general ventilation or respiratory arts. In addition, the system can be used for children and adults of all ages.

<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to ventilators, e.g., continuous positive air pressure (“CPAP”) systems comprising a mask and an air flow generator, wherein the air flow generator is mountable to the mask's wearer. In one embodiment, the present invention provides CPAP systems wherein an air flow generator is mounted on the mask. In other embodiments, the air flow generator may be provided to the body of the wearer, e.g., the arm, leg, chest or waist, and a short air delivery tube can be used to connect the mask with the air flow generator. 2. Description of Related Art CPAP administration is commonly used to treat respiratory conditions such as obstructive sleep apnea. The procedure for CPAP administration typically involves sealingly engaging a mask over a patient's nasal and/or oral region and supplying pressurized air to a chamber formed by the interior of the mask. In conventional systems, the air is supplied to the mask by an air flow generator typically placed in proximity to the patient's bed. An air delivery tube is thus needed to deliver air generated by the air flow generator to the mask. There are two main sources of instability of a mask system during use or sleep. Normal patient movement can create instability, for example, a patient rolling on his or her side, which may cause the mask to interfere with the bedding material. Another concern of using an air delivery tube that is connected to an apparatus away from the patient is so-called “tubing drag”, which refers to a drag force on the air delivery tube which is draped over the back or side of the bed. Tubing drag can be created or complicated by movement of the wearer. Tubing drag may cause relative movement between the mask seal and the patient's face during the CPAP administration and produce leaks and/or discomfort. Another concern involving the air delivery tube is the length thereof (often about 2 meters or more), which may impart a lag in the response and rise times in delivering pressured air from the air flow generator to the mask. Increased flow impedance and/or pressure drop due to diameter and length of tubing may also necessitate a larger blower motor to compensate for the pressure drop along the air delivery tube. U.S. Pat. Nos. 4,590,951; 5,372,130; and 6,435,184 describe masks for safety applications.

<SOH> SUMMARY OF THE INVENTION <EOH>Aspects of the present invention include addressing the concerns in the art, e.g., by reducing or eliminating the risk of tubing drag during CPAP administration. A further aspect of the present invention is to provide the wearer with a greater freedom of movement in bed without compromising seal and/or comfort. Another aspect of the present invention includes reducing or eliminating the lag in response/rise times in delivering pressured air from the generator to the mask. In one embodiment, a ventilator or CPAP system comprises a mask and an air flow generator, wherein both the mask and the air flow generator are provided to or on the wearer. In one embodiment, the mask is configured to be fitted to the patient's face and the air flow generator is mountable to the wearer's body. The air flow generator may be provided directly to the mask. According to one embodiment a CPAP system comprises a face mask and an air flow generator, wherein the air flow generator is mounted on the face mask. In a further embodiment, a ventilator or CPAP system comprises: (i) a face mask configured to be placed over an area of a wearer's face, the face mask having: (1) a shell; (2) a cushion provided to a perimeter of the shell to sealingly connect the face mask to the area of a wearer's face and thereby form a chamber between the shell and the wearer's face; and (3) an inlet port in the shell to receive a flow of breathable gas; (ii) an air flow generator, said air flow generator being mounted on said mask and being capable of creating a pressure of about 2-40 cm H2O in the chamber. In embodiments, a ventilator or CPAP system includes an air flow generator able to be located sufficiently close to a wearer so that an air delivery tube may be less than 1.5 meters in length. In one embodiment, a ventilator or CPAP system comprises: a face mask having an inlet port, an air flow generator having an outlet, and at least one air delivery tube for delivering breathable gas from the gas outlet to the inlet port, wherein the at least one air delivery tube does not exceed about 1.5 meters in length. The at least one air delivery tube may include two or more air delivery tubes having a combined overall length of not more than about 1.5 meters. In a further embodiment, a ventilator or CPAP system comprises: (i) a face mask having (1) a shell; (2) a cushion provided to the shell to sealingly connect the face mask to a wearer's face and thereby form a chamber between the shell and the wearer's face, and; (3) an air inlet port in the shell to receive a flow of breathable gas; (ii) an air flow generator; and (iii) an air delivery tube not exceeding 1.5 meters in length, the air delivery tube being functionally connected to the air inlet port and the air flow generator to create a pressure of about 2-40 cm H 2 O in the chamber by delivery of breathable gas from the air flow generator to the air inlet port. Additional aspects, advantages and features of the present invention are set forth in this specification, and in part will become apparent to those skilled in the art on examination of the following, or may be learned by practice of the invention. The inventions disclosed in this application are not limited to any particular set of or combination of aspects, advantages and features. It is contemplated that various combinations of the stated aspects, advantages and features make up the inventions disclosed in this application.

20060417

20110329

20061026

94629.0

A61M1600

DOUGLAS, STEVEN O

CPAP MASK AND SYSTEM

UNDISCOUNTED

ACCEPTED

A61M

ACCEPTED

METHOD AND MOBILE STATION FOR AUTOMATIC CREATION OF TALK GROUP

A method of automatic creation of a talk group in a wireless radio communication system comprising a plurality of mobile stations, said method comprising the steps of: transmitting by a first mobile station an emergency message containing at least its ID and localization data; transmitting by other mobile stations their IDs and localization data in response to said emergency message; creating said talk group by selecting those mobile stations which transmitted their IDs and localization data.

1. A method of automatic creation of a talk group in a wireless radio communication system comprising a plurality of mobile stations, said method comprising the steps of: a) transmitting by a first mobile station an emergency message, wherein said emergency message comprises a first mobile station ID, localization data, and an indication that said emergency message is an emergency message; b) transmitting by other mobile stations said other mobile stations IDs and localization data in response to said emergency message; c) creating said talk group by selecting said other mobile stations which transmitted said other mobile stations IDs and localization data. 2. A method according to claim 1, wherein only said other other mobile stations, which are within a predefined distance from said first mobile station transmits said other mobile stations IDs and localization data. 3. A method according to claim 2, wherein for communication system operating in trunking mode said predefined distance is limited to the borders of a cell within which said first mobile station is located or to a group of cells. 4. The method according to claim 2, wherein said other mobile stations, which distance from said first mobile station is larger than said predefined distance, transmit said other mobile stations localization data if there is no other mobile station within said second predefined distance. 5. The method according to claim 4 comprising the step of: a) increasing said predefined distance if no one of said other mobile stations responded to said emergency message; and b) re-sending said emergency message. 6. The method according to claim 1, wherein said other mobile stations transmit said other mobile stations IDs and localization data with a predefined delay and said predefined delay increases with increasing distance from said first mobile station. 7. The method according to claim 1, wherein only those of said other mobile stations which are within a predefined distance from said first mobile station are selected to said talk group. 8. The method according to claim 7, wherein some of said other mobile stations, which are located beyond said predefined distance, are selected to said talk group if there is no one mobile station of said other mobile stations within said predefined distance or the number of said other mobile stations is below a predefined threshold. 9. The method according to claim 1, wherein after receiving said IDs and localization data of said other mobile stations, said step of selecting is performed by said first mobile station. 10. The method according to claim 9, wherein after creation of talk group information on said talk group, said talk group information is transmitted to a dispatch centre, said information includes IDs of members of said talk group and said other mobile stations localization data. 11. The method according to claim 1, wherein after receiving said IDs and localization data of said other mobile stations, said step of selecting is performed by an infrastructure. 12. The method according to claim 1, wherein at least one emergency service unit, located closest to said first mobile station, is added to said talk group. 13. The method according to claim 10, wherein a dispatch centre transmits driving directions to said emergency service unit. 14. The method according to claim 1, wherein said localization data are Global Positioning System Data or triangulation based data. 15. The method according to claim 1, wherein said emergency message comprises an indication of type of emergency service requested. 16. The method according to claim 1, wherein said emergency message is transmitted to a dispatch centre, and said dispatch centre forwards said emergency message to said other mobile stations. 17. The method according to claim 1, wherein said dispatch centre is added to said talk group. 18. A mobile station comprising means for signal transmission, means for signal reception, a microphone, an audio processing circuitry, a keypad, a microprocessor, a memory, a localization circuitry, and an emergency switch being adapted to initiate transmission of an emergency message, said emergency message comprising localization data, an ID of said mobile station and an indication that said emergency message is an emergency message. 19. The mobile station according to claim 18 being adapted to receive emergency messages from other mobile stations. 20. The mobile station according to claim 18 being adapted to send its ID and localization data in response to emergency message received from any one of said other mobile stations. 21. The mobile station according to 18 being adapted to receive response to emergency message from said other mobile stations. 22. The mobile station according to claim 19, wherein said microprocessor being adapted to calculate distance between said mobile station and any one of said other mobile stations. 23. The mobile station according to claim 18, wherein said microprocessor is adapted to store in said memory localization data and IDs received from said other mobile stations. 24. The mobile station according to claim 23, wherein said microprocessor is adapted to calculate distances between said first mobile station and any one of said other mobile stations which have responded to said emergency message and create a talk group comprising other mobile stations based on said calculated distances. 25. The mobile station according to claim 18 wherein said localization circuitry is a Global Positioning System unit. 26. The mobile station according to claim 18 wherein said microprocessor is adapted to calculate localization of said mobile station based on triangulation data.

FIELD OF THE INVENTION The present invention relates to digital radio communication systems, in general, and to automatic creation of emergency talk group, in particular. BACKGROUND OF THE INVENTION Two-way wireless communication systems include a plurality of mobile stations (MSs), a limited number of wireless communication resources (or can be built without an infrastructure), and a communication resource controller. Digital addressing used in these systems allows for partitioning of the plurality of MSs into talk groups. Mobile stations arranged in talk groups usually have a similar function or geographic location however other basis for partitioning is also possible. A mobile station initiating a talk group call to other mobile stations within its talk group such that the other members will receive the communication simultaneously. Selection of talk group programmed into the mobile station allows the user to select and operate on one of many possible talk groups at any instant in time. This functionality of talk groups is important and very useful especially in public safety applications. Ability of simultaneous communication with plurality of other MSs is particularly important in emergency situations. One method of controlling operation of mobile stations known in the art is to rely on a dispatcher. Verbal or text messages are broadcasted from the dispatcher to all mobile stations in the talk group. In emergency situations, e.g. in case of an accident it takes time for the dispatcher to create a talk group and to assign as well as communicate the messages to the personnel closest to an incident. Such method causes some delay as usually additional exchange of information is required. SUMMARY OF THE INVENTION There is a need for a method of automatic creation of a talk group in a digital radio communication system and for a mobile station for use in such communication system, which alleviate or overcome the disadvantages of the prior art. According to a first aspect of the present invention there is thus provided a method of automatic creation of a talk group in a digital radio communication system as claimed in claim 1. According to a second aspect of the present invention there is thus provided a mobile station for use in a digital radio communication as claimed in claim 18. The present invention beneficially allows for short-cutting the manually process of coordinating a dispatch in response to an emergency message, by immediately and automatically creating a talk group which may provide support to the unit sending the emergency message and automatically adding the closest emergency service unit (or units) to the dynamically created talk group. BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be understood and appreciated more fully from the following detailed description taken in conjunction with the drawings in which: FIG. 1 is a schematic illustration of a communication system operating in accordance with one embodiment of the present invention, FIG. 2 is a flow chart illustrating a method of automatic creation of a talk group in a first embodiment of the present invention, FIG. 3 is a flow chart illustrating a method of automatic creation of a talk group in a second embodiment of the present invention, FIG. 4 is a flow chart illustrating a method of automatic creation of a talk group in a third embodiment of the present invention, FIG. 5 is a flow chart illustrating a method of automatic creation of a talk group in a fourth embodiment of the present invention, FIG. 6 is a block diagram of a mobile station in one embodiment of the present invention. DETAILED DESCRIPTION OF AN EMBODIMENT OF THE INVENTION The term a dispatch centre herein below refers to a specialized radio communication unit, preferably equipped with additional computer operated support units, which is adapted to control at least portion of mobile stations of a communication system The term infrastructure herein below refers to hardware and software elements that forms a communication network and allow for transmitting voice and/or data over the radio channel(s). Referring to FIG. 1 one embodiment of a wireless communication system 100 according to the present invention is shown. The communication system comprises a plurality of mobile stations (MSs) 102-116, a dispatch centre 148 and an infrastructure 120, 136-146, which allows for communication in trunking mode as well as in direct mode. Alternatively the communication system 100 may comprise only the plurality of MSs 102-116 and said dispatch centre. The invention allows for automatic creation of a talk group in a wireless communication system 100 in a situation when a user of one of said MSs 102-116 is in an emergency situation or is a witness of an emergency situation (e.g. a car accident). With reference to FIG. 2 and FIG. 6 one embodiment of a method of automatic creation of a talk group according to the present invention is shown. When a user of a first mobile station 102 is in an emergency situation and presses a dedicated button on the first MS 102 an emergency message is transmitted over the air 200 on a broadcast channel. Said emergency message contains at least an ID of the mobile station 102, identification that this is an emergency message and current geographical localization of the transmitting MS. Said emergency message may optionally contain a short indication what type of emergency service is required (e.g. police, an ambulance, a fire brigade, etc). Transmitting this additional information could require manual typing by the user or choosing from the list stored in a memory 612 of the MS 600. Other mobile stations 104-116, after receiving said message, automatically transmit 202 their IDs and localization data also on said broadcast channel. In a next step 204, 206 those MSs which transmitted their IDs and localization data and are located within a predefined distance D1 from said first mobile station 102 are selected to a talk group. Alternatively all MSs that replied to said emergency message are selected to said talk group. If there is no MS within said predefined distance or the number of MSs within said predefined distance is too small 208 said predefined distance D1 is increased 216 to D2 and other MSs located within distance D2 are selected to said talk group. In one embodiment said selection 204, 206 is performed by said first mobile station, which is equipped with a microprocessor 610 and a memory 612. Said IDs and localization data received in response to said emergency message are stored in said memory 612 and said microprocessor 610 is adapted to calculate the distances between said first mobile station and any one of said other mobile stations which have responded to said emergency message and then create a talk group comprising other mobile stations based on said calculated distances. This embodiment is applicable to communication systems without an infrastructure or to a situation when infrastructure is not used. Alternatively for a communication system with an infrastructure said step of selecting MSs to said talk group is performed by said infrastructure 120, 136-146. When said talk group is created or at the time of selecting said MSs to said talk group an emergency service unit 118 is localized 210 and selected 212 to said talk group. The emergency service unit 118 closest to said first mobile station is selected even if its distance is bigger than the predefined distance D1. If the emergency situation requires it is possible that more that one emergency service unit is selected to said talk group. For communication systems with said infrastructure 120, 136-146 a dispatch centre 148 transmits driving directions to said emergency service unit (or units) 118. Referring to FIG. 3 and FIG. 6 a second embodiment of a method of automatic creation of a talk group according to the present invention is shown. When a user of a first mobile station 102 is in an emergency situation and presses a dedicated button on the first MS 102 an emergency message is transmitted over the air 200. Other mobile stations 104-116, after receiving said message, automatically transmit 202 their IDs and localization data but only if they are localized within a predefined distance D1 from said first mobile station. If there is response from said other MSs 304 a talk group is being created 206. If there is no other mobile station within said predefined distance D1 from said first mobile station 304 said other mobile stations, which distance from said first mobile station is larger than said predefined distance D1, transmit their ID and localization data 306 in response to said emergency message. As the emergency message and the responses are transmitted on the broadcast channel said other MSs listen to messages transmitted over the air and they know that no response was transmitted to said emergency message. They reply if there was no response from within D1 within a predefined period of time. In alternative embodiments said response messages can be transmitted also over a dedicated channel. After creation of said talk group or at the time of selecting MSs to said talk group, which can be done in the same way as in case of the first embodiment described above, a closest emergency service unit (or units) 118 is localized 210 and selected 212 to said talk group. For communication systems with an infrastructure 120, 136-146 a dispatch centre 148 transmits driving directions to said emergency service unit (or units) 118. For communication systems with infrastructure said selection 304, 206, 210, 212 is being done by said infrastructure or by a dispatch centre 148 and for communication systems without infrastructure or when infrastructure is not used said selection is being done by said first mobile station 102. With reference to FIG. 4 and FIG. 6 a third embodiment of a method of automatic creation of a talk group according to the present invention is shown. When a user of a first mobile station 102 is in an emergency situation and presses a dedicated button on the first MS 102 an emergency message is transmitted over the air 200 on a broadcast channel. Other mobile stations 104-116, after receiving said message, automatically transmit 202 their IDs and localization data but only if they are localized within a predefined distance D1 from said first mobile station. If there is no response 304 to said emergency message said predefined distance is increased 402 and said emergency message is transmitted again 404. (The other mobile stations 106, 108, 114, 116 located beyond said predefined distance transmit their IDs and localization data if they receive the same emergency message transmitted again.) If there is a response from at least portion of said other mobile stations 106, 108, 114, 116, the talk group is being created which consist of the first mobile station 102 and other mobile stations that responded to said emergency message. After creation of said talk group or at the time of selecting MSs to said talk group, which can be done in the same way as in case of the first embodiment described above, a closest emergency service unit (or units) 118 is localized 210 and selected 212 to said talk group. For communication systems with an infrastructure 120, 136-146 a dispatch centre 148 transmits driving directions to said emergency service unit (or units) 118. For communication systems with said infrastructure 120, 136-146 said selection 304, 206, 210, 212 is being done by said infrastructure 120, 136-146 or by said dispatch centre 148 and for communication systems without said infrastructure or when said infrastructure is not used said selection is being done by said first mobile station 102. With reference to FIG. 5 and FIG. 6 a fourth embodiment of a method of automatic creation of a talk group according to the present invention is shown. When a user of a first mobile station 102 is in an emergency situation and presses a dedicated button on the first MS 102 an emergency message is transmitted over the air 200 on a broadcast channel. Other mobile stations 104-116, after receiving said message, automatically transmit 202 their IDs and localization data. Said other mobile stations 104-116 transmit their responses 502, 504, 506 with some delay and the value of said delay depends on the distance from said first mobile station to any one of said of the mobile stations 104-116. A relation between said delay and said distance is presented in Table 1. It is obvious that the delay may be increased in many different ways and the one presented in Table 1 is an example only. TABLE 1 Distance D Delay D ≦ D1 No delay D1 < D ≦ D2 Ti D2 < D ≦ D3 2 × Ti . . . . . . If there is a response from the other mobile stations located within distance D1 said other mobile stations are selected and said talk group is created 206. If there is no other mobile station 508 within distance D1 from said first mobile station 102 other mobile stations located within distance D2 are selected and said talk group is created 206. If there is no other mobile station 510 within distance D2 other mobile stations located within distance D3 are selected and said talk group is created 206. This procedure may be repeated as long as at least one of the other mobile stations will be found within some predefined distance from said first mobile station 102. After creation of said talk group or at the time of selecting MSs to said talk group, which can be done in the same way as in case of the first embodiment described above, a closest emergency service unit (or units) 118 is localized 210 and selected 212 to said talk group. For communication systems with an infrastructure 120, 136-146 a dispatch centre 148 transmits driving directions to said emergency service unit (or units) 118. For communication systems with said infrastructure 120, 136-146 said selection 508, 510, 512, 206, 210, 212 is being done by said infrastructure 120, 136-146 or by a dispatch centre 148 and for communication systems without infrastructure or when infrastructure is not used said selection is being done by said first mobile station 102. Alternatively for communication systems with the infrastructure, when the talk group is created, information on the talk group (including IDs of members of the talk group and their localization data) can be transmitted to a dispatch centre 148. After this transfer the dispatch centre 148 takes over control of the talk group. Importantly, an advantage of this invention is that by limiting the number of said other mobile stations that respond at the same time (e.g. only those MSs located within predefined distance are allowed to respond or by introducing delay for transmitting response, etc.) allows for limitation of the risk of system congestion. The localization data transmitted by said first mobile station and said other mobile stations are data obtained via GPS system or calculated based on triangulation data. It is obvious for those skilled in the art that other localization/positioning system's data may be used. In those embodiments where the communication system operates in trunking mode, said predefined distance can be limited to the borders of a cell 122 or to the borders of a group of cells 124-134 within which said first mobile station is located. However actual distance measured in length units may also be applied. It is obvious for those skilled in the art that the mobile unit can be either a portable or mobile radio. Referring to FIG. 6 one embodiment of a mobile station capable of operating in accordance with the disclosed method is depicted. The mobile station of FIG. 6 may be either a portable- or a mobile digital or analog radio. The mobile station 600 comprises a microphone 620 which provides a signal for transmission by transmission circuit 602. Transmission circuit 602 transmits via Radio Frequency (RF) switch 604 and antenna 606. The mobile station 600 also has a microprocessor 610 and a memory 612. The mobile station 600 also comprises a display 618 and keypad 616. Voice activation of the radio, or other means of interaction with a user, may also be implemented. Signals received by the radio are routed by the RF switch 604 to a receiving circuit 608. The received signals are routed from the receiving circuit 608 to microprocessor 610 and audio processing circuitry 624 and 626. A localization circuitry 614, which in one embodiment may be a GPS circuitry is connected to said microprocessor 610. A dedicated emergency switch 622 is also connected to said microprocessor 610. In operation said emergency switch 622 when activated initiate the microprocessor to transmit an emergency message which contains at least indication that this is an emergency message, ID of said mobile station and current geographical position of said mobile station. Said geographical position is provided by said localization circuitry 614. When said communication 600 unit receives an emergency message said microprocessor calculates distance between said mobile station and another mobile station, which has sent the emergency message. For these calculations the microprocessor uses localization data received in said emergency message and obtained from said localization circuitry 614. Depending on the result of calculations and on the embodiment of the method according to the present invention used the microprocessor initiate transmission of the response message (containing ID and its localization data) or not. When said mobile station 600 receives messages with said IDs and localization data in response to said emergency message the microprocessor 610 stores them in a memory 612. The microprocessor 610 uses the data stored in the memory 612 to calculate distances between said first mobile station and any one of said other mobile stations which have responded to said emergency message. Next the microprocessor selects to a talk group those of said other mobile stations, which are located within a predefined distance from the mobile station, which transmitted the emergency message. When the selection is completed the talk group is created. In any of the embodiments the dispatch centre 148 is preferably added to said talk group. It is worth to emphasise that all these embodiments of the method according to the present invention may be implemented in a communication system with an infrastructure (for communication in direct mode as well as in trunking mode) or without an infrastructure. In implementation in a communication system with an infrastructure selection of MSs to the talk group is done by said infrastructure (e.g. zone controller). Said calculation of distance can be done by either by the infrastructure or by the MSs. When the method is implemented in a communication system without infrastructure or when the infrastructure is not used then selection of MSs to the talk group and calculation of the distances is done by said the first mobile station (some calculations are also to be done by the other mobile stations). It is also possible that the steps of calculation and selection are performed by said first mobile station and said step of transmitting directions 214 to said emergency service unit (or units) is performed by a dispatch centre 148.

<SOH> BACKGROUND OF THE INVENTION <EOH>Two-way wireless communication systems include a plurality of mobile stations (MSs), a limited number of wireless communication resources (or can be built without an infrastructure), and a communication resource controller. Digital addressing used in these systems allows for partitioning of the plurality of MSs into talk groups. Mobile stations arranged in talk groups usually have a similar function or geographic location however other basis for partitioning is also possible. A mobile station initiating a talk group call to other mobile stations within its talk group such that the other members will receive the communication simultaneously. Selection of talk group programmed into the mobile station allows the user to select and operate on one of many possible talk groups at any instant in time. This functionality of talk groups is important and very useful especially in public safety applications. Ability of simultaneous communication with plurality of other MSs is particularly important in emergency situations. One method of controlling operation of mobile stations known in the art is to rely on a dispatcher. Verbal or text messages are broadcasted from the dispatcher to all mobile stations in the talk group. In emergency situations, e.g. in case of an accident it takes time for the dispatcher to create a talk group and to assign as well as communicate the messages to the personnel closest to an incident. Such method causes some delay as usually additional exchange of information is required.

<SOH> SUMMARY OF THE INVENTION <EOH>There is a need for a method of automatic creation of a talk group in a digital radio communication system and for a mobile station for use in such communication system, which alleviate or overcome the disadvantages of the prior art. According to a first aspect of the present invention there is thus provided a method of automatic creation of a talk group in a digital radio communication system as claimed in claim 1 . According to a second aspect of the present invention there is thus provided a mobile station for use in a digital radio communication as claimed in claim 18 . The present invention beneficially allows for short-cutting the manually process of coordinating a dispatch in response to an emergency message, by immediately and automatically creating a talk group which may provide support to the unit sending the emergency message and automatically adding the closest emergency service unit (or units) to the dynamically created talk group.

20081016

20120814

20090226

61619.0

H04B700

LEE, JOHN J

METHOD AND MOBILE STATION FOR AUTOMATIC CREATION OF TALK GROUP

UNDISCOUNTED

ACCEPTED

H04B

ACCEPTED

Quinazoline derivatives as tyrosine kinase inhibitors

The invention concerns quinazoline derivatives of the Formula (I); wherein each of R1, R2, W, X1, X2, Z, a and b are as defined in the description; processes for their preparation; pharmaceutical compositions containing them and their use in the manufacture of a medicament for providing an anti-proliferative effect. The quinazoline derivatives of Formula (I) are expected to be useful in the treatment of diseases such as certain cancers mediated by erbB receptor tyrosine kinases, particularly EGFR tyrosine kinase.

1. A quinazoline derivative of the Formula I: wherein: R1 is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula: Q2-X3— wherein X3is a direct bond or is O, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R3), CO, CH(OR3), CON(R3), N(R3)CO, SO2N(R3), N(R3)SO2, CH═CH and C≡C wherein R3 is hydrogen or (1-6C)alkyl, and wherein any CH2═CH— or HC≡C— group within a R1 substituent optionally bears at the terminal CH2═ or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula: Q3-X4— wherein X4 is a direct bond or is selected from CO and N(R4)CO, wherein R4 is hydrogen or (1-6C)alkyl, and Q3 is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula: —X5-Q4 wherein X5 is a direct bond or is selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)CO, SO2N(R5), N(R5)SO2, C(R5)2O, C(R5)2S and C(R5)2N(R5), wherein R5 is hydrogen or (1-6C)alkyl, and Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears one or more substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto, sulfamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula: —X6—R6 wherein X6 is a direct bond or is selected from O, N(R7) and C(O), wherein R7 is hydrogen or (1-6C)alkyl, and R6 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl, (1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl, N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents; b is 1, 2, 3, 4 or 5; each R2, which may be the same or different, is selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, trifluoromethyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula: —X7—R8 wherein X7 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (1-6C)alkyl, and R8 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or (1-6C)alkoxycarbonylamino-(1-6C)alkyl; Q1 is piperidinyl; a is 0, 1, 2, 3 or 4; each W, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, oxo, amino, formyl, mercapto, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: —X8—R10 wherein X8 is a direct bond or is selected from O, CO, SO2 and N(R11), wherein R11 is hydrogen or (1-6C)alkyl, and R10 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl or N,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl; X1 is selected from CO and SO2; X2 is a group of the formula: —(CR12R13)p-(Q5)m-(CR14R15)q— wherein m is 0 or 1, p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3 or 4, each of R12, R13, R14 and R15, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and Q5 is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene, and wherein any CH2 or CH3 group within an X2 group, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula: Q6-X9— wherein X9 is a direct bond or is selected from O, N(R16), SO2 and SO2N(R16), wherein R16 is hydrogen or (1-6C)alkyl, and Q6 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl; provided that when X9 is a direct bond, Q6 is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R17), CO, —C═C— and —C≡C— wherein R17 is hydrogen or (1-6C)alkyl, and wherein and wherein any CH2 or CH3 group within any Z group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: —X10—R18 wherein X10 is a direct bond or is selected from O, CO, SO2 and N(R19), wherein R19 is hydrogen or (1-4C)alkyl, and R18 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; provided that: when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino and R1 is hydrogen or (1-3C)alkoxy, then a is 0 and Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula Q6-X9—; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. 2. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 wherein: R1 is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula: Q2-X3— wherein X3 is a direct bond or is O, and Q2 is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R3), CON(R3), N(R3)CO, CH═CH and C≡C wherein R3 is hydrogen or (1-6C)alkyl, and wherein any CH2═CH— or HC≡C— group within a R1 substituent optionally bears at the terminal CH2═ or HC≡ position a substituent selected from carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl and wherein any CH2 or CH3 group within a R1 substituent, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, cyano, carbamoyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl and N,N-di-[(1-6C)alkyl]carbamoyl, or from a group of the formula: —X5-Q4 wherein X5 is a direct bond or is selected from O, N(R5), CON(R5), N(R5)CO and C(R5)2O, wherein R5 is hydrogen or (1-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, or from a group of the formula: —X6—R6 wherein X6 is a direct bond or is selected from O and N(R7), wherein R7 is hydrogen or (1-6C)alkyl, and R6 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents. 3. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 wherein: R1 is selected from hydrogen, hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula: Q2-X3— wherein X3 is O, and Q2 is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, and (2-4C)alkanoyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 oxo substituent. 4. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 wherein R1 is (1-3C)alkoxy. 5. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein: b is 1, 2 or 3; and each R2, which may be the same or different, is selected from fluoro, chloro, bromo, (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl. 6. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein: b is 1, 2 or 3 and one R2 is at the meta (3-) position on the anilino group in Formula I and is halogeno. 7. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 4 wherein the anilino group at the 4-position on the quinazoline ring in the compound of Formula I is selected from 3-chloro-2-bromoanilino, 3-chloro-2-fluoroanilino, 3-ethynylanilino and 3-bromoanilino. 8. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein: X2 is a group of the formula —(CR12R13)q—(CR12R13aa)—, wherein q is 1, 2 or 3, each of R12, R13 and R13aa, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, R12aa is selected from amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and wherein any CH2 or CH3 group within an X2 group, optionally bears on each said CH2 or CH3 group one or more halogeno substituents, and wherein any CH2 group which is attached to 2 carbon atoms or any CH3 group which is attached to a carbon atom within a X2 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino. 9. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 7 wherein: X2 is a group of the formula (CR12R13)q—, wherein q is 1, 2, 3 or 4, each of R12 and R13, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, provided that at least one of the R12 or R13 groups in X2 is (1-6C)alkyl, and wherein any CH2 or CH3 group within an X2 group, optionally bears on each said CH2 or CH3 group one or more halogeno substituents, and wherein any CH2 group which is attached to 2 carbon atoms or any CH3 group which is attached to a carbon atom within a X2 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, and (1-6C)alkoxy. 10. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 7 wherein: X2 is selected from a group of the formula —CH2—, —CH2CH2—, —(CHR12a)—, —(CHR12aCH2)—, —(C(R12a)2CH2)—, —(CH2C(R12a)2)— and —(CH2CHR12a)—, wherein each R12a, which may be the same or different, is (1-4C)alkyl. 11. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein: Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy and a group of the formula: Q6-X9— wherein X9 is a direct bond and Q6 is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl linked to X1 by a ring carbon atom, and wherein any heterocyclyl group in Z is selected from azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, and wherein and wherein any CH2 or CH3 group within a Z group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-4C)alkyl substituents or a substituent selected from hydroxy and (1-4C)alkoxy, and wherein any heterocyclyl group within a Z substituent optionally bears one or more substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino and (2-4C)alkanoyl. 12. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein: Z is hydroxy or (1-4C)alkoxy; and the sum of m+p+q is at least 1. 13. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 7 wherein: X2 is selected from a group of the formula —CH2—, —CH2CH2—, —(CHR12a)—, —(CHR12aCH2)—, —(C(R12a)2CH2)—, —(CH2C(R12a)2)— and —(CH2CHR12a)—, wherein each R12a, which may be the same or different, is (1-4C)alkyl; and Z is hydroxy or (1-4C)alkoxy. 14. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein: Q1 is piperidin-4-yl; a is 0 or 1; and W is selected from halogeno, hydroxy, (1-3C)alkyl and (1-3C)alkoxy. 15. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims wherein X1 is CO. 16. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 wherein: R1 is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy, cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy, cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy and tetrahydropyranyl-(1-4C)alkoxy, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno substituents, or a substituent selected from hydroxy and (1-4C)alkoxy; b is 1, 2 or 3; each R2, which may be the same or different, is selected from halogeno, cyano, hydroxy, trifluoromethyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy; Q1 is piperidin-4-yl; a is 0, 1 or 2; each W, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy, and from a group of the formula: —X8—R10 wherein X8 is a direct bond or is O, and R10 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl or (1-6C)alkoxy-(1-6C)alkyl; X1 is CO; X2 is a group selected from (3-6C)cycloalkylene, —CH2—, —CH2CH2—, —CH2CH2CH2—, —(CR12R13)—, —(CR12R13CH2)— and —(CH2CR12R13)—, wherein each of R12 and R13, which may be the same or different, is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl, provided that R12 and R13 are not both hydrogen, and wherein any CH2 group within a (3-6C)cycloalkylene group in X2, optionally bears on each said CH2 or group one or more (1-4C)alkyl substituents or a substituent selected from hydroxy, (1-4C)alkoxy, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl; and Z is selected from hydroxy and (1-4C)alkoxy; provided that: when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino, R1 is hydrogen or (1-3C)alkoxy, and X1 is CO, then a is 0. 17. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 wherein: the 4-anilino group on the quinazoline ring in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and 3-ethynylanilino; R1 is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula: Q2-X3— wherein X3 is O, and Q2 is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; Z is hydroxy or (1-4C)alkoxy; Q1 is piperidin-4-yl; a is 0 or 1; each W, which may be the same or different is selected from hydroxy, (1-3C)alkyl and (1-3C)alkoxy; X1 is CO; X2 is selected from a group of the formula —(CHR12a)— and —(CH2CHR12b)—, wherein R12a is (1-4C)alkyl, and wherein R12b is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino. 18. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to claim 1 of the Formula Id: wherein: R1b is (1-4C)alkoxy, and wherein any CH2 or CH3 group within a R1b substituent optionally bears on each said CH2 or CH3 group one or more halogeno substituents, or any CH2 or CH3 group within a R1 which is not attached to an oxygen atom optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy and (1-3C)alkoxy; X2b is selected from a group of the formula —CH2—, —CH2CH2—, —(CHR12)—, —(CHR12CH2)— and —(CH2CHR12)— wherein R12 is selected from (1-3C)alkyl, hydroxy-(1-3C)alkyl and (1-3C)alkoxy-(1-3C)alkyl; and Z2 is selected from hydroxy, (1-3C)alkoxy, hydroxy-(2-3C)alkoxy, (1-3C)alkoxy-(2-3C)alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and 1,4-dioxanyl; and wherein any heterocyclyl group within Z2-X2b optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-3C)alkyl, (1-3C)alkoxy and (2-3C)alkanoyl; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. 19. A quinazoline derivative according to claim 18, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, wherein Z2 is hydroxy and R12 is (1-3C)alkyl; 20. A quinazoline derivative according to claim 18, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, wherein: R1b is (1-3C)alkoxy; and the group Z2-X2b— is selected from hydroxymethyl, methoxymethyl, (S)-1-hydroxyethyl, (R)-1-hydroxyethyl, (S)-1-methoxyethyl and (R)-1-methoxyethyl. 21. A quinazoline derivative of the Formula I according to claim 1 selected from: N-(3-chloro-2-fluorophenyl)-7-({1-[(dimethylamino)acetyl]piperidin4-yl}oxy)-6-methoxyquinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methoxyacetyl)piperidin-4-yl]oxy}quinazolin4-amine; 2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol; N-(3-chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(3-methoxypropanoyl)piperidin-4-yl]oxy}quinazolin4-amine; 3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol; (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; (2S,3S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-methyl-1-oxopentan-2-ol; 4-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-methyl-4-oxobutan-2-ol; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]oxy}quinazolin-4-amine; 3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-ol; (3R,5S)-1-acetyl-5-{[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]carbonyl}pyrrolidin-3-ol; and N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(4-methylpiperazin-1-yl)acetyl]piperidin-4-yl}oxy)quinazolin4-amine; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. 22. A quinazoline derivative of the Formula I selected from: N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methoxyacetyl)piperidin-4-yl]oxy}quinazolin4-amine; 2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol; N-(3-chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine; (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; 3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-ol; (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3,3-dimethyl-1-oxobutan-2-ol; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(1-methyl-L-prolyl)piperidin-4-yl]oxy}quinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)quinazolin4-amine; (2R)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine; (2R)-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-(dimethylamino)-3-oxopropan-1-ol; (2S)-1-[4-({4-[(3-chloro-4-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; (2S)-1-[4-({4-[3-bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; (2S)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; (2R)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; and (2R)-1-[4-({4-[3-bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. 23. A quinazoline derivative of the Formula I according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition which comprises a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of the preceding claims, in association with a pharmaceutically acceptable diluent or carrier. 25. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, according to any one of claims 1 to 23, for use as a medicament. 26. Use of a quinazoline derivative of the Formula I, a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23 in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as a human. 27. Use of a quinazoline derivative of the Formula I, a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23 in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of EGFR tyrosine kinases, that are involved in the signal transduction steps which lead to the proliferation of tumour cells. 28. Use of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23 in the manufacture of a medicament for use in providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal such as a human. 29. Use of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23 in the manufacture of a medicament for use in the treatment of a cancer in a warm-blooded animal such as a human. 30. A method for producing an anti-proliferative effect in a warm-blooded animal, such as a human, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23. 31. A method for the prevention or treatment of those tumours in a warm-blooded animal such as a human which are sensitive to inhibition of EGFR tyrosine kinases, that are involved in the signal transduction steps which lead to the proliferation and/or survival of tumour cells which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23. 32. A method for providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23. 33. A method for treating a cancer in a warm-blooded animal, such as a human, in need of such treatment, which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined in any one of claims 1 to 23. 34. A process for the preparation of a quinazoline derivative of the Formula I as defined in claim 1 which comprises: Process (a): for the preparation of compounds of the Formula I wherein X1 is CO, the coupling of a quinazoline of the formula II or a salt thereof: wherein R1, R2, W, a, b and Q1 are as defined in claim 1, except that any functional group is protected if necessary, with an acid of the formula m, or a reactive derivative thereof: Z-X2—COOH III wherein Z and X2 are as defined in claim 1, except that any functional group is protected if necessary; or Process (b) the reaction of a quinazoline of the formula II or a salt thereof, as defined in relation to Process (a), with a compound of the formula IV: Z-X2—X1-L1 IV wherein L1 is a displaceable group and Z, X1 and X2 are as defined in claim 1, except that any functional group is protected if necessary; or Process (c) for the preparation of those quinazoline derivatives of the Formula I wherein Z is linked to X2 by nitrogen, the reaction of a compound of the formula V: wherein L2 is a displaceable group and R1, R2, W, X1, X2, a, b and Q1 are as defined in claim 1, except that any functional group is protected if necessary, with a compound of the formula ZH, wherein Z is as hereinbefore defined, except that any functional group is protected if necessary; or Process (d) for the preparation of those quinazoline derivatives which carry a mono- or di-(1-6C)alkylamino group, the reductive amination of the corresponding quinazoline derivative of the Formula I which contains an N—H group using formaldehyde or a (2-6C)alkanolaldehyde; or Process (e) for the preparation of those quinazoline derivatives of the Formula I wherein R1 is hydroxy, the cleavage of a quinazoline derivative of the Formula I wherein R1 is a (1-6C)alkoxy group; or Process (f) for the preparation of those quinazoline derivatives of the Formula I wherein R1 is linked to the quinazoline ring by an oxygen atom, by coupling a compound of the Formula VI: wherein R2, W, X1, X2, Z, a, b and are as defined in claim 1 except that any functional group is protected if necessary, with a compound of the formula R1′OH, wherein the group R1′O is one of the oxygen linked groups as defined for R1 in claim 1, except that any functional group is protected if necessary; and thereafter, if necessary (in any order): (i) converting a quinazoline derivative of the Formula I into another quinazoline derivative of the Formula I; (ii) removing any protecting group that is present by conventional means; and (iii) forming a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester of the quinazoline derivative of the Formula I. 35. A quinazoline derivative of the Formula II: wherein: R1, W, Q1 and a are as defined in claim 1; and R2c and R2d, which may be the same or different are halogeno; or a salt thereof.

The invention concerns certain novel quinazoline derivatives, or pharmaceutically acceptable salts, or pharmaceutically acceptable esters thereof, which possess anti-tumour activity and are accordingly useful in methods of treatment of the human or animal body. The invention also concerns processes for the manufacture of said quinazoline derivatives, to pharmaceutical compositions containing them and to their use in therapeutic methods, for example in the manufacture of medicaments for use in the prevention or treatment of solid tumour disease in a warm-blooded animal such as man. Many of the current treatment regimes for diseases resulting from the abnormal regulation of cellular proliferation such as psoriasis and cancer, utilise compounds that inhibit DNA synthesis and cellular proliferation. To date, compounds used in such treatments are generally toxic to cells however their enhanced effects on rapidly dividing cells such as tumour cells can be beneficial. Alternative approaches to these cytotoxic anti-tumour agents are currently being developed, for example selective inhibitors of cell signalling pathways. These types of inhibitors are likely to have the potential to display an enhanced selectivity of action against tumour cells and so are likely to reduce the probability of the therapy possessing unwanted side effects. Eukaryotic cells are continually responding to many diverse extracellular signals that enable communication between cells within an organism. These signals regulate a wide variety of physical responses in the cell including proliferation, differentiation, apoptosis and motility. The extracellular signals take the form of a diverse variety of soluble factors including growth factors as well as paracrine and endocrine factors. By binding to specific transmembrane receptors, these ligands integrate the extracellular signal to the intracellular signalling pathways, therefore transducing the signal across the plasma membrane and allowing the individual cell to respond to its extracellular signals. Many of these signal transduction processes utilise the reversible process of the phosphorylation of proteins that are involved in the promotion of these diverse cellular responses. The phosphorylation status of target proteins is regulated by specific kinases and phosphatases that are responsible for the regulation of about one third of all proteins encoded by the mammalian genome. As phosphorylation is such an important regulatory mechanism in the signal transduction process, it is therefore not surprising that aberrations in these intracellular pathways result in abnormal cell growth and differentiation and so promote cellular transformation (reviewed in Cohen et al, Curr Opin Chem Biol, 1999, 3, 459-465). It has been widely shown that a number of these tyrosine kinases are mutated to constitutively active forms and/or when over-expressed result in the transformation of a variety of human cells. These mutated and over-expressed forms of the kinase are present in a large proportion of human tumours (reviewed in Kolibaba et al, Biochimica et Biophysica Acta, 1997, 133, F217-F248). As tyrosine kinases play fundamental roles in the proliferation and differentiation of a variety of tissues, much focus has centred on these enzymes in the development of novel anti-cancer therapies. This family of enzymes is divided into two groups—receptor and non-receptor tyrosine kinases e.g. EGF Receptors and the SRC family respectively. From the results of a large number of studies including the Human Genome Project, about 90 tyrosine kinase have been identified in the human genome, of this 58 are of the receptor type and 32 are of the non-receptor type. These can be compartmentalised in to 20 receptor tyrosine kinase and 10 non-receptor tyrosine kinase sub-families (Robinson et al, Oncogene, 2000, 19, 5548-5557). The receptor tyrosine kinases are of particular importance in the transmission of mitogenic signals that initiate cellular replication. These large glycoproteins, which span the plasma membrane of the cell possess an extracellular binding domain for their specific ligands (such as Epidermal Growth Factor (EGF) for the EGF Receptor). Binding of ligand results in the activation of the receptor's kinase enzymatic activity that is encoded by the intracellular portion of the receptor. This activity phosphorylates key tyrosine amino acids in target proteins, resulting in the transduction of proliferative signals across the plasma membrane of the cell. It is known that the erbB family of receptor tyrosine kinases, which include EGFR, erbB2, erbB3 and erbB4, are frequently involved in driving the proliferation and survival of tumour cells (reviewed in Olayioye et al., EMBO J., 2000, 19, 3159). One mechanism in which this can be accomplished is by overexpression of the receptor at the protein level, generally as a result of gene amplification. This has been observed in many common human cancers (reviewed in Klapper et al., Adv. Cancer Res., 2000, 77, 25) such as breast cancer (Sainsbury et al., Brit. J. Cancer, 1988, 58, 458; Guerin et al., Oncogene Res., 1988, 3, 21; Slamon et al., Science, 1989, 244, 707; Klijn et al., Breast Cancer Res. Treat., 1994, 29, 73 and reviewed in Salomon et al., Crit. Rev. Oncol. Hematol., 1995, 19, 183), non-small cell lung cancers (NSCLCs) including adenocarcinomas (Cerny et al., Brit. J. Cancer, 1986, 54, 265; Reubi et al., Int. J. Cancer, 1990, 45, 269; Rusch et al., Cancer Research, 1993, 53, 2379; Brabender et al, Clin. Cancer Res., 2001, 7, 1850) as well as other cancers of the lung (Hendler et al., Cancer Cells, 1989, 7, 347; Ohsaki et al., Oncol. Rep., 2000, 7, 603), bladder cancer (Neal et al., Lancet, 1985, 366; Chow et al., Clin. Cancer Res., 2001, 7, 1957, Zhau et al., Mol Carcinog., 3, 254), oesophageal cancer (Mukaida et al., Cancer, 1991, 68, 142), gastrointestinal cancer such as colon, rectal or stomach cancer (Bolen et al., Oncogene Res., 1987, 1, 149; Kapitanovic et al., Gastroenterology, 2000, 112, 1103; Ross et al., Cancer Invest., 2001, 19, 554), cancer of the prostate (Visakorpi et al., Histochem. J., 1992, 24, 481; Kumar et al., 2000, 32, 73; Scher et al., J. Natl. Cancer Inst., 2000, 92, 1866), leukaemia (Konaka et al., Cell, 1984, 37, 1035, Martin-Subero et al., Cancer Genet Cytogenet., 2001, 127, 174), ovarian (Hellstrom et al., Cancer Res., 2001, 61, 2420), head and neck (Shiga et al., Head Neck, 2000, 22, 599) or pancreatic cancer (Ovotny et al., Neoplasma, 2001, 48, 188). As more human tumour tissues are tested for expression of the erbB family of receptor tyrosine kinases it is expected that their widespread prevalence and importance will be further enhanced in the future. As a consequence of the mis-regulation of one or more of these receptors, it is widely believed that many tumours become clinically more aggressive and so correlate with a poorer prognosis for the patient (Brabender et al, Clin. Cancer Res., 2001, 7, 1850; Ross et al, Cancer Investigation, 2001, 19, 554, Yu et al., Bioessays, 2000, 22.7, 673). In addition to these clinical findings, a wealth of pre-clinical information suggests that the erbB family of receptor tyrosine kinases are involved in cellular transformation. This includes the observations that many tumour cell lines overexpress one or more of the erbB receptors and that EGFR or erbB2 when transfected into non-tumour cells have the ability to transform these cells. This tumourigenic potential has been further verified as transgenic mice that overexpress erbB2 spontaneously develop tumours in the mammary gland. In addition to this, a number of pre-clinical studies have demonstrated that anti-proliferative effects can be induced by knocking out one or more erbB activities by small molecule inhibitors, dominant negatives or inhibitory antibodies (reviewed in Mendelsohn et al., Oncogene, 2000, 19, 6550). Thus it has been recognised that inhibitors of these receptor tyrosine kinases should be of value as a selective inhibitor of the proliferation of mammalian cancer cells (Yaish et al. Science, 1988, 242, 933, Kolibaba et al, Biochimica et Biophysica Acta, 1997, 133, F217-F248; Al-Obeidi et al, 2000, Oncogene, 19, 5690-5701; Mendelsohn et al, 2000, Oncogene, 19, 6550-6565). Recently the small molecule EGFR tyrosine kinase inhibitor, Iressa (also known as gefitinib, and ZD1834) has been approved for use in the treatment of advanced non-small cell lung cancer. Furthermore, findings using inhibitory antibodies against EGFR and erbB2 (c-225 and trastuzumab respectively) have proven to be beneficial in the clinic for the treatment of selected solid tumours (reviewed in Mendelsohn et al, 2000, Oncogene, 19, 6550-6565). Amplification and/or activity of members of the erbB receptor tyrosine kinases have been detected and so have been implicated to play a role in a number of non-malignant proliferative disorders such as psoriasis (Ben-Bassat, Curr. Pharm. Des., 2000, 6, 933; Elder et al., Science, 1989, 243, 811), benign prostatic hyperplasia (BPH) (Kumar et al., Int. Urol. Nephrol., 2000, 32,73), atherosclerosis and restenosis (Bokemeyer et al., Kidney Int., 2000, 58, 549). It is therefore expected that inhibitors of erbB receptor tyrosine kinases will be useful in the treatment of these and other non-malignant disorders of excessive cellular proliferation. European patent application EP 566 226 discloses certain 4-anilinoquinazolines that are receptor tyrosine kinase inhibitors. International patent applications WO 96/33977, WO 96/33978, WO 96/33979, WO 96/33980, WO 96/33981, WO 97/30034, WO 97/38994 disclose that certain quinazoline derivatives which bear an anilino substituent at the 4-position and a substituent at the 6- and/or 7-position possess receptor tyrosine kinase inhibitory activity. European patent application EP 837 063 discloses aryl substituted 4-aminoquinazoline derivatives carrying moiety containing an aryl or heteroaryl group at the 6-or 7-position on the quinazoline ring. The compounds are stated to be useful for treating hyperproliferative disorders. International patent applications WO 97/30035 and WO 98/13354 disclose certain 4-anilinoquinazolines substituted at the 7-position are vascular endothelial growth factor receptor tyrosine kinase inhibitors. WO 00/55141 discloses 6,7-substituted 4-anilinoquinazoline compounds characterised in that the substituents at the 6-and/or 7-position carry certain ester groups. WO 00/56720 discloses 6,7-dialkoxy-4-anilinoquinazoline compounds for the treatment of cancer or allergic reactions. WO01/21596 discloses the use of certain 4-anilinoquinazoline derivatives as aurora 2 kinase inhibitors. WO 02/18351 and WO 02/18372 disclose certain 4-anilinoquinazoline compounds substituted at the 6- and/or 7-position which are stated to have an inhibitory effect upon signal transduction mediated by tyrosine kinases. WO 02/41882 discloses 4-anilinoquinazoline compounds substituted at the 6- and/or 7-position by a substituted pyrrolidinyl-alkoxy or piperidinyl-alkoxy group. We have now found that surprisingly certain quinazoline derivatives substituted at the 7-position with a substituent containing certain substituted alkanoyl groups possess potent anti-tumour activity. The compounds of the present invention also generally possess high cellular potency, and favourable physical properties, particularly solubility, which may provide advantages in the formulation and delivery of the compound to patients. Many of the compounds of the invention posses favourable DMPK properties, for example high bioavailability and/or high free-plasma levels and/or advantageous half life and/or advantageous volume of distribution and such properties are expected to provide improved in-vivo efficacy and may reduce inter-patient variability in exposure to the compound compared to other EGFR tyrosine kinase inhibitors such as gefitinib. Furthermore, many of the compounds according to the present invention are inactive or only weakly active in a hERG assay. Without wishing to imply that the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it is believed that the compounds provide an anti-tumour effect by way of inhibition of one or more of the erbB family of receptor tyrosine kinases that are involved in the signal transduction steps which lead to the proliferation of tumour cells. In particular, it is believed that the compounds of the present invention provide an anti-tumour effect by way of inhibition of EGFR tyrosine kinase. Generally the compounds of the present invention possess potent inhibitory activity against the erbB receptor tyrosine kinase family, for example by inhibition of EGF and/or erbB2 and/or erbB4 receptor tyrosine kinases, whilst possessing less potent inhibitory activity against other kinases, such as VEGF and KDR receptor tyrosine kinases. Furthermore, the compounds of the present invention possess substantially better potency against the EGFR tyrosine kinase over that of the erbB2 tyrosine kinase. Accordingly, it may be possible to administer a compound according to the present invention at a dose that is sufficient to inhibit EGFR tyrosine kinase whilst having no significant effect upon erbB2 (or other) tyrosine kinases. The selective inhibition provided by the compounds according to the present invention may provide treatments for conditions mediated by EGFR tyrosine kinase, whilst reducing undesirable side effects that may be associated with the inhibition of other tyrosine kinases. According to a first aspect of the invention there is provided a quinazoline derivative of the Formula I: wherein: R1 is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula: Q2-X3— wherein X3is a direct bond or is O, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R3), CO, CH(OR3), CON(R3), N(R3)CO, SO2N(R3), N(R3)SO2, CH═CH and C≡C wherein R3 is hydrogen or (1-6C)alkyl, and wherein any CH2═CH— or HC≡C— group within a R1 substituent optionally bears at the terminal CH2═ or HC≡ position a substituent selected from halogeno, carboxy, carbamoyl, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula: Q3-X4— wherein X3 is a direct bond or is selected from CO and N(R4)CO, wherein R4 is hydrogen or (1-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, thioxo, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula: —X5-Q4 wherein X5 is a direct bond or is selected from O, S, SO, SO2, N(R5), CO, CH(OR5), CON(R5), N(R5)CO, SO2N(R5), N(R5)SO2, C(R5)2O, C(R5)2S and C(R5)2N(R5), wherein R5 is hydrogen or (1-6C)alkyl, and Q4 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, formyl, mercapto, sulfamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, or from a group of the formula: —X6—R6 wherein X6 is a direct bond or is selected from O, N(R7) and C(O), wherein R7 is hydrogen or (1-6C)alkyl, and R6 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl, (1-6C)alkoxycarbonylamino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl, N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, (2-6C)alkanoyl-(1-6C)alkyl or (1-6C)alkoxycarbonyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo or thioxo substituents; b is 1, 2, 3, 4 or 5; each R2, which may be the same or different, is selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, trifluoromethyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula: —X7—R8 wherein X7 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (1-6C)alkyl, and R8 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, (2-6C)alkanoylamino-(1-6C)alkyl or (1-6C)alkoxycarbonylamino-(1-6C)alkyl; Q1 is piperidinyl; a is 0, 1, 2, 3 or 4; each W, which may be the same or different, is selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, oxo, amino, formyl, mercapto, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: —X8—R10 wherein X8 is a direct bond or is selected from O, CO, SO2 and N(R11), wherein R11 is hydrogen or (1-6C)alkyl, and R10 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, N-(1-6C)alkylamino-(1-6C)alkyl or N,N-di-[(1-6C)alkyl]amino-(1-6C)alkyl; X1 is selected from CO and SO2; X2 is a group of the formula: —(CR12R13)p-(Q5)m-(CR14R15)q— wherein m is 0 or 1, p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3 or 4, each of R12, R13, R14 and R15, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and Q5 is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene, and wherein any CH2 or CH3 group within an X2 group, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula: Q6-X9— wherein X9 is a direct bond or is selected from O, N(R16), SO2 and SO2N(R16), wherein R16 is hydrogen or (1-6C)alkyl, and Q6 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl; provided that when X9 is a direct bond, Q6 is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R17), CO, —C═C— and —C≡C— wherein R17 is hydrogen or (1-6C)alkyl, and wherein and wherein any CH2 or CH3 group within any Z group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: —X10—R18 wherein X10 is a direct bond or is selected from O, CO, SO2 and N(R19), wherein R19 is hydrogen or (1-4C)alkyl, and R18 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; provided that: when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino and R1 is hydrogen or (1-3C)alkoxy, then a is 0 and Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula Q6-X9—; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. In a particular embodiment of the invention there is provided a quinazoline derivative of the Formula I as defined above, or a pharmaceutically acceptable salt thereof. In this specification the generic term “alkyl” includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl, and (3-7C)cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However references to individual alkyl groups such as “propyl” are specific for the straight-chain version only, references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only and references to individual cycloalkyl groups such as “cyclopentyl” are specific for that 5-membered ring only. An analogous convention applies to other generic terms, for example (1-6C)alkoxy includes methoxy, ethoxy, cyclopropyloxy and cyclopentyloxy, (1-6C)alkylamino includes methylamino, ethylamino, cyclobutylamino and cyclohexylamino, and di-[(1-6Calkyl]amino includes dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino. It is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity. It is further to be understood that in the names of chiral compounds (R,S) denotes any scalemic or racemic mixture while (R) and (S) denote the enantiomers. In the absence of (R,S), (R) or (S) in the name it is to be understood that the name refers to any scalemic or racemic mixture, wherein a scalemic mixture contains R and S enantiomers in any relative proportions and a racemic mixture contains R and S enantiomers in the ratio 50:50. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter. Suitable values for the generic radicals referred to above include those set out below. A suitable value for any one of the ‘Q’ groups (for example Q2, Q4 or Q6) when it is (3-7C)cycloalkyl or for the (3-7C)cycloalkyl group within a ‘Q’ or R group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1 ]heptyl and a suitable value for any one of the ‘Q’ groups (for example Q2, Q4 or Q6) when it is (3-7C)cycloalkenyl or for the (3-7C)cycloalkenyl group within a ‘Q’ group is, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. It is to be understood that reference to (3-7C)cycloalkylene used herein for Q5 refers to a divalent (3-7C)cycloalkane linking group, which group may be linked via different carbon atoms in the (3-7C)cycloalkylene ring, or which may be linked via a single carbon atom in the (3-7C)cycloalkylene ring. Accordingly, reference to, for example, a “cyclopropylene” group includes cycloprop-1,2-ylene and a cyclopropylidene group of the formula: However references to an individual (3-7C)cycloalklene group such as cyclopropylidene are specific for that group only. A silmilar convention is adopted for the (3-7C)cycloalkenylene groups represented by Q5. A suitable value for the ‘Q’ groups, other than Q1 (for example Q2, Q3, Q4 or Q6) when it is heterocyclyl or for the heterocyclyl group within a ‘Q’ group is a non-aromatic saturated (i.e. ring systems with the maximum degree of saturation) or partially saturated (i.e. ring systems retaining some, but not the full, degree of unsaturation) 3 to 10 membered monocyclic or bicyclic ring with up to five heteroatoms selected from oxygen, nitrogen and sulfur, which, unless specified otherwise, may be carbon or nitrogen linked, for example oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, decahydroisoquinolinyl or decahydroquinolinyl, particularly tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,4-oxazepanyl, thiamorpholinyl 1,1-dioxotetrahydro-4H-1,4-thiazinyl, piperidinyl or piperazinyl, more particularly tetrahydrofuran-3-yl, tetrahydropyran-4-yl, tetrahydrothien-3-yl, tetrahydrothiopyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, morpholino, morpholin-2-yl, piperidino, piperidin-4-yl, piperidin-3-yl, piperidin-2-yl or piperazin-1-yl. A nitrogen or sulfur atom within a heterocyclyl group may be oxidized to give the corresponding N or S oxide, for example 1,1-dioxotetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothiopyranyl or 1-oxotetrahydrothiopyranyl. A suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Q1 is piperidinyl, which group is linked to the oxygen in Formula I by a ring carbon atom. A suitable value for a ‘Q’ group when it is heterocyclyl-(1-6C)alkyl is, for example, heterocyclylmethyl, 2-heterocyclylethyl and 3-heterocyclylpropyl. The invention comprises corresponding suitable values for ‘Q’ groups when, for example, rather than a heterocyclyl-(1-6C)alkyl group, an (3-7C)cycloalkyl-(1-6C)alkyl or (3-7C)cycloalkenyl-(1-6C)alkyl is present. Suitable values for any of the ‘R’ groups (R1 to R19), W, or for various groups within a X1, X2 or Z group include: for halogeno fluoro, chloro, bromo and iodo; for (1-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (2-8C)alkenyl: vinyl, isopropenyl, allyl and but-2-enyl; for (2-8C)alkynyl: ethynyl, 2-propynyl and but-2-ynyl; for (1-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (2-6C)alkenyloxy: vinyloxy and allyloxy; for (2-6C)alkynyloxy: ethynyloxy and 2-propynyloxy; for (1-6C)alkylthio: methylthio, ethylthio and propylthio; for (1-6C)alkylsulfinyl: methylsulfinyl and ethylsulfinyl; for (1-6C)alkylsulfonyl: methylsulfonyl and ethylsulfonyl; for (1-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-[(1-6C)alkyl]amino: dimethylamino, diethylamino, N-ethyl-N-methylamino and diisopropylamino; for (1-6C)alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for N-(1-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl; for N,N-di-[(1-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and N,N-diethylcarbamoyl; for (2-6C)alkanoyl: acetyl, propionyl, butyryl and isobuyryl; for (2-6C)alkanoyloxy: acetoxy and propionyloxy; for (2-6C)alkanoylamino: acetamido and propionamido; for N-(1-6C)alkyl-(2-6C)alkanoylamino: N-methylacetamido and N-methylpropionamido; for N-(1-6C)alkylsulfamoyl: N-methylsulfamoyl and N-ethylsulfamoyl; for N,N-di-[(1-6C)alkyl]sulfamoyl: N,N-dimethylsulfamoyl; for (1-6C)alkanesulfonylamino: methanesulfonylamino and ethanesulfonylamino; for N-(1-6C)alkyl-(1-6C)alkanesulfonylamino: N-methylmethanesulfonylamino and N-methylethanesulfonylamino; for (3-6C)alkenoylamino: acrylamido, methacrylamido and crotonamido; for N-(1-6C)alkyl-(3-6C)alkenoylamino: N-methylacrylamido and N-methylcrotonamido; for (3-6C)alkynoylamino: propiolamido; for N-(1-6C)alkyl-(3-6C)alkynoylamino: N-methylpropiolamido; for amino-(1-6C)alkyl: aminomethyl, 2-aminoethyl, 1-aminoethyl and 3-aminopropyl; for (1-6C)alkylamino-(1-6C)alkyl: methylaminomethyl, ethylaminomethyl, 1-methylaminoethyl, 2-methylaminoethyl, 2-ethylaminoethyl and 3-methylaminopropyl; for di-[(1-6C)alkyl]amino-(1-6C)alkyl: dimethylaminomethyl, diethylaminomethyl, 1-dimethylaminoethyl, 2-dimethylaminoethyl and 3-dimethylaminopropyl; for halogeno-(1-6C)alkyl: chloromethyl, 2-chloroethyl, 1-chloroethyl and 3-chloropropyl; for hydroxy-(1-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl; for (1-6C)alkoxy-(1-6C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxypropyl; for cyano-(1-6C)alkyl: cyanomethyl, 2-cyanoethyl, 1-cyanoethyl and 3-cyanopropyl; for (1-6C)alkylthio-(1-6C)alkyl: methylthiomethyl, ethylthiomethyl, 2-methylthioethyl, 1-methylthioethyl and 3-methylthiopropyl; for (1-6C)alkylsulfinyl-(1-6C)alkyl: methylsulfinylmethyl, ethylsulfinylmethyl, 2-methylsulfinylethyl, 1-methylsulfinylethyl and 3-methylsulfinylpropyl; for (1-6C)alkylsulfonyl-(1-6C)alkyl: methylsulfonylmethyl, ethylsulfonylmethyl, 2-methylsulfonylethyl, 1-methylsulfonylethyl and 3-methylsulfonylpropyl; for (2-6C)alkanoylamino-(1-6C)alkyl: acetamidomethyl, propionamidomethyl and 2-acetamidoethyl; for N-(1-6C)alkyl-(2-6C)alkanoylamino-(1-6C)alkyl: N-methylacetamidomethyl, 2-(N-methylacetamido)ethyl and 2-(N-methylpropionamido)ethyl; for (1-6C)alkoxycarbonylamino-(1-6C)alkyl: methoxycarbonylaminomethyl, ethoxycarbonylaminomethyl, tert-butoxycarbonylaminomethyl and 2-methoxycarbonylaminoethyl; (2-6C)alkanoyloxy-(1-6C)alkyl: acetoxymethyl, 2-acetoxyethyl and 2-propionyloxyethyl; for carbamoyl-(1-6C)alkyl: carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl and 3-carbamoylpropyl; for (2-6C)alkanoyl-(1-6C)alkyl: acetylmethyl and 2-acetylethyl; for N-(1-6C)alkylcarbamoyl-(1-6C)alkyl: N-methylcarbamoylmethyl, N-ethylcarbamoylmethyl, N-propylcarbamoylmethyl, 1-(N-methylcarbamoyl)ethyl, 1-(N-ethylcarbamoyl)ethyl, 2-(N-methylcarbamoyl)ethyl, 2-(N-ethylcarbamoyl)ethyl and 3-(N-methylcarbamoyl)propyl; for N,N-di[(1-6C)alkyl]carbamoyl-(1-6C)alkyl: N,N-dimethylcarbamoylmethyl, N,N-diethylcarbamoylmethyl, 2-(N,N-dimethylcarbamoyl)ethyl, and 3-(N,N-dimethylcarbamoyl)propyl; for sulfamoyl(1-6C)alkyl: sulfamoylmethyl, 1-sulfamoylethyl, 2-sulfamoylethyl and 3-sulfamoylpropyl; for N-(1-6C)alkylsulfamoyl(1-6C)alkyl: N-methylsulfamoylmethyl, N-ethylsulfamoylmethyl, N-propylsulfamoylmethyl, 1-(N-methylsulfamoyl)ethyl, 2-(N-methylsulfamoyl)ethyl and 3-(N-methylsulfamoyl)propyl; and for N,N di-(1-6C)alkylsulfamoyl(1-6C)alkyl: N,N-dimethylsulfamoylmethyl, N,N-diethylsulfamoylmethyl, N methyl, N-ethylsulfamoylmethyl, 1-(N,N-dimethylsulfamoyl)ethyl, 1-(N,N-diethylsulfamoyl)ethyl, 2-(N,N-dimethylsulfamoyl)ethyl, 2-(N,N-diethylsulfamoyl)ethyl and 3-(N,N-dimethylsulfamoyl)propyl. When, as defined hereinbefore Z in Formula I is a group of the formula Q6-X9—, and X9 is SO2N(R16), the SO2 group is attached to Q6 and the nitrogen atom is attached to X2 in Formula I. The same convention is applied to other groups defined herein. For example when X2 is a group of the formula Q5-(CR14R15)p, the Q5 group is attached to the group Z in Formula I and the (CR14R15)p group is attached to the X1 group in Formula I. As defined hereinbefore, adjacent carbon atoms in any (2-6C)alkylene chain within, for example, a R1 substituent may be optionally separated by the insertion into the chain of a group such as O, CON(R3), N(R3) or C≡C. For example, insertion of a C≡C group into the ethylene chain within a 2-morpholinoethoxy group gives rise to a 4morpholinobut-2-ynyloxy group and, for example, insertion of a CONH group into the ethylene chain within a 3-methoxypropoxy group gives rise to, for example, a 2-(2-methoxyacetamido)ethoxy group. It is to be understood that the term (2-6C)alkylene chain refers to any CH2CH2 group (for example within R1) and includes, for example alkylene chains within a (1-6C)alkyl, (1-6C)alkoxy, (2-8C)alkenyl, (2-8C)alkenyloxy, (2-8C)alkynyl and (2-8C)alkynyloxy group. For example the insertion of a N(CH3) group between the third and fourth carbon atoms in a hex-5-enyloxy group in R1 gives rise to a 3-(N-methyl-N-allylamino)propoxy group. When, as defined hereinbefore, any CH2═CH— or HC≡C— group within a R1 substituent optionally bears at the terminal CH2═or HC≡ position a substituent such as a group of the formula Q3-X4— wherein X4 is, for example, NHCO and Q3 is a heterocyclyl-(1-6C)alkyl group, suitable R1 substituents so formed include, for example, N-[heterocyclyl-(1-6C)alkyl]carbamoylvinyl groups such as N-(2-pyrrolidin-1-ylethyl)carbamoylvinyl or N-[heterocyclyl-(1-6C)alkyl]carbamoylethynyl groups such as N-(2-pyrrolidin-1-ylethyl)carbamoylethynyl. When reference is made herein to a CH2 or CH3 group optionally bearing on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents, there are suitably 1 or 2 halogeno or (1-6C)alkyl substituents present on each said CH2 group and there are suitably 1, 2 or 3 such substituents present on each said CH3 group. Where reference is made herein to any CH2 or CH3 group optionally bearing on each said CH2 or CH3 group a substituent as defined herein, suitable substituents so formed include, for example, hydroxy-substituted heterocyclyl-(1-6C)alkoxy groups such as 2-hydroxy-3-piperidinopropoxy and 2-hydroxy-3-morpholinopropoxy, hydroxy-substituted heterocyclyl-(1-6C)alkylamino groups such as 2-hydroxy-3-piperidinopropylamino and 2-hydroxy-3-morpholinopropylamino, and hydroxy-substituted (2-6)alkanoyl groups such as hydroxyacetyl, 2-hydroxypropionyl and 2-hydroxybutyryl. Where reference is made herein to “any CH2 or CH3 group, other than a CH2 group within a heterocyclyl group, optionally bearing a substituent”, it is to be understood that such a statement is present only to distinguish between optional substituents that may be present on, for example, a CH3 group in an alkyl group from substituents that may be present on carbon atoms of a heterocyclyl group. Accordingly, it is to be understood, that this statement does not exclude other substituents being present on ring carbon atoms in a heterocyclyl group when it is stated herein that said heterocyclyl group may also optionally bear one or more substituents. For example, if R1 is 3-(pyrrolidin-1-yl)propoxy and herein it is stated that a CH2 or CH3 group within, for example, a R1 substituent, other than a CH2 group within a heterocyclyl group, optionally bears a hydroxy substituent, and that any heterocyclyl group within R1 optionally bears an alkyl substituent, then the optional hydroxy substituent may be present on a CH2 of the propoxy group to give for example a 2-hydroxy-3-(pyrrolidin-1-yl)propoxy group. Similarly an alkyl group such as methyl may be present on the pyrrolidinyl ring to give, for example, a 3-(3-methylpyrrolidin-1-yl)propoxy group. Equally, the propoxy group may be substituted by a hydroxy group and the pyrrolidinyl ring may be substituted by a methyl group to give, for example, a 2-hydroxy-3-(3-methylpyrrolidin-1-yl)propoxy group. For the avoidance of doubt, when W is oxo, a CH2 in Q1 is substituted by O to give a C(O) group. It is to be understood that reference herein to Q1 being, for example piperidin-4-yl refers to the attachment of the piperidine ring to the oxygen in Formula I. The piperidine ring is further substituted at the 1-position by the group Z-X2—X1— and optionally bears one or more W substituents on one or more of the available piperidinyl ring carbon atoms. It is to be understood that certain compounds of the Formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which exhibit an inhibitory effect on an erbB receptor tyrosine kinase. It is also to be understood that certain compounds of the Formula I may exhibit polymorphism, and that the invention encompasses all such forms which exhibit an inhibitory effect on an erbB receptor tyrosine kinase. It is also to be understood that the invention relates to all tautomeric forms of the compounds of the Formula I forms which exhibit an inhibitory effect on an erbB receptor tyrosine kinase. A suitable pharmaceutically acceptable salt of a compound of the Formula I is, for example, an acid-addition salt of a compound of the Formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the Formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. The term “pharmaceutically acceptable ester” used herein refers to an ester of a quinazoline derivative of the Formula I which hydrolyses in vivo to leave the parent compound or a pharmaceutically acceptable salt thereof. An in-vivo hydrolysable ester of a quinazoline of Formula I may be used to alter or improve the physical and/or pharmacokinetic profile of the parent compound, for example the solubility. Suitable ester groups that may be used in the formation of pharmaceutically acceptable ester prodrugs are well known, for example as discussed in for example: Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of the ACS Symposium Series, and in Edward B. Roche, ed.; Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991); H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984). A particular pharmaceutically acceptable ester of a quinazoline derivative of the Formula I or a pharmaceutically acceptable salt thereof is, an ester formed with a carboxy or, particularly, a hydroxy group (for example when Z is hydroxy) in Formula I, which ester is hydrolysed in the human or animal body to produce the parent quinazoline of Formula I when administered to a warm blooded animal such as a human. Suitable pharmaceutically acceptable esters for a carboxy group in Formula I include C1-6alkoxymethyl esters for example methoxymethyl, C1-6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3-8cycloalkoxycarbonyloxyC1-6alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C1-6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention. Suitable pharmaceutically acceptable esters for a hydroxy group in Formula I or a pharmaceutically acceptable salt thereof include inorganic esters such as phosphate esters, α-acyloxyalkyl ethers and related compounds, and esters derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms, and may be formed at any hydroxy group in the compounds of this invention, for example when Z is hydroxy or contains a hydroxy group. Following administration, the pharmaceutically acceptable ester undergoes in-vivo hydrolysis breakdown to give the parent carboxy/hydroxy group in the quinazoline derivative of Formula I. Examples of α-acyloxyalkyl ethers that may be used to form a pharmaceutically acceptable ester include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of pharmaceutically acceptable ester forming groups for a hydroxy group in Formula I (for example when Z is hydroxy) include (1-6C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, (1-6C)alkoxycarbonyl (to give alkyl carbonate esters), di-(1-4C)alkylcarbamoyl and N-(di-(1-4C)alkylaminoethyl)-N-(1-4C)alkylcarbamoyl (to give carbamates), di-(1-4C)alkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include chloromethyl or aminomethyl, (1-4C)alkylaminomethyl and di-((1-4C)alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4-position of the benzoyl ring. Particular pharmaceutically acceptable esters are phosphate esters formed with a hydroxy group in the quinazoline derivative for the Formula I (for example when Z is hydroxy or contains a hydroxy group), or a pharmaceutically acceptable salt thereof. More particularly, pharmaceutically acceptable esters include quinazoline derivatives of the Formula I in which a hydroxy group in Formula I forms a phosphoryl (npd is 1) or phosphiryl (npd is 0) ester of the formula (PD1), or a pharmaceutically acceptable salt thereof: Another particular pharmaceutically acceptable ester is a quinazoline derivative of the Formula I in which a hydroxy in Formula I (for example when Z is hydroxy) forms a phosphoryl to give a group of the formula (PD1) wherein npd is 1. Useful intermediates for the preparation of such esters include compounds containing a group of formula (PD1) in which either or both of the —OH groups in (PD1) is independently protected by (1-4C)alkyl (such compounds also being interesting compounds in their own right), phenyl or phenyl-(1-4C)alkyl (such phenyl groups being optionally substituted by 1 or 2 groups independently selected from (1-4C)alkyl, nitro, halo and (1-4C)alkoxy). Pharmaceutically acceptable esters of a quinazoline derivative of Formula I containing a group such as (PD1), may be prepared by reaction of a quinazoline derivative Formula I with a suitably protected phosphorylating agent (for example, containing a chloro or dialkylamino leaving group), followed by oxidation (if necessary) and deprotection. Suitable phosphorylating agents are well known and include, for example protected phosphoramidite compounds such as a N,N-di-[(1-6C)alkyl]-phosphoramidite, for example di-tert-butyl N,N-diethylphosphoramidite. It is to be understood that an ester group in the quinazoline derivative of the Formula I may form a pharmaceutically acceptable salt of the ester group and that such salts form part of the present invention. Where pharmaceutically acceptable salts of a pharmaceutically acceptable ester is required this is achieved by conventional techniques well known to those of ordinary skill in the art. Thus, for example, compounds containing a group of formula (PD1), may ionise (partially or fully) to form salts with an appropriate number of counter-ions. By way of example, if a pharmaceutically acceptable ester pro-drug of a quinazoline derivative Formula I contains a (PD1) group, there are two HO—P— functionalities present, each of which may form an appropriate salt with a suitable counter-ion. Suitable salts of a group of the formula (PD1) are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium or an organic amine salt for example triethylamine, or tris-(2-hydroxyethyl)amine. Thus for example the group (PD1) may form, a mono- or di-sodium salt). Particular novel compounds of the invention include, for example, quinazoline derivatives of the Formula I, or pharmaceutically acceptable salts, or pharmaceutically acceptable esters thereof, wherein, unless otherwise stated, each of R1, R2, W, Q1, X1, X2, a, b and Z has any of the meanings defined hereinbefore or in paragraphs (a) to (nnnn) hereinafter: (a) R1 is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula: Q2-X3— wherein X3 is a direct bond or is O, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R3), CON(R3), N(R3)CO, CH═CH and C≡C wherein R3 is hydrogen or (1-6C)alkyl, and wherein any CH2═CH— or HC≡C— group within a R1 substituent optionally bears at the terminal CH2═or HC≡ position a substituent selected from carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl or from a group of the formula: Q3-X4— wherein X4 is a direct bond or is selected from CO and N(R4)CO, wherein R4is hydrogen or (1-6C)alkyl, and Q3 is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, cyano, carbamoyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl and N,N-di-[(1-6C)alkyl]carbamoyl, or from a group of the formula: —X5-Q4 wherein X5 is a direct bond or is selected from O, N(R5), CON(R5), N(R5)CO and C(R5)2O, wherein R5 is hydrogen or (1-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, or from a group of the formula: —X6—R6 wherein X6 is a direct bond or is selected from O and N(R7), wherein R7 is hydrogen or (1-6C)alkyl, and R6 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl and N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; (b) R1 is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy, (2-6C)alkynyloxy, or from a group of the formula: Q2-X3— wherein X3 is a direct bond or is O, and Q2 is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R3), CON(R3), N(R3)CO, CH═CH and C≡C wherein R3is hydrogen or (1-6C)alkyl, and wherein any CH2═CH— or HC≡C— group within a R1 substituent optionally bears at the terminal CH2═or HC≡ position a substituent selected from carbamoyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl and wherein any CH2 or CH3 group within a R1 substituent, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, cyano, carbamoyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl and N,N-di-[(1-6C)alkyl]carbamoyl, or from a group of the formula: —X5-Q4 wherein X5 is a direct bond or is selected from O, N(R5), CON(R5), N(R5)CO and C(R5)2O, wherein R5 is hydrogen or (1-6C)alkyl, and Q4 is heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, or from a group of the formula: —X6—R6 wherein X6 is a direct bond or is selected from O and N(R7), wherein R7 is hydrogen or (1-6C)alkyl, and R6 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl and di-[(1-6C)alkyl]amino-(1-6C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; (c) R1 is selected from hydrogen, hydroxy, (1-6C)alkoxy, (2-6C)alkenyloxy and (2-6C)alkynyloxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, N(R3), CON(R3), N(R3)CO, CH═CH and C≡C wherein R3 is hydrogen or (1-6C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, cyano, carbamoyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl and N,N-di-[(1-6C)alkyl]carbamoyl; (d) R1 is selected from hydrogen, hydroxy, (1-6C)alkoxy, or from a group of the formula: Q2-X3— wherein X3 is O, and Q2 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-6C)alkyl, heterocyclyl or heterocyclyl-(1-6C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O and N(R3), wherein R3 is hydrogen or (1-4C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, cyano, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, carbamoyl, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl and (2-6C)alkanoyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; (e) R1 is selected from hydrogen, hydroxy, (1-6C)alkoxy, or from a group of the formula: Q2-X3— wherein X3 is O, and Q2 is azetidin-3-yl-(1-4C)alkyl, azetidin-1-yl-(2-4C)alkyl, pyrrolidin-2-yl-(1-4C)alkyl, pyrrolidin-3-yl-(1-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidin-2-yl-(1-4C)alkyl, piperidin-3-yl-(1-4C)alkyl, piperidin4-yl-(1-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O and N(R3), wherein R3 is hydrogen or (1-4C)alkyl, and wherein any CH2 or CH3 group within a R1 substituent, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, (1-4C)alkoxy, amino, (1-4C)alkylamino and di-[(1-4C)alkyl]amino, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, carbamoyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, N-(1-4C)alkylcarbamoyl, N,N-di-(1-4C)alkyl]carbamoyl and (2-4C)alkanoyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 oxo substituent (preferably any oxo group on a morpholino group in R1 is located at the 3 or 5 position on the morpholino ring); (f) R1 is selected from hydrogen, hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula: Q2-X3— wherein X3 is O, and Q2 is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, and (2-4C)alkanoyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 oxo substituent; (g) R1 is selected from hydrogen, hydroxy, methoxy, ethoxy, propoxy, isopropyloxy, 2-hydroxyethoxy, 2-fluoroethoxy, cyclopropylmethoxy, 2-cyclopropylethoxy, vinyloxy, allyloxy, ethynyloxy, 2-propynyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofurfuryloxy, tetrahydrofuran-3-ylmethoxy, 2-(tetrahydrofuran-2-yl)ethoxy, 3-(tetrahydrofuran-2-yl)propoxy, 2-(tetrahydrofuran-3-yl)ethoxy, 3-(tetrahydrofuran-3-yl)propoxy, tetrahydropyranylmethoxy, 2-tetrahydropyranylethoxy, 3-tetrahydropyranylpropoxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, pyrrolidin-3-yloxy, pyrrolidin-2-ylmethoxy, 2-pyrrolidin-2-ylethoxy, 3-pyrrolidin-2-ylpropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)ethoxy, 3-(1,1-dioxotetrahydro-4H-1,4-thiazin-4-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropoxy, piperidin-3-yloxy, piperidin-4-yloxy, piperidin-3-ylmethoxy, 2-piperidin-3-ylethoxy, piperidin-4-ylmethoxy, 2-piperidin-4-ylethoxy, 2-homopiperidin-1-ylethoxy, 3-homopiperidin-1-ylpropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-homopiperazin-1-ylethoxy, 3-homopiperazin-1-ylpropoxy, pyrrolidin-1-yl, morpholino, piperidino and piperazin-1-yl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of a group selected from O, NH, N(CH3), CH═CH and C≡C, and when R1 is a vinyloxy, allyloxy, ethynyloxy or 2-propynyloxy group, the R1 substituent optionally bears at the terminal CH2═ or HC≡ position a substituent selected from N-(2-dimethylaminoethyl)carbamoyl, N-(3-dimethylaminopropyl)carbamoyl, methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl, 4-methylaminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl and 4-dimethylaminobutyl, or from a group of the formula: Q3-X4— wherein X4 is a direct bond or is NHCO or N(CH3)CO and Q3 is pyrrolidin-1-ylmethyl, 2-pyrrolidin-1-ylethyl, 3-pyrrolidin-1-ylpropyl, 4-pyrrolidin-1-ylbutyl, pyrrolidin-2-ylmethyl, 2-pyrrolidin-2-ylethyl, 3-pyrrolidin-2-ylpropyl, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 4-morpholinobutyl, piperidinomethyl, 2-piperidinoethyl, 3-piperidinopropyl, 4-piperidinobutyl, piperidin-3-ylmethyl, 2-piperidin-3-ylethyl, piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperazin-1-ylmethyl, 2-piperazin-1-ylethyl, 3-piperazin-1-ylpropyl or 4-piperazin-1-ylbutyl, and wherein any CH2 group which is attached to 2 carbon atoms (other than a CH2 group within a heterocyclyl ring) or any CH3 group which is attached to a carbon atom within a R1 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, amino, methoxy, ethoxy, methylsulfonyl, methylamino and dimethylamino, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, trifluoromethyl, hydroxy, amino, methylamino, ethylamino, dimethylamino, diethylamino, carbamoyl, methyl, ethyl, n-propyl, isopropyl and methoxy, and any piperidin-3-ylmethyl, piperidin-4-ylmethyl or piperazin-1-yl group within a R1 substituent is optionally N-substituted with 2-methoxyethyl, 3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, acetyl or propionyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 or 2 oxo substituents; (h) R1 is selected from hydrogen, hydroxy, (1-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents, or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, oxo, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, N-(1-6C)alkylsulfamoyl and N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino; (i) R1 is selected from hydrogen, hydroxy, (1-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro substituents, or a substituent selected from hydroxy, amino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; (j) R1 is selected from hydrogen, hydroxy, (1-6C)alkoxy, (3-7C)cycloalkyl-oxy and (3-7C)cycloalkyl-(1-6C)alkoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of an O atom, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro substituents, or a substituent selected from hydroxy and (1-4C)alkoxy; (k) R1 is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy, cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy, cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy and tetrahydropyranyl-(1-4C)alkoxy, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a R1 substituent are optionally separated by the insertion into the chain of an O atom, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro substituents, or a substituent selected from hydroxy and (1-3C)alkoxy; (l) R1 is selected from hydrogen, (1-6C)alkoxy, cyclopropylmethoxy and 2-cyclopropylethoxy, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more fluoro or chloro substituents, or a substituent selected from hydroxy, methoxy and ethoxy; (m) R1 is selected from methoxy, ethoxy, propyloxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2,2-difluoroethoxy 2,2,2-trifluoroethoxy, 2-(pyrrolidin-1-yl)ethoxy, 3-(pyrrolidin-1-yl)propoxy, 2-piperidinoethoxy, 3-piperidinopropyl, 2-piperazinoethoxy, 3-piperazinopropoxy, 2-morpholinoethoxy and 3-morpholinopropoxy; (n) R1 is selected from hydrogen methoxy, ethoxy, propyloxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy; (o) R1 is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-3C)alkoxy-(2-3C)alkoxy; (p) R1 is selected from hydrogen and (1-3C)alkoxy (particularly R1 is (1-3C)alkoxy such as methoxy, ethoxy and isopropyloxy); (q) R1 is hydrogen; (r) R1 is methoxy; (s) each R2, which may be the same or different, is selected from halogeno, cyano, nitro, hydroxy, amino, carboxy, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy, and a group of the formula: —X7—R8 wherein X7 is a direct bond or is selected from O and N(R9), wherein R9 is hydrogen or (1-6C)alkyl, and R8 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl; (t) each R2, which may be the same or different, is selected from halogeno, hydroxy, amino, (1-6C)alkyl, (2-8C)alkenyl, (2-8C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; (u) each R2, which may be the same or different, is selected from fluoro, chloro, bromo, iodo, cyano, hydroxy, trifluoromethyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy; (v) each R2, which may be the same or different, is selected from fluoro, chloro, bromo, (1-4C)alkyl, (2-4C)alkenyl and (2-4C)alkynyl; (w) each R2, which may be the same or different, is selected from fluoro, chloro, bromo, iodo, cyano, carbamoyl, hydroxy, trifluoromethyl, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, allyl, ethynyl, 1-propynyl, 2-propynyl, N-methylcarbamoyl, N-ethylcarbamoyl and N,N-dimethylcarbamoyl; (x) each R2, which may be the same or different, is selected from fluoro, chloro, bromo, iodo, cyano, hydroxy, trifluoromethyl, methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, allyl, ethynyl, 1-propynyl, and 2-propynyl; (y) each R2, which may be the same or different, is selected from fluoro, chloro, bromo, cyano, hydroxy, trifluoromethyl, methyl, ethyl, methoxy, ethoxy and ethynyl; (z) each R2, which may be the same or different, is selected from fluoro, chloro, bromo and ethynyl; (aa) each R2, which may be the same or different, is selected from halogeno (particularly fluoro, chloro and bromo); (bb) b is 1, 2 or 3 and one R2 is at the meta (3-) position on the anilino group in Formula 1; (cc) b is 1, 2 or 3 and each R2, which may be the same or different, is as defined in any of (s) to (aa) above; (dd) b is 1, 2 or 3, one R2 is at the meta (3-) position on the anilino group in Formula 1 and is halogeno, and when b is 2 or 3 the other R2 group(s), which may be the same or different, are as defined in any of any of (s) to (aa) above; (ee) b is 1, 2 or 3, each R2, which may be the same or different, is halogeno, and wherein one R2 is at the meta (3-) position on the anilino group; (ff) b is 1 or 2, each R2, which may be the same or different, is halogeno (particularly fluoro, chloro or bromo) and wherein one R2 is at the meta (3-) position and the other R2 is at the ortho (2-) or para (4-) position on the anilino group; (gg) b is 1 or 2, one R2 is at the meta (3-) position on the anilino group and is chloro or bromo (particularly chloro), and when b is 2 the other R2 group is selected from fluoro, chloro and bromo; (hh) the anilino group at the 4-position on the quinazoline ring in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and 3-ethynylanilino; (ii) the anilino group at the 4-position on the quinazoline ring in Formula I is selected from 3-chloro-4-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino, 3-methylanilino and 3-ethynylanilino; (jj) the anilino group at the 4-position on the quinazoline ring in Formula I is 3-chloro-4-fluoroanilino; (kk) the anilino group at the 4-position on the quinazoline ring in Formula I is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino (more particularly the anilino is 3-chloro-2-fluoroanilino); (ll) Q1 is selected from piperidin-3-yl and piperidin-4-yl; (mm) Q1 is piperidin-4-yl; (nn) each W, which may be the same or different, is selected from halogeno, trifluoromethyl, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy, and from a group of the formula: —X8—R10 wherein X8 is a direct bond or is O, and R10 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl or (1-6C)alkoxy-(1-6C)alkyl; (oo) each W, which may be the same or different, is selected from halogeno, hydroxy, oxo, (1-6C)alkyl and (1-6C)alkoxy; (pp) each W, which may be the same or different, is selected from halogeno (particularly fluoro), hydroxy, (1-3C)alkyl and (1-3C)alkoxy; (qq) a is 0, 1, or 2 and each W, which may be the same or different, is as defined in any of (nn) to (pp); (rr) a is 0 or 1 and W is as defined in any of (nn) to (pp); (ss) a is 0; (tt) Q1 is piperidin-4-yl, a is 0 or 1 and W is as defined in any of (nn) to (pp); (uu) X1 is CO; (vv) X1 is SO2; (ww) X2 is a group of the formula: —(CR12R13)p-(Q5)m-(CR14R15)q- wherein m is 0 or 1, p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3 or 4, each of R12, R13, R14 and R15, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and Q5 is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene, and wherein any CH2 or CH3 group within an X2 group, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents, and wherein any CH2 group which is attached to 2 carbon atoms or any CH3 group which is attached to a carbon atom within a X2 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; (xx) X2 is selected from a group of the formula -(Q5)m-(CR14R15)q- and a group of the formula —(CR12R13)q-(Q5)m-, wherein m is 0 or 1, q is 1, 2, 3 or 4, and Q5, R12, R13, R14 and R15 are as hereinbefore defined; (yy) X2 is a group of the formula -Q5-, for example (3-7C)cycloalkylene such as cyclopropylidene; (zz) X2 is selected from cyclopropylene, cyclopbutylene, cyclopentylene, cyclohexylene, methylene-(3-6C)cycloalkylene, (3-6C)cycloalkylene-methylene-, ethylene-(3-6C)cycloalkylene and (3-6C)cycloalkylene-ethylene-, and wherein and wherein any CH2 or CH3 group within X2, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; (aaa) X2 is a group of the formula —(CR12R13)q—, q is 1, 2, 3 or 4 (particularly 1 or 2), each of R12 and R13, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, and wherein and wherein any CH2 or CH3 group within X2, optionally bears on each said CH2 or CH3 group one or more halogeno substituents, and wherein any CH2 group which is attached to 2 carbon atoms or any CH3 group which is attached to a carbon atom within a X2 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; (bbb) X2 is a group of the formula —(CR12R13)q—, q is 1, 2 or 3, each of R12 and R13, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, and wherein any CH2 or CH3 group within an X2 group, optionally bears on each said CH2 or CH3 group one or more halogeno substituents, and wherein any CH2 group which is attached to 2 carbon atoms or any CH3 group which is attached to a carbon atom within a X2 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, and (1-6C)alkoxy; (ccc) X2 is a group of the formula —(CR12R13)q—(CR12aaR13aa)—, q is 1, 2 or 3 (particularly 1 or 2, more particularly 1), each of R12, R13 and R13aa, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, R12aa is selected from amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and wherein any CH2 or CH3 group within an X2 group, optionally bears on each said CH2 or CH3 group one or more halogeno substituents, and wherein any CH2 group which is attached to 2 carbon atoms or any CH3 group which is attached to a carbon atom within a X2 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; (ddd) X2 is a group of the formula —(CR12R13)q—, q is 1, 2, 3 or 4 (particularly 1 or 2, more particularly 1), each of R12 and R13, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, provided that at least one of the R12 or R13 groups in X2 is (1-6C)alkyl, and wherein any CH2 or CH3 group within an X2 group, optionally bears on each said CH2 or CH3 group one or more halogeno substituents, and wherein any CH2 group which is attached to 2 carbon atoms or any CH3 group which is attached to a carbon atom within a X2 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, and (1-6C)alkoxy; (eee) X2 is selected from a group of the formula —(CR12R13)—, —(CR12R13CH2)—, —(CR12R13CH2CH2)—, —(CH2CR2R13)— and —(CH2CH2CR12R13)—, each of R12 and R3, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, and wherein any CH2 or CH3 group within X2, optionally bears on each said CH2 or CH3 group one or more halogeno substituents, and wherein any CH2 group which is attached to 2 carbon atoms or any CH3 group which is attached to a carbon atom within a X2 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; (fff) X2 is selected from a group of the formula —(CR12R13)—, —(CR12R13CH2)—, —(CR12R13CH2CH2)—, —(CH2CR12R13)— and —(CH2CH2CR12R13)—, each of R12 and R3, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, provided that at least one of R12 or R13 is a branched (1-6C)alkyl group, and wherein any CH2 or CH3 group within X2, optionally bears on each said CH2 or CH3 group one or more halogeno substituents, and wherein any CH2 group which is attached to 2 carbon atoms or any CH3 group which is attached to a carbon atom within a X2 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; (ggg) X2 is selected from a group of the formula —(CR12R13)—, —(CR12R13CH2)—, —(CR12R13CH2CH2)—, —(CH2CR12R13)— and —(CH2CH2CR12R13)—, each of R12 and R13, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, provided that at least one of R2 or R13 in X2 is a branched alkyl group, which branched alkyl group is preferably selected from iso-propyl, iso-butyl, sec-butyl and tert-butyl, and wherein any CH2 or CH3 group within X2, optionally bears on each said CH2 or CH3 group one or more fluoro or chloro substituents, and wherein any CH2 group which is attached to 2 carbon atoms or any CH3 group which is attached to a carbon atom within a X2 substituent optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy and (1-3C)alkoxy; (hhh) X2 is selected from a group of the formula —CH2—, —CH2CH2—, —CH2CH2CH2—(CR12R13)—, —(CR12R13CH2)— and —(CH2CR12R13)— wherein each of R12 and R13, which may be the same or different, is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl and (1-4C)alkoxy-(1-4C)alkyl, provided that R12 and R13 are not both hydrogen; (iii) X2 is selected from a group of the formula —CH2—, —CH2CH2—, —(CHR12a), —(CHR12aCH2)—, —(C(R12a)2CH2)—, —(CH2C(R12a)2)— and —(CH2CHR12b)—, wherein each R12a, which may be the same or different, is selected from (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl, and wherein R12b is selected from hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]-amino, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl; (jjj) X2 is selected from a group of the formula —CH2—, —CH2CH2—, —(CHR12a)—, —(CHR12aCH2)— and —(CH2CHR12b)— wherein R12a is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl, and wherein R12b is selected from hydrogen, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl; (kkk) X2 is selected from a group of the formula —CH2—, —CH2CH2—, —(CHR12a)—, —(CHR12aCH2)—, —(C(R12a)2CH2)—, —(CH2C(R12a)2)— and —(CH2CHR12b)—, wherein each R12a, which may be the same or different, is (1-4C)alkyl, and wherein R12b is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino; (lll) X2 is selected from a group of the formula —(CHR12a)—, —(CHR12aCH2)—, —(C(R12a)2CH2)—, —(CH2C(R12a)2)— and —(CH2CHR12b)—, wherein each R12a, which may be the same or different, is (1-4C)alkyl (particularly (1-3C)alkyl), and wherein R12b is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino (particularly R12b is selected from (1-4C)alkylamino and di-[(1-4C)alkyl]-amino, more particularly di-[(1-3C)alkyl]-amino); (mmm) X2 is selected from a group of the formula —CH2—, —CH2CH2—, —CHR12)—, —(CHR12CH2)— and —(CH2CHR12)— wherein R12 is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl; (nnn) X2 is selected from a group of the formula —CH2—, —CH2CH2—, —(CHR12a)—, —(CHR12aCH2)—, —(C(R12a)2CH2)—, —(CH2C(R12a)2)— and —(CH2CHR12a)—, wherein each R12a, which may be the same or different, is (1-4C)alkyl; (ooo) X2 is selected from a group of the formula —(CHR12a)—, —(CHR12aCH2)—, —(C(R12a)2CH2)—, —(CH2C(R12a)2)— and —(CH2CHR12a)— (particularly, X2 is —CHR12a)—), wherein each R12a, which may be the same or different, is (1-4C)alkyl; (ppp) X2 is selected from a group of the formula —(CH2)q—, wherein q is 1, 2 or 3, particularly q is 1 or 2, more particularly 1; (qqq) Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino and a group of the formula: Q6-X9— wherein X9 is a direct bond or is selected from O, N(R16), SO2 and SO2N(R16), wherein R16 is hydrogen or (1-6C)alkyl, and Q6 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, provided that when X9 is a direct bond, Q6 is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein any heterocyclyl group in Z is a monocyclic fully saturated 4, 5, 6 or 7-membered heterocyclyl group containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, and wherein and wherein any CH2 or CH3 group within a Z group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: —X10—R18 wherein X10 is a direct bond or is selected from O, CO, SO2 and N(R19), wherein R19 is hydrogen or (1-4C)alkyl, and R18 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; (rrr) Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy and a group of the formula: Q6-X9— wherein X9 is a direct bond or is selected from O and N(R16), wherein R16 is hydrogen or (1-6C)alkyl, and Q6 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, provided that when X9 is a direct bond, Q6 is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein any heterocyclyl group in Z is a monocyclic non-aromatic fully saturated or partially saturated 4, 5, 6 or 7-membered heterocyclyl group containing 1 heteroatom selected from oxygen and nitrogen and optionally a further heteroatom selected from oxygen, nitrogen and sulfur, and wherein and wherein any CH2 or CH3 group within a Z group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: —X10—R18 wherein X10 is a direct bond or is selected from O, CO, SO2 and N(R19), wherein R19 is hydrogen or (1-4C)alkyl, and R18 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; (sss) Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl~amino, (1-6C)alkoxy and a group of the formula: Q6-X9— wherein X9 is a direct bond or is selected from O and N(R16), wherein R16 is hydrogen or (1-6C)alkyl, and Q6 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, provided that when X9 is a direct bond, Q6 is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein any heterocyclyl group in Z is selected from tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl group may be carbon or nitrogen linked to the group to which it is attached, and wherein and wherein any CH2 or CH3 group within a Z group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: —X10—R18 wherein X10 is a direct bond or is selected from O, CO, SO2 and N(R19), wherein R19 is hydrogen or (1-4C)alkyl, and R18 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; (ttt) Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy and a group of the formula: Q6-X9— wherein X9 is a direct bond and Q6 is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl (preferably carbon linked to X1), and wherein any heterocyclyl group in Z is selected from azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, and wherein and wherein any CH2 or CH3 group within a Z group optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy and (1-6C)alkoxy, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and (2-6C)alkanoyl; (uuu) Z is selected from hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino, di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl and a group of the formula: Q6-X9— wherein X9 is selected from O and N(R16), wherein R16 is hydrogen or (1-4C)alkyl, and Q6 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, and wherein any heterocyclyl group in Q6 is selected from tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, which heterocyclyl group may be carbon or nitrogen linked to the group to which it is attached, and provided that when m, p and q are all 0, then Z is heterocyclyl, preferably one of the above mentioned heterocyclyl groups that may be represented by Q6, (which heterocyclyl group is preferably carbon linked to X1), and wherein and wherein any CH2 or CH3 group within a Z group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: —X10—R18 wherein X10 is a direct bond or is selected from O, CO, SO2 and N(R19), wherein R19 is hydrogen or (1-4C)alkyl, and R18 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; (vvv) Z is selected from amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-1-6C)alkylamino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino, di-[hydroxy-2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl and homopiperazin-1-yl, and wherein and wherein any CH2 or CH3 group within a Z group, optionally bears on each said CH2 or CH3 group one or more fluoro substituents or a substituent selected from hydroxy, cyano, amino, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, cyano, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (2-4C)alkanoyl, (1-4C)alkylamino and di-[(1-4C)alkyl]amino, and provided that when m, p and q are all 0, then Z is one of the above mentioned heterocyclyl groups that may be represented by Z, such as pyrrolidin-1-yl or piperidino (preferably the sum of m+p+q is at least 1); (www) Z is selected from hydroxy, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydropyranyl and a group of the formula: Q6-X9— wherein X9 is O, and Q6 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, wherein any heterocyclyl group represented by Q6 is preferably selected from tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, 1,4-dioxanyl and tetrahydropyranyl, and provided that when m, p and q are all 0, then Z is selected from tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydropyranyl and oxepanyl, and wherein any CH2 or CH3 group within a Z group, optionally bears on each said CH2 or CH3 group one or more fluoro substituents or a substituent selected from hydroxy, cyano, amino, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, cyano, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; (xxx) Z is selected from hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino, di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy and (1-4C)alkoxy-(2-6C)alkoxy, and wherein the sum of m+p+q is at least 1; (yyy) Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy and (1-4C)alkoxy-(2-6C)alkoxy, and the sum of m+p+q is at least 1; (zzz) Z is selected from hydroxy, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy), and the sum of m+p+q is at least 1; (aaaa) Z is selected from hydroxy, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, amino, methylamino, ethylamino, N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino, dimethylamino, N-methyl-N-ethylamino, di-ethylamino, N-(2-hydroxyethyl)-N-methylamino, N-(2-hydroxyethyl)-N-ethylamino, N,N-di-(2-hydroxyethyl)amino, N-(2-methoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-ethylamino, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl, and wherein any heterocyclyl group within Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (2-4C)alkanoyl and (1-4C)alkoxy, and provided that when m, p and q are all 0, then Z is one of the above mentioned heterocyclyl groups that may be represented by Z, such as pyrrolidin-1-yl, tetrahydrofuranyl or piperidino (preferably the sum of m+p+q is at least 1); (bbbb) Z is selected from pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl, homopiperazin-1-yl, (particularly Z is selected from pyrrolidin-1-yl, piperidino, piperazin-1-yl and morpholino), and wherein the heterocyclyl group within Z optionally bears one or more (for example 1, 2 or 3) substituents, which may be the same or different selected from fluoro, chloro, cyano, hydroxy, amino, carbamoyl, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, N-(1-4C)alkylcarbamoyl, N,N-di-[(1-4C)alkyl]carbamoyl, acetyl, propionyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, cyanomethyl, hydroxyacetyl, aminoacetyl, methylaminoacetyl, ethylaminoacetyl, dimethylaminoacetyl and N-methyl-N-ethylaminoacetyl (preferably the sum of m+p+q is at least 1); (cccc) Z is selected from hydroxy, (1-4C)alkoxy, tetrahydrofuranyl and tetrahydropyranyl and wherein any tetrahydrofuranyl or tetrahydropyranyl group within Z optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy, and provided that when m, p and q are all 0, then Z is selected from tetrahydrofuranyl and tetrahydropyranyl (preferably the sum of m+p+q is at least 1); (dddd) Z is hydroxy or (1-4C)alkoxy (particularly Z is hydroxy), and the sum of m+p+q is at least 1; (eeee) Z is as defined in any of (qqq) to (dddd) above, and wherein X2 is selected from —CH2—, —CH2CH2—, —(CR12R13)—, —(CR12R13CH2)—, —(CH2CR12R13)— and (3-6C)cycloalkenylene (for example cyclopropylene such as cyclopropylidene), wherein each of R12 and R13, which may be the same or different, is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl, provided that R12 and R13 are not both hydrogen, and wherein X1 is CO; (ffff) Z is as defined in any of (qqq) to (dddd) above; X2 is selected from a group of the formula —CH2—, —CH2CH2—, —(CHR12a)—, —(CHR12aCH2)—, —(C(R12a)2CH2)—, —(CH2C(R12a)2)— and —(CH2CHR12b)— (particularly, X2 is —(CHR12a)—), wherein each R12a, which may be the same or different, is selected from (1-4C)alkyl, hydroxy-(1-4C)alkyl and (1-3C)alkoxy-(1-4C)alkyl, and wherein R12b is selected from hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]-amino, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl; and wherein X1 is CO; (gggg) Z is selected from hydroxy and (1-4C)alkoxy, X2 is selected from a group of the formula —CH2—, —CH2CH2—, —(CHR12a)—, —(CHR12aCH2)—, —C(R12a)2CH2)—, —(CH2C(R12a)2)— and —(CH2CHR12b)— (particularly, X2 is —(CHR12a)—), wherein each R12a, which may be the same or different, is (1-4C)alkyl, and wherein R12b is selected from hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino, and wherein X1 is CO; (hhhh) Z-X2—X1 is hydroxy-(2-4C)alkanoyl, for example hydroxyacetyl, 2-hydroxypropionyl or 3-hydroxypropionyl, particularly Z-X2—X1 is 2-hydroxypropionyl); (iiii) Z-X2—X1 is (1-4C)alkoxy-(2-4C)alkanoyl, for example methoxyacetyl, 2-methoxypropionyl or 3-methoxypropionyl); (jjjj) Z-X2—X1 is selected from amino-(2-4C)alkanoyl, (1-4C)alkylamino-(2-4C)alkanoyl and di-[(1-4C)alkyl]amino-(2-4C)alkanoyl (for example Z-X2—X1 is di-[(1-4C)alkyl]amino-acetyl such as dimethylaminoacetyl); (kkkk) Z-X2— is selected from tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl is linked to the carbonyl group in Formula I, by a ring carbon, and wherein the heterocyclyl group within Z-X2 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; (llll) Z-X2— is selected from tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl (for example Z-X2 is selected tetrahydrofuran-2-yl or tetrahydropyran-2-yl); (mmmm) Z-X2— is selected from pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl is linked to X1 in Formula I, by a ring carbon, and wherein the heterocyclyl group within Z-X2 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; and (nnnn) Z-X2 is selected from pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, homopiperidin-1-yl and homopiperazin-1-yl, and wherein the heterocyclyl group within Z-X2 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl. A particular embodiment of the present invention is a quinazoline derivative of the Formula I wherein: R1 is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy, cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy, cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy and tetrahydropyranyl-(1-4C)alkoxy, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno substituents, or a substituent selected from hydroxy and (1-4C)alkoxy; b is 1, 2 or 3; each R2, which may be the same or different, is selected from halogeno (particularly fluoro, chloro or bromo), cyano, hydroxy, trifluoromethyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy; Q1 is piperidin-4-yl; a is 0, 1 or 2; each W, which may be the same or different, is selected from halogeno (particularly fluoro), trifluoromethyl, hydroxy, oxo, (1-6C)alkyl, (1-6C)alkoxy, and from a group of the formula: —X8—R10 wherein X8 is a direct bond or is O, and R10 is halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl or (1-6C)alkoxy-(1-6C)alkyl; X1 is CO; and Z and X2 have any of the values hereinbefore defined; provided that: when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4chloro-2-fluoroanilino, R1 is hydrogen or (1-3C)alkoxy, and X1 is CO, then a is 0 and Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula Q6-X9—, wherein Q6-X9— is as hereinbefore defined; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. In this embodiment, a particular value for X2 is a group selected from (3-6C)cycloalkylene (such as cyclopropylidene), —CH2—, —CH2CH2—, —CH2CH2CH2— —CR12R13)—, —(CR12R13CH2)— and —(CH2CR12R13)— wherein each of R12 and R13, which may be the same or different, is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl, provided that R2 and R13 are not both hydrogen, and wherein any CH2 group within a (3-6C)cycloalkylene group in X2, optionally bears on each said CH2 or group one or more (1-4C)alkyl substituents or a substituent selected from hydroxy, (1-4C)alkoxy, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl. In this embodiment, a particular value for Z is a group selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy and a group of the formula: Q6-X9— wherein X9 is a direct bond or is selected from O and N(R16), wherein R16 is hydrogen or (1-6C)alkyl, and Q6 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, provided that when X9 is a direct bond, Q6 is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein any heterocyclyl group in Z is selected from tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, tetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl group may be carbon or nitrogen linked to the group to which it is attached, and wherein and wherein any CH2 or CH3 group within a Z group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: —X10—R18 wherein X10 is a direct bond or is selected from O, CO, SO2 and N(R19), wherein R19 is hydrogen or (1-4C)alkyl, and R18 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl. Another particular value for Z in this embodiment is a group selected from hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino, di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and 1,4-dioxanyl, and provided that when m, p and q are all 0, then Z is one of the heterocyclyl groups mentioned above, and wherein any heterocyclyl group in Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy. Another particular value for Z in this embodiment is a group selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy more particularly Z is hydroxy or(1-4C)alkoxy. In this embodiment a particular value for each R2, which may be the same or different, is a group selected from fluoro, chloro or bromo and (2-4C)alkynyl; In this embodiment a particular 4-anilino group in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and 3-ethynylanilino. Still more particularly the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino. Another particular embodiment of the present invention is a quinazoline derivative of the Formula I wherein: R1 is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula: Q2-X3— wherein X3 is O, and Q2 is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, and (2-4C)alkanoyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 oxo substituent; b is 1, 2 or 3; each R2, which may be the same or different, is selected from fluoro, chloro, bromo and (2-4C)alkynyl; Q1 is piperidin-4-yl; a is 0 or 1 (preferably 0); each W, which may be the same or different is selected from halogeno (particularly fluoro), hydroxy, (1-3C)alkyl and (1-3C)alkoxy; X1 is CO; X2 is selected from a group of the formula —CH2—, —CH2CH2—, —(CHR12a)—, —(CHR12aCH2)—, —C(R12a)2CH2)—, —(CH2C(R12a)2)— and —(CH2CHR12b)—, wherein each R12a, which may be the same or different, is selected from (1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl (particularly R12a is (1-4C)alkyl), and wherein R12b is selected from hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino, di-[(1-4C)alkyl]-amino, hydroxy-(1-4C)alkyl, (1-3C)alkoxy-(1-4C)alkyl, amino-(1-4C)alkyl, (1-4C)alkylamino-(1-4C)alkyl and di-[(1-4C)alkyl]-amino-(1-4C)alkyl (particularly R12b selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino); Z is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy, or Z-X2 is selected from tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, wherein Z-X2 is linked to X1 by a ring carbon atom, and wherein any heterocyclyl group within Z optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; provided that: when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino and R1 is (1-3C)alkoxy, then a is 0; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. In this embodiment a particular value for Z is a group selected from hydroxy, and (1-4C)alkoxy (for example Z is hydroxy, methoxy or ethoxy). In this embodiment a particular 4-anilino group in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and 3-ethynylanilino. Still more particularly the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino. Another particular embodiment of the present invention is a quinazoline derivative of the Formula I wherein: R1 is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula: Q2-X3— wherein X3 is O, and Q2 is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkylamino, di-[(1-4C)alkyl]amino, and (2-4C)alkanoyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1 oxo substituent (particularly R1 is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-3C)alkoxy-(2-4C)alkoxy, more particularly R1 is (1-4C)alkoxy; b is 1, 2 or 3 (particularly b is 1, more particularly b is 2); each R2, which may be the same or different, is selected from fluoro, chloro, bromo and (2-4C)alkynyl; Q1 is piperidin-4-yl; a is 0 or 1 (preferably 0); each W, which may be the same or different is selected from halogeno (particularly fluoro), hydroxy, (1-3C)alkyl and (1-3C)alkoxy; X1 is CO; X2 is a group of the formula —(CR12R13)q—(CR12aaR13aa)—, q is 1, 2 or 3 (particularly 1 or 2, more particularly 1), each of R12, R13 and R13aa, which may be the same or different, is selected from hydrogen and (1-6C)alkyl, R12aa is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl]amino; Z is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy, or Z-X2 is Z is selected from tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, wherein Z-X2 is linked to X1 by a ring carbon atom, and wherein any heterocyclyl group within Z optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; provided that: when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino and R1 is (1-3C)alkoxy, then a is 0; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. In this embodiment a particular value for Z is a group selected from hydroxy, and (1-4C)alkoxy (for example Z is hydroxy, methoxy or ethoxy). In this embodiment a particular 4-anilino group in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino 3-bromoanilino and 3-ethynylanilino. More particularly in this embodiment the 4-anilino group in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino and 3-bromoanilino. Still more particularly the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino. Preferably the anilino group is 3-chloro-2-fluoroanilino. Another particular embodiment of the present invention is a quinazoline derivative of the Formula I wherein: R1 is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula: Q2-X3— wherein X3 is O, and Q2 is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino (particularly R1 is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-3C)alkoxy-(2-4C)alkoxy, more particularly R1 is (1-4C)alkoxy, for example methoxy, ethoxy, isopropyloxy, still more particularly R1 is methoxy); the 4-anilino group in Formula I is selected from 3-chloro4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and 3-ethynylanilino; b is 1 or 2; each R2, which may be the same or different, is selected from fluoro, chloro, bromo and ethynyl; Q1 is piperidin-4-yl; a is 0 or 1 (preferably 0); each W, which may be the same or different is selected from halogeno (particularly fluoro), hydroxy, (1-3C)alkyl and (1-3C)alkoxy; X1 is CO; X2 is selected from a group of the formula —(CHR12a)—, —(CHR12aCH2)—, —(C(R12a)2CH2)—, —(CH2C(R12a)2)— and —(CH2CHR12b)—, wherein each R12a, which may be the same or different, is (1-4C)alkyl (particularly (1-3C)alkyl), and wherein R12b is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino (particularly R12b is selected from (1-4C)alkylamino and di-[(1-4C)alkyl]-amino, more particularly di-[(1-3C)alkyl]-amino); Z is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy, or Z-X2 is selected from tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl, which is linked to X1 by a ring carbon atom, and wherein any heterocyclyl group within Z optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. In this embodiment a particular value for Z is a group selected from hydroxy, and (1-4C)alkoxy (for example Z is hydroxy, methoxy or ethoxy). In this embodiment a particular 4-anilino group in Formula I is selected from 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and 3-ethynylanilino. Still more particularly the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino. Another particular embodiment of the present invention is a quinazoline derivative of the Formula I wherein: R1 is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy, (1-3C)alkoxy-(2-4C)alkoxy or from a group of the formula: Q2-X3— wherein X3 is O, and Q2 is azetidin-1-yl-(2-4C)alkyl, pyrrolidin-1-yl-(2-4C)alkyl, piperidino-(2-4C)alkyl, piperazino-(2-4C)alkyl or morpholino-(2-4C)alkyl, and wherein any heterocyclyl group within a substituent on R1 optionally bears 1, 2 or 3 substituents, which may be the same or different, selected from halogeno, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino (particularly R1 is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-3C)alkoxy-(2-4C)alkoxy, more particularly R1 is (1-4C)alkoxy, for example methoxy, ethoxy, isopropyloxy, still more particularly R1 is methoxy); the 4-anilino group in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and 3-ethynylanilino; Z is hydroxy or (1-4C)alkoxy, (particularly Z is hydroxy, methoxy or ethoxy, more particularly Z is hydroxy or methoxy, especially Z is hydroxy); Q1 is piperidin-4-yl; a is 0 or 1 (preferably 0); each W, which may be the same or different is selected from hydroxy, (1-3C)alkyl and (1-3C)alkoxy; X1 is CO; X2 is selected from a group of the formula —(CHR12a)— and —(CH2CHR12b)—, wherein R12a is (1-4C)alkyl (particularly (1-3C)alkyl, more particularly methyl), and wherein R12b is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino (particularly R12b is selected from (1-3C)alkylamino and di-[(1-3C)alkyl]-amino, more particularly di-[(1-3C)alkyl]-amino, still more particularly R12b is methylamino and especially dimethylamino); or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. In this embodiment a particular 4-anilino group in Formula I is selected from 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and 3-ethynylanilino. Still more particularly the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino. Another particular embodiment of the present invention is a quinazoline derivative of the Formula I wherein: R1 is (1-4C)alkoxy (for example methoxy, ethoxy, isopropyloxy, particularly methoxy); the 4-anilino group in Formula I is selected from 3-chloro-4-fluoroanilino, 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 2-fluoro-5-chloroanilino, 3-bromoanilino and 3-ethynylanilino; Q1 is piperidin-4-yl; a is 0 or 1 (preferably 0); each W, which may be the same or different is selected from hydroxy, (1-3C)alkyl and (1-3C)alkoxy; X1 is CO; Z-X2 is selected from tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl and morpholinyl (particularly Z-X2 is tetrahydrofuranyl or pyrrolidinyl), wherein Z-X2 is linked to X1 by a ring carbon atom, and wherein any heterocyclyl group within Z optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, methyl, methoxy and acetyl; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. In this embodiment a particular 4-anilino group in Formula I is selected from 3-bromo-2-fluoroanilino, 3-chloro-2-fluoroanilino, 3-bromoanilino and 3-ethynylanilino, more particularly the anilino group is selected from 3-bromo-2-fluoroanilino and 3-chloro-2-fluoroanilino. Another embodiment of the compounds of Formula I is a quinazoline derivative of the Formula Ia: wherein: R1 is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy, cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy, cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy and tetrahydropyranyl-(1-4C)alkoxy, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno substituents, or a substituent selected from hydroxy and (1-4C)alkoxy; b1 is 0, 1 or 2; each R2, which may be the same or different, is selected from halogeno (particularly fluoro, chloro or bromo), cyano, hydroxy, trifluoromethyl, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl and (1-4C)alkoxy (particularly R2 is selected from fluoro, chloro, bromo or ethynyl, more particularly R2 is selected from fluoro, chloro and bromo); R2a is halogeno (particularly fluoro, chloro or bromo, more particularly fluoro or chloro, still more particularly chloro or bromo, and especially R2a is chloro); a is 0, 1 or 2; each W, which may be the same or different, is selected from halogeno (particularly fluoro), hydroxy, (1-4C)alkyl and (1-4C)alkoxy; X2 is a group of the formula: —(CR12R13)p-(Q5)m-(CR14R15)q wherein m is 0 or 1, p is 0, 1, 2, 3 or 4 and q is 0, 1, 2, 3 or 4, each of R12, R13, R14 and R15, which may be the same or different, is selected from hydrogen, (1-6C)alkyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino, and Q5 is selected from (3-7C)cycloalkylene and (3-7C)cycloalkenylene, and wherein any CH2 or CH3 group within an X2 group, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, (1-6C)alkoxy, (1-6C)alkylamino and di-[(1-6C)alkyl]amino; Z is selected from hydroxy, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxy, (1-6C)alkylsulfonyl, (1-6C)alkanesulfonylamino, N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and a group of the formula: Q6-X9— wherein X9 is a direct bond or is selected from O, N(R16), SO2 and SO2N(R16), wherein R16 is hydrogen or (1-6C)alkyl, and Q6 is (3-7C)cycloalkyl, (3-7C)cycloalkyl-(1-4C)alkyl, (3-7C)cycloalkenyl, (3-7C)cycloalkenyl-(1-4C)alkyl, heterocyclyl or heterocyclyl-(1-4C)alkyl, provided that when X9 is a direct bond, Q6 is heterocyclyl, and provided that when m, p and q are all 0, then Z is heterocyclyl, and wherein adjacent carbon atoms in any (2-6C)alkylene chain within a Z substituent are optionally separated by the insertion into the chain of a group selected from O, S, SO, SO2, N(R17), CO, —C═C— and —C≡C— wherein R17 is hydrogen or (1-6C)alkyl, and wherein and wherein any CH2 or CH3 group within any Z group, other than a CH2 group within a heterocyclyl ring, optionally bears on each said CH2 or CH3 group one or more halogeno or (1-6C)alkyl substituents or a substituent selected from hydroxy, cyano, amino, carboxy, carbamoyl, sulfamoyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (2-6C)alkanoylamino, N-(1-6C)alkyl-(2-6C)alkanoylamino, N-(1-6C)alkylsulfamoyl, N,N-di-[(1-6C)alkyl]sulfamoyl, (1-6C)alkanesulfonylamino and N-(1-6C)alkyl-(1-6C)alkanesulfonylamino, and wherein any heterocyclyl group within a Z substituent optionally bears one or more (for example 1, 2 or 3) substitutents which may be the same or different, selected from halogeno, trifluoromethyl, cyano, nitro, hydroxy, amino, formyl, mercapto, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylsulfinyl, (1-6C)alkylsulfonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (2-6C)alkanoyl, (2-6C)alkanoyloxy and from a group of the formula: —X10—R18 wherein X10 is a direct bond or is selected from O, CO, SO2 and N(R19), wherein R19 is hydrogen or (1-4C)alkyl, and R18 is halogeno-(1-4C)alkyl, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, cyano-(1-4C)alkyl, amino-(1-4C)alkyl, N-(1-4C)alkylamino-(1-4C)alkyl and N,N-di-[(1-4C)alkyl]amino-(1-4C)alkyl; provided that: when the 4-anilino group in Formula I is 4-bromo-2-fluoroanilino or 4-chloro-2-fluoroanilino and R1 is (1-3C)alkoxy, then a is 0; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. Another embodiment of the present invention is a quinazoline derivative of the Formula Ia as hereinbefore defined, wherein X2 is a group selected from (3-6C)cycloalkylene (such as cyclopropylidene), —CH2—, —CH2CH2—, —CH2CH2CH2— —(CR12R13)—, —CR12R13CH2)— and —(CH2CR12R13)— wherein each of R12 and R13, which may be the same or different, is selected from hydrogen, (1-4C)alkyl, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl, provided that R12 and R13 are not both hydrogen, and wherein any CH2 group within a (3-6C)cycloalkylene group in X2, optionally bears on each said CH2 or group one or more (1-4C)alkyl substituents or a substituent selected from hydroxy, (1-4C)alkoxy, hydroxy-(1-4C)alkyl, and (1-3C)alkoxy-(1-4C)alkyl. Another embodiment of the present invention is a quinazoline derivative of the Formula 1a as hereinbefore defined, wherein X2 is a group selected from cyclopropylidene, —CH2—, —CH2CH2—, —(CR12R13)—, —(CR12R13CH2)— and —(CH2CR12R13)—, wherein each of R12 and R13, which may be the same or different, is selected from hydrogen and (1-4C)alkyl. Another embodiment of the present invention is a quinazoline derivative of the Formula 1a as hereinbefore defined, wherein Z is selected from hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino, di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and 1,4-dioxanyl; or the group Z-X2 is selected from is selected from tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl represented by Z-X2 is linked to the carbonyl group in Formula Ia, by a ring carbon, and wherein any heterocyclyl group within Z-X2 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl. More particularly, in Formula 1a, Z is selected from hydroxy, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, amino, methylamino, ethylamino, N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino, dimethylamino, N-methyl-N-ethylamino, di-ethylamino, N-(2-hydroxyethyl)-N-methylamino, N-(2-hydroxyethyl)-N-ethylamino, N,N-di-(2-hydroxyethyl)amino, N-(2-methoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-ethylamino, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl; or the group Z-X2 is selected from is selected from tetrahydrofuranyl and tetrahydropyranyl, and wherein any heterocyclyl group within Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy. More particularly Z is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy, still more particularly Z is selected from hydroxy and (1-4C)alkoxy (for example Z is hydroxy or methoxy). Preferably Z is hydroxy. Another embodiment of the present invention is a quinazoline derivative of the Formula 1a as hereinbefore defined, wherein: R2a is bromo or chloro (particularly chloro); and b is 0 or 1 and R2 is at the ortho (2-) position and is halogeno (particularly R2 is fluoro); or b is 0 or 1 and R2 is at the para (4-) position and is halogeno (particularly R2 is fluoro) and wherein R1, W, a, X2 and Z have any of the meanings defined hereinabove in relation to the quinazoline derivative of Formula 1a. Another particular embodiment of the invention is a quinazoline derivative of the Formula 1a as hereinbefore defined wherein the anilino group at the 4-position on the quinazoline ring is selected from 3-bromo-2-fluoroanilino, 3-bromoanilino, 3-chloro-4-fluoroanilino and 3-chloro-2-fluoroanilino. Particularly the anilino group is selected from 3-chloro-4-fluoroanilino and 3-chloro-2-fluoroanilino. More particularly the anilino group is 3-chloro-4-fluoroanilino. It is preferred that the anilino group is 3-chloro-2-fluoroanilino. Wherein in this embodiment R1, W, a, X2 and Z have any of the meanings defined hereinabove in relation to the quinazoline derivative of Formula 1a. Another embodiment of the compounds of Formula I is a quinazoline derivative of the Formula Ib: wherein: R1 is selected from hydrogen, (1-6C)alkoxy, cyclopropyl-(1-4C)alkoxy, cyclobutyl-(1-4C)alkoxy, cyclopentyl-(1-4C)alkoxy, cyclohexyl-(1-6C)alkoxy, tetrahydrofuranyl-(1-4C)alkoxy and tetrahydropyranyl-(1-4C)alkoxy, and wherein any CH2 or CH3 group within a R1 substituent optionally bears on each said CH2 or CH3 group one or more halogeno substituents, or a substituent selected from hydroxy and (1-4C)alkoxy; R2b is bromo or chloro (particularly chloro); a is 0, 1 or 2 (particularly a is 0); each W, which may be the same or different, is selected from hydroxy, halogeno (particularly fluoro), (1-4C)alkyl and (1-4C)alkoxy; X2 is selected from a group of the formula —CH2—, —CH2CH2—, —CH2CH2CH2— —(CR12R13)—, —(CR12R13CH2)— and —(CH2CR12R13)— wherein each of R2 and R13, which may be the same or different, is selected from hydrogen and (1-4C)alkyl (particularly X2 is CH2, more particularly X2 is(CHR12a)—, wherein R12a is (1-4C)alkyl); Z is selected from hydroxy, amino, (1-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-4C)alkoxy-(2-6C)alkylamino, di-[(1-6C)alkyl]amino, N-[hydroxy-(2-6C)alkyl]-N-(1-6C)alkylamino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-(1-6C)alkylamino, di-[hydroxy-(2-6C)alkyl]-amino, di-[(1-4C)alkoxy-(2-6C)alkyl]amino, N-[(1-4C)alkoxy-(2-6C)alkyl]-N-[hydroxy-(2-6C)alkyl]-amino, (1-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-4C)alkoxy-(2-6C)alkoxy, azetidin-1-yl, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, homopiperidin-1-yl homopiperazin-1-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and 1,4-dioxanyl; or the group Z-X2 is selected from is selected from tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydropyranyl, 1,4-dioxanyl, oxepanyl, pyrrolidinyl, morpholinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl, which heterocyclyl represented by Z-X2 is linked to the carbonyl group in Formula Ib, by a ring carbon, and wherein any heterocyclyl group within Z-X2 optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. In an embodiment in Formula Ib, Z is selected from hydroxy, methoxy, ethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, amino, methylamino, ethylamino, N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino, dimethylamino, N-methyl-N-ethylamino, di-ethylamino, N-(2-hydroxyethyl)-N-methylamino, N-(2-hydroxyethyl)-N-ethylamino, N,N-di-(2-hydroxyethyl)amino, N-(2-methoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-ethylamino, pyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, tetrahydrofuranyl and tetrahydropyranyl; or the group Z-X2 is selected from is selected from tetrahydrofuranyl and tetrahydropyranyl, and wherein any heterocyclyl group within Z optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-4C)alkyl and (1-4C)alkoxy. In another embodiment in formula Ib, R1 is selected from hydrogen methoxy, ethoxy, propyloxy, isopropyloxy, cyclopropylmethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy (Particularly R1 is selected from hydrogen and (1-3C)alkoxy, more particularly R1 is (1-3C)alkoxy such as methoxy). In another embodiment in Formula Ib, R1 is selected from (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-3C)alkoxy-(2-4C)alkoxy; a is 0; Z is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy, more particularly Z is selected from hydroxy and (1-4C)alkoxy, particularly Z is hydroxy or methoxy (especially hydroxy); and X2 has any of the meanings defined hereinabove in relation to the quinazoline of the Formula 1b. Another embodiment of the compounds of Formula I is a quinazoline derivative of the Formula Ic: wherein: R1a is selected from (1-3C)alkoxy, hydroxy-(2-3C)alkoxy and (1-3C)alkoxy-(2-3C)alkoxy (particularly R1a is methoxy); X2a is selected from a group of the formula —(CHR12a)— and —(CH2CHR12b)—, wherein R12a is (1-4C)alkyl (particularly (1-3C)alkyl, more particularly methyl), and wherein R12b is selected from amino, (1-4C)alkylamino and di-[(1-4C)alkyl]-amino (particularly R12b is selected from (1-3C)alkylamino and di-[(1-3C)alkyl]-amino, more particularly di-[(1-3C)alkyl]-amino, still more particularly R12b is methylamino and especially di methyl amino); Z1 is selected from hydroxy, (1-4C)alkoxy, hydroxy-(2-4C)alkoxy and (1-4C)alkoxy-(2-4C)alkoxy (particularly Z1 is hydroxy or (1-4C)alkoxy, for example hydroxy or methoxy), or the group Z1-X2a is selected from tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl, wherein Z1-X2a is linked to the carbonyl group by a ring carbon atom, and wherein any heterocyclyl group within Z1 optionally bears one or two substituents, which may be the same or different selected from fluoro, chloro, hydroxy, (1-4C)alkyl, (1-4C)alkoxy and (2-4C)alkanoyl; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. In this embodiment, preferably Z1 is selected from hydroxy and (1-4C)alkoxy (particularly Z1 is hydroxy or methoxy, still more particularly Z1 is hydroxy). In this embodiment, preferably X2a is a group of the formula —(CHR12a)—, wherein R12a is (1-4C)alkyl (particularly (1-3C)alkyl, more particularly methyl), Another embodiment of the compounds of Formula I is a quinazoline derivative of the Formula Id: wherein: R1b is (1-4C)alkoxy, and wherein any CH2 or CH3 group within a R1b substituent optionally bears on each said CH2 or CH3 group one or more halogeno substituents, or any CH2 or CH3 group within a R1 which is not attached to an oxygen atom optionally bears on each said CH2 or CH3 group a substituent selected from hydroxy and (1-3C)alkoxy; X2b is selected from a group of the formula —CH2—, —CH2CH2—, —(CHR12)—, —(CHR12CH2)— and —(CH2CHR12)— wherein R12 is selected from (1-3C)alkyl, hydroxy-(1-3C)alkyl and (1-3C)alkoxy-(1-3C)alkyl; and Z2 is selected from hydroxy, (1-3C)alkoxy, hydroxy-(2-3C)alkoxy, (1-3C)alkoxy-(2-3C)alkoxy, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 1,3-dioxolanyl, tetrahydropyranyl and 1,4-dioxanyl; and wherein any heterocyclyl group within Z2-X2b optionally bears 1 or 2 substituents, which may be the same or different, selected from fluoro, chloro, hydroxy, (1-3C)alkyl, (1-3C)alkoxy and (2-3C)alkanoyl; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof. In an embodiment in formula Id, R1b is selected from methoxy, ethoxy, 2-hydroxyethoxy, 2-fluoroethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy (Particularly R1b is (1-3C)alkoxy such as methoxy). In another embodiment in formula Id, X2b is selected from a group of the formula —CH2—, —CH2CH2— and —(CHR12)—, wherein R12 is selected from (1-3C)alkyl, hydroxy-(1-3C)alkyl and (1-3C)alkoxy-(1-3C)alkyl (for example R12 is methyl). In another embodiment in formula Id, X2b is selected from a group of the formula —CH2— and —(CHR12)—, wherein R2 is (1-3C)alkyl (for example methyl). For example X2b is selected from —CH2— and —CH(CH3)—, particularly X2b is —CH(CH3)—. In another embodiment in formula Id, Z2 is selected from hydroxy and (1-3C)alkoxy (especially hydroxy). In another embodiment in formula Id, the group Z2-X2b— is selected from hydroxymethyl, methoxymethyl, (S)-1-hydroxyethyl, (R)-1-hydroxyethyl, (S)-1-methoxyethyl, (R)-1-methoxyethyl. Particularly the group Z2-X2b— is 1-hydroxyethyl, more particularly (S)-1-hydroxyethyl or (R)-1-hydroxyethyl. In another embodiment in formula Id R1b is (1-3C)alkoxy such as methoxy; and the group Z2-X2b— is selected from hydroxymethyl, methoxymethyl, (S)-1-hydroxyethyl, (R)-1-hydroxyethyl, (S)-1-methoxyethyl, (R)-1-methoxyethyl. Particularly in this embodiment Z2-X2b is 1-hydroxyethyl, more particularly (S)-1-hydroxyethyl or (R)-1-hydroxyethyl. A particular compound of the invention is, for example, a quinazoline derivative of the Formula I selected from: N-(3-chloro-2-fluorophenyl)-7-({1-[(dimethylamino)acetyl]piperidin4-yl}oxy)-6-methoxyquinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methoxyacetyl)piperidin-4-yl]oxy}quinazolin-4-amine; 2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol; N-(3-chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(3-methoxypropanoyl)piperidin-4-yl]oxy}quinazolin-4-amine; 3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol; (2S)-1-[4-({4-[3chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; (2S,3S)-1-[4-({4-[3chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-methyl-1-oxopentan-2-ol; 4-[4-({4-[3chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-methyl-4-oxobutan-2-ol; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]oxy}quinazolin-4-amine; 3-[4-({4-[3chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-ol; (3R,5S)-1-acetyl-5-{[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]carbonyl}pyrrolidin-3-ol; and N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(4-methylpiperazin-1-yl)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine; or a pharmaceutically acceptable salt, or pharmaceutically acceptable ester thereof. Another particular compound of the invention is, for example, a quinazoline derivative of the Formula I selected from: N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-{[1-(methoxyacetyl)piperidin-4-yl]oxy}quinazolin-4-amine; 2-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol; N-(3-chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin-4-yl]oxy}-6-methoxyquinazolin-4-amine; (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; and 3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-ol; (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3,3-dimethyl-1-oxobutan-2-ol; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(1-methyl-L-prolyl)piperidin-4-yl]oxy}quinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)quinazolin-4-amine; (2R)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine; N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine; (2R)-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-(dimethylamino)-3-oxopropan-1-ol; (2S)-1-[4-({4-[(3-chloro-4-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; (2S)-1-[4-({4-[3-bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; (2S)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; (2R)-1-[4-({4-[3-bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; and (2R)-1-[4-({4-[3-bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol; or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof. In a particular embodiment the invention there is provided a quinazoline derivative of the Formula I described herein, or a pharmaceutically acceptable salt thereof. A quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Suitable processes include, for example, those illustrated in WO94/27965, WO 95/03283, WO 96/33977, WO 96/33978, WO 96/33979, WO 96/33980, WO 96/33981, WO 97/30034, WO 97/38994, WO01/66099, U.S. Pat. No. 5,252,586, EP 520 722, EP 566 226, EP 602 851 and EP 635 507. Such processes, when used to prepare a quinazoline derivative of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants in which, unless otherwise stated, R1, R2, X1, X2, Q1, W, a, b and Z have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. Process (a): For the preparation of compounds of the Formula I wherein X1 is CO, the coupling, conveniently in the presence of a suitable base, of a quinazoline of the formula II or a salt thereof: wherein R1, R2, W, a, b and Q1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an acid of the formula III, or a reactive derivative thereof: Z-X2—COOH III wherein Z and X2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (b) the reaction, conveniently in the presence of a suitable base, of a quinazoline of the formula II, or salt thereof, as hereinbefore defined in relation to Process (a), with a compound of the formula IV: Z-X2-X1-L1 IV wherein L1 is a displaceable group and Z, X1 and X2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (c) for the preparation of those quinazoline derivatives of the Formula I wherein Z is linked to X2 by nitrogen, the reaction, conveniently in the presence of a suitable base, of a compound of the formula V: wherein L2 is a displaceable group and R1, R2, W, X1, X2, a, b and Q1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the formula ZH, wherein Z is as hereinbefore defined, except that any functional group is protected if necessary; or Process (d) for the preparation of those quinazoline derivatives which carry a mono- or di-(1-6C)alkylamino group, the reductive amination of the corresponding quinazoline derivative of the Formula I which contains an N—H group using formaldehyde or a (2-6C)alkanolaldehyde (for example acetaldehyde or propionaldehyde); or Process (e) for the production of those quinazoline derivatives of the Formula I wherein R1 is hydroxy, the cleavage of a quinazoline derivative of the Formula I wherein R1 is a (1-6C)alkoxy group; or Process (f) for the production of those quinazoline derivatives of the Formula I wherein R1 is linked to the quinazoline ring by an oxygen atom, by coupling a compound of the Formula VI: wherein R2, W, X1, X2, Z, a, b and Q1 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a compound of the formula R1′OH, wherein the group R1′O is one of the oxygen linked groups as hereinbefore defined for R1 (for example R1′ is (1-6C)alkoxy or Q2-O—), except that any functional group is protected if necessary; and thereafter, if necessary (in any order): (i) converting a quinazoline derivative of the Formula I into another quinazoline derivative of the Formula I; (ii) removing any protecting group that is present by conventional means; and (iii) forming a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester. Specific conditions for the above reactions are as follows: Conditions for Process (a) The coupling reaction is conveniently carried out in the presence of a suitable coupling agent, such as a carbodiimide, or a suitable peptide coupling agent, such as a uronium coupling agent, for example O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (HATU) or O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium tetrafluoroborate (TBTU); or a carbodiimide such as dicyclohexylcarbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-pyrrolidinopyridine. The coupling reaction is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di-isopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate, cesium carbonate or calcium carbonate. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ester such as or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, from 0 to 120° C., conveniently at or near ambient temperature. By the term “reactive derivative” of the acid of the formula III is meant a carboxylic acid derivative that will react with the quinazoline of formula II to give the corresponding amide. A suitable reactive derivative of a carboxylic acid of the formula III is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a chloroformate such as isobutyl chloroformate; an active ester, for example an ester formed by the reaction of the acid and a phenol such as pentafluorophenol, or N-hydroxybenzotriazole; or an acyl azide, for example an azide formed by the reaction of the acid and azide such as diphenylphosphoryl azide; an acyl cyanide, for example a cyanide formed by the reaction of an acid and a cyanide such as diethylphosphoryl cyanide. The reaction of such reactive derivatives of carboxylic acid with amines (such as a compound of the formula II) is well known in the art, for Example they may be reacted in the presence of a base, such as those described above, and in a suitable solvent, such as those described above. The reaction may conveniently be performed at a temperature as described above. Preparation of Starting Materials for Process (a) The quinazoline of the formula II may be obtained by conventional procedures, for example as illustrated in Reaction Scheme 1: wherein R1, R2, Q1, W, a and b are as hereinbefore defined, except any functional group is protected if necessary, and whereafter any protecting group that is present is removed by conventional means, Pg is a suitable hydroxy protecting group, Pg1 is a suitable amino protecting group and L3 is a displaceable group. Conditions in Reaction Scheme 1 Step(i): Suitable hydroxy protecting groups represented by Pg are well known in the art and include those mentioned herein, for example a lower alkanoyl group such as acetyl, or a benzyl group. A suitable displaceable group L3 is, for example, a halogeno (particularly chloro), alkoxy, aryloxy, mercapto, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, alkylsulfonyloxy or arylsulfonyloxy group, for example a chloro, bromo, methoxy, phenoxy, pentafluorophenoxy, methylthio, methanesulfonyl, methanesulfonyloxy or toluene-4-sulfonyloxy group. A particular displaceable group L3 is chloro. The reaction is conveniently carried out in the presence of an acid. Suitable acids include, for example hydrogen chloride gas (conveniently dissolved in a suitable solvent such as diethyl ether or dioxane) or hydrochloric acid. Alternatively the quinazoline derivative of the formula IIa, wherein L3 is halogeno (for example chloro), may be reacted with the aniline in the absence of an acid or a base. In this reaction displacement of the halogeno leaving group L3 results in the formation of the acid HL3 in-situ and the autocatalysis of the reaction. Alternatively, the reaction of the quinazoline of formula IIa with the aniline may be carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di-isopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, an alkali or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate, cesium carbonate or calcium carbonate, or an alkali metal hydride, for example sodium hydride, an alkali metal fluoride such as cesium fluoride, or an alkali metal disilazide such as sodium hexamethyldisilazide. The above reactions are conveniently carried out in the presence of a suitable inert solvent or diluent, for example an alcohol or ester such as methanol, ethanol, isopropanol or ethyl acetate, a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxan, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide or acetonitrile. The above reactions are conveniently carried out at a temperature in the range, for example, 0 to 250° C., conveniently in the range 40 to 80° C. or, preferably, at or near the reflux temperature of the solvent when used. The aniline and the compound of the formula IIa are commercially available or can be prepared using conventional methods. Step (ii): Deprotection using well-known methods. For example when Pg is a benzyl group it may be removed by treating the compound of formula IIb with a suitable acid such as trifluoroacetic acid. Alternatively a benzyl protecting group may be removed by metal-catalysed hydrogenation, for example by hydrogenation in the presence of a palladium on carbon catalyst. Similarly, when Pg is a lower alkanoyl group such as acetyl it may be removed by hydrolysis under basic conditions, for example using ammonia, conveniently as a methanolic ammonia solution. Step (iiia): Suitable amino protecting groups Pg2 are well known, for example tert-butoxycarbonyl (BOC) groups. L4 is a suitable displaceable group, for example as described above in relation to L2, such as halogeno (particularly chloro or bromo), or an alkylsulfonyloxy (particularly methanesulfonyloxy) or arylsulfonyloxy (particularly toluene-4-sulfonyloxy or 4-nitrophenylsulfonyloxy) group. The reaction of the compound of formula IIc with the compound of formula IId is conveniently carried out in the presence of a suitable base. Suitable bases include those described above in relation to step (i), such as cesium fluoride or potassium carbonate. The reaction is conveniently carried out in the presence of a suitable inert solvent, for example, a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide or acetonitrile. The above reaction is conveniently carried out at a temperature in the range, for example, 0 to 250° C., conveniently in the range 40 to 80° C. or, preferably, at or near the reflux temperature of the solvent when used. Step (iiib): An alternative to step (iiia) is the coupling of the compound of formula IIc with the alcohol of the formula IIe using the Mitsunobu coupling reaction. Suitable Mitsunobu conditions are well known and include, for example, reaction in the presence of a suitable tertiary phosphine and a di-alkylazodicarboxylate in an organic solvent such as THF, or suitably dichloromethane and in the temperature range 0° C. to 100° C., for example 0° C. to 60° C., but suitably at or near ambient temperature. A suitable tertiary phosphine includes for example tri-n-butylphosphine or particularly tri-phenylphosphine. A suitable di-alkylazodicarboxylate includes, for example, diethyl azodicarboxylate (DEAD) or suitably di-tert-butyl azodicarboxylate (DTAD). Details of Mitsunobu reactions are contained in Tet. Letts., 31, 699, (1990); The Mitsunobu Reaction, D. L. Hughes, Organic Reactions, 1992, Vol. 42, 335-656 and Progress in the Mitsunobu Reaction, D. L. Hughes, Organic Preparations and Procedures International, 1996, Vol. 28, 127-164. The compounds of the formulae IId and IIe are commercially available or can be prepared using conventional methods. Step (iv): Removal of the amino protecting group Pg1 using well known methods. For example when Pg1 is a BOC group, by treatment with a suitable acid such as trifluoroacetic acid or hydrochloric acid. In an alternative route to that shown in Reaction Scheme 1, the aniline in step (i) may be reacted with the unprotected variant of the compound of the formula IIa (i.e. Pg is hydrogen), to give the compound of formula IIc directly. The compound of formula II may also be prepared according to Reaction Scheme 2: wherein R1, R2, Q1, W, a, b, L3 and Pg1 are as hereinbefore defined, except any functional group is protected if necessary, and whereafter any protecting group that is present is removed by conventional means. Conditions in Reaction Scheme 2 Step (i): Coupling under Mitsunobu conditions as described above in relation to step (iiib) in Reaction Scheme 1. Step (ii): The reaction is conveniently carried out in the presence of an acid. Suitable acids include, for example hydrogen chloride gas (conveniently dissolved in a suitable solvent such as diethyl ether or dioxane) or hydrochloric acid. The reaction is conveniently carried out in a suitable inert solvent, for example as described in step (i) of Reaction Scheme 1. Conveniently, the protecting group Pg1 is removed in-situ as a result of the acidic conditions during the aniline coupling reaction, for example when Pg1 is tert-butoxycarbonyl. Alternatively, the protecting group may be removed using conventional methods following the reaction. The quinazoline of the formula IIg is commercially available or can be prepared using conventional methods. Quinazoline derivatives of the Formula II wherein R1 is heterocyclyl-(2-6C)alkoxy, wherein the heterocyclyl group is nitrogen linked to the (2-6C)alkoxy group may be prepared according to Reaction Scheme 3: wherein R1, R2, Q1, W, X2, L1, L2, a, b and Pg1 are as hereinbefore defined, except any functional group is protected if necessary, X3′ is (2-6C)-alkylene and Q2 is a heterocyclyl group containing an NH ring group, and whereafter any protecting group that is present is removed by conventional means. Step (i): L1 and L2 are displaceable groups as defined in relation to Process (b), for example halogeno such as chloro. The reaction with the compound of Formula IIj may be carried out under analogous conditions to those used in Process (b) described herein. The compound of Formula IIj may be prepared using standard methods, for example as described in WO03/082831 to give a compound of the Formula IIj carrying a 2,3-di-haloanilines. Analogous methods may be used to prepare compounds of the Formula IIj by coupling 4-chloro-6-hydroxy-7-methoxyquinazoline with the appropriate aniline. Step (ii): Analogous conditions to Process (b) described herein. Step (iii): Cleavage of the methoxy group under standard conditions for such reactions, for example by treatment of the compound of Formula IIm with pyridinium hydrochloride at elevated temperature, for example from 60 to 180° C. conveniently about 170° C. Step(iv): Coupling under Mitsunobu conditions as described above in relation to step (iiib) in Reaction Scheme 1. Step (v): Deprotection to remove the amine protecting group Pg1, for example when Pg1 is tert-butoxycarbonyl, by treating the compound of Formula (IIo) with a suitable acid such a trifluoroacetic acid. Reaction Conditions for Process (b) A suitable displaceable group L1 includes for example halogeno such as chloro. The reaction is conveniently performed in the presence of a suitable base, for example, conveniently in the presence of a suitable base, for example an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, di-isopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, or an alkali metal hydride, for example sodium hydride, or an alkali metal disilazide such as sodium hexamethyldisilazide. The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is suitably carried out at a temperature of from 0° C. to 30° C., conveniently at ambient temperature. When Z is hydroxy, the hydroxy group is conveniently protected during the reaction with the compound of Formula II. Suitable protecting groups are well known, for example an alkanoyl group such as acetyl. The protecting group may be removed following reaction with the compound of Formula II by conventional means, for example alkaline hydrolysis in the presence of a suitable base such as sodium hydroxide. Compounds of the formula IV are commercially available compounds or they are known in the literature, or they can be can be prepared by standard processes known in the art. Reaction Conditions for Process (c): A suitable displaceable group represented by L2 includes, for example a halogeno or a sulfonyloxy group, for example chloro, bromo, methylsulfonyloxy or toluene4-sulfonyloxy group. A particular group L2 is chloro. The reaction is conveniently performed in the presence of a suitable base, for example one of the bases described in relation to Process (b). The reaction is conveniently carried out in the presence of a suitable inert solvent or diluent, for example a halogenated solvent such as methylene chloride, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an ester such as ethyl acetate, an aromatic solvent such as toluene, or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is suitably carried out at a temperature of from 0° C. to 80° C., conveniently at ambient temperature. Preparation of Starting Materials for Process (c) The compound of formula V used as starting material may be prepared by, for example, reacting, conveniently in the presence of a suitable base, a quinazoline of the formula II, or salt thereof, as hereinbefore defined in relation to Process (a), with a compound of the formula Va: L2-X2-X1-L5 Va wherein X1 and X2 are as hereinbefore defined, and L2 and L5 are suitable displaceable groups, provided that L5 is more labile than L2. Suitable displaceable groups represented by L2 and L5 include for example halogeno such as chloro. The reaction is conveniently carried out in the presence of a suitable base and in a suitable inert solvent or diluent as defined above for the reaction of the quinazoline of formula V with the compound of the formula ZH. The compounds of the formulae ZH and Va are commercially available compounds or they are known in the literature, or they can be can be prepared by standard processes known in the art. Conveniently, in an embodiment of Process (c), a quinazoline of Formula I may be prepared directly from a quinazoline of formula II by reacting the quinazoline of formula II with a compound of formula Va and then reacting the resultant product directly with the compound of the formula ZH without isolating the compound of formula V. This reaction enables the quinazoline of Formula I to be prepared in a single reaction vessel starting with the quinazoline of formula H. Reaction Conditions for Process (d) Process (d) may be used to alkylate an NH group in a quinazoline derivative of Formula I, for example when Z is amino or (1-6C)alkylamino, or when the group Z-X2 carries an amino or (1-6C)alkylamino substituent. Suitable reductive amination conditions are well known in the art. For example, for the production of those quinazoline derivatives of the Formula I which contain an N-methyl group, the corresponding compound containing a N—H group may be reacted with formaldehyde in the presence of a suitable reducing agent. A suitable reducing agent is, for example, a hydride reducing agent, for example formic acid, an alkali metal aluminium hydride such as lithium aluminium hydride, or, suitably, an alkali metal borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triethylborohydride, sodium trimethoxyborohydride and sodium triacetoxyborohydride. The reaction is conveniently performed in a suitable inert solvent or diluent, for example tetrahydrofuran and diethyl ether for the more powerful reducing agents such as lithium aluminium hydride, and, for example, methylene chloride or a protic solvent such as methanol and ethanol for the less powerful reducing agents such as sodium triacetoxyborohydride and sodium cyanoborohydride. The reaction is suitably performed under acidic conditions in the presence of a suitable acid such as hydrogen chloride or acetic acid, a buffer may also be used to maintain pH at the desired level during the reaction. When the reducing agent is formic acid the reaction is conveniently carried out using an aqueous solution of the formic acid. The reaction is performed at a temperature in the range, for example, −10 to 100° C., such as 0 to 50° C., conveniently, at or near ambient temperature. Quinazoline derivatives of the Formula I which contain an NH group (for example when Z is amino or (1-6C)alkylamino) may be prepared using one of the processes described hereinbefore. For example by coupling a compound of the Formula II with a suitable, optionally protected, amino acid using Process (a) followed by removal of any protecting groups. Reaction Conditions for Process (e) The cleavage reaction may conveniently be carried out by any of the many procedures known for such a transformation. A particularly suitable cleavage reaction is the treatment of a quinazoline derivative of the Formula I wherein R1 is a (1-6C)alkoxy group with an alkali metal halide such as lithium iodide in the presence of 2,4,6-collidine (2,4,6-trimethylpyridine). We have found that the use of 2,4,6-collidine provides selective cleavage of the (1-6C)alkoxy group at the C6 position on the quinazoline ring. The reaction may be carried out in the presence of a suitable inert solvent or diluent as defined hereinbefore. Conveniently however the reaction may be performed using only the 2,4,6-collidine without the need for additional solvents/diluents. The reaction is suitably carried out at a temperature in the range, for example, 10 to 170° C., preferably at elevated temperature for example 120 to 170° C., for example approximately 130° C. Reaction Conditions for Process (f) The coupling reaction is conveniently carried out under Mitsunobu conditions as described above in relation to step (iiib) in Reaction Scheme 1. Preparation of Starting Materials for Process (f) The compound of Formula VI used as starting material may be prepared by, for example, the cleavage of a quinazoline derivative of the Formula I, wherein R1 is, for example, methoxy using Process (e) described hereinbefore. Alternatively, compound of Formula VI may be prepared using conventional procedures. For example, when X1 is CO, a compound of the Formula VI may be prepared using the method illustrated in Reaction Scheme 4: wherein R1, R2, Q1, W, X2, a, b, Pg and Pg1 are as hereinbefore defined, except any functional group is protected if necessary, and whereafter any protecting group that is present is removed by conventional means. Conditions in Reaction Scheme 4 Step (i): Cleavage of methoxy group under analogous conditions to those described in step (iii) in Reaction Scheme 3. Step (ii) Pg is a suitable hydroxy protecting group as hereinbefore defined, for example an alkanoyl such as acetyl. The group Pg may be introduced under standard conditions for example by reacting the compound of Formula VIb with acetic anhydride. Step (iii) Coupling under Mitsunobu conditions as described above in relation to step (iiib) in Reaction Scheme 1. Step (iv): Deprotection to remove the protecting group Pg. For example when Pg is acetyl by alkaline hydrolysis in an alcohol, for example using a methanolic ammonia solution. Step (v): Deprotection to remove the amine protecting group Pg1, for example when Pg1 is tert-butoxycarbonyl, by treating the compound of Formula (VId) with a suitable acid such a trifluoroacetic acid. Step (vi): Coupling with acid Z-X2—COOH using the method described above for Process (a). The quinazoline derivative of the Formula I may be obtained from the above processes in the form of the free base or alternatively it may be obtained in the form of a salt, an acid addition salt. When it is desired to obtain the free base from a salt of the compound of Formula I, the salt may be treated with a suitable base, for example, an alkali or alkaline earth metal carbonate or hydroxide, for example sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide, or by treatment with ammonia for example using a methanolic ammonia solution such as 7N ammonia in methanol. The protecting groups used in the processes above may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. Specific examples of protecting groups are given below for the sake of convenience, in which “lower”, as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention. A carboxy protecting group may be the residue of an ester-forming aliphatic or arylaliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (1-12C)alkyl groups (for example isopropyl, and tert-butyl); lower alkoxy-lower alkyl groups (for example methoxymethyl, ethoxymethyl and isobutoxymethyl); lower acyloxy-lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl and pivaloyloxymethyl); lower alkoxycarbonyloxy-lower alkyl groups (for example 1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl); aryl-lower alkyl groups (for example benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and tert-butyldimethylsilyl); tri(lower alkyl)silyl-lower alkyl groups (for example trimethylsilylethyl); and (2-6C)alkenyl groups (for example allyl). Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed cleavage. Examples of hydroxy protecting groups include lower alkyl groups (for example tert-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (for example trimethylsilyl and tert-butyldimethylsilyl) and aryl-lower alkyl (for example benzyl) groups. Examples of amino protecting groups include formyl, aryl-lower alkyl groups (for example benzyl and substituted benzyl, 4-methoxybenzyl, 2-nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-4-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example tert-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); aryl-lower alkoxycarbonyl groups (for example benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl); lower alkanoyloxyalkyl groups (for example pivaloyloxymethyl); trialkylsilyl (for example trimethylsilyl and tert-butyldimethylsilyl); alkylidene (for example methylidene) and benzylidene and substituted benzylidene groups. Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis for groups such as 2-nitrobenzyloxycarbonyl, hydrogenation for groups such as benzyl and photolytically for groups such as 2-nitrobenzyloxycarbonyl. For example a tert butoxycarbonyl protecting group may be removed from an amino group by an acid catalysed hydrolysis using trifluoroacetic acid. The reader is referred to Advanced Organic Chemistry, 4th Edition, by J. March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents and to Protective Groups in Organic Synthesis, 2nd Edition, by T. Green et al., also published by John Wiley & Son, for general guidance on protecting groups. It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. When a pharmaceutically acceptable salt of a quinazoline derivative of the Formula I is required, for example an acid-addition salt, it may be obtained by, for example, reaction of said quinazoline derivative with a suitable acid using a conventional procedure. When a pharmaceutically acceptable ester of a quinazoline derivative of the Formula I is required, it may be obtained by, for example, reaction of said quinazoline derivative with a suitable acid or alcohol using a conventional procedure as herein described in relation to definition of pharmaceutically acceptable esters. As mentioned hereinbefore some of the compounds according to the present invention may contain one of more chiral centers and may therefore exist as stereoisomers (for example when Q1 is piperidin-3-yl). Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The enantiomers may be isolated by separation of a racemate for example by fractional crystallisation, resolution or HPLC. The diastereoisomers may be isolated by separation by virtue of the different physical properties of the diastereoisomers, for example, by fractional crystallisation, HPLC or flash chromatography. Alternatively particular stereoisomers may be made by chiral synthesis from chiral starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, with a chiral reagent. When a specific stereoisomer is isolated it is suitably isolated substantially free for other stereoisomers, for example containing less than 20%, particularly less than 10% and more particularly less than 5% by weight of other stereoisomers. In the section above relating to the preparation of the quinazoline derivative of Formula I, the expression “inert solvent” refers to a solvent which does not react with the starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product. Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative and in some occasions, more convenient manner, the individual process steps mentioned hereinbefore may be performed in different order, and/or the individual reactions may be performed at different stage in the overall route (i.e. chemical transformations may be performed upon different intermediates to those associated hereinbefore with a particular reaction). Certain intermediates used in the processes described above are novel and form a further feature of the present invention. According to a further aspect of the present invention there is provided a quinazoline derivative of the Formula II as hereinbefore defined wherein a is 2 and each R2, which may be the same or different, is halogeno (particularly selected from fluoro and chloro) and wherein the R2 groups are located at the ortho (2-) and meta (3-) positions on the aniline ring; or a salt thereof. A particular compound of the Formula II is a compound of the Formula II wherein the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino, more particularly the anilino group is 3-chloro-2-fluoroanilino. In an embodiment in the compound of Formula II, or a salt thereof, R1 is (1-4C)alkoxy; a is 0 or 1; W, when present is on a ring carbon atom in Q1 and is selected from (1-4C)alkyl, hydroxy and (1-4C)alkoxy (preferably W is 0); Q1 is piperidin-4-yl and the anilino group is 3-chloro-2-fluoroanilino or 3-bromo-2-fluoroanilino, more particularly the anilino group is 3-chloro-2-fluoroanilino. The intermediate of Formula II may be in the form of a salt of the intermediate. Such salts need not be a pharmaceutically acceptable salt. For example it may be useful to form prepare an intermediate in the form of a pharmaceutically non-acceptable salt if, for example, such salts are useful in the manufacture of a compound of Formula I. Preferably, salts of the compound of Formula II are pharmaceutically acceptable salts as hereinbefore defined in relation to the quinazoline derivative of Formula I. Biological Assays The inhibitory activities of compounds were assessed in non-cell based protein tyrosine kinase assays as well as in cell based proliferation assays before their in vivo activity was assessed in Xenograft studies. a) Protein Tyrosine Kinase Phosphorylation Assays This test measures the ability of a test compound to inhibit the phosphorylation of a tyrosine containing polypeptide substrate by EGFR, erbB2 or erbB4 tyrosine kinase enzyme. Recombinant intracellular fragments of EGFR, erbB2 and erbB4 (accession numbers X00588, X03363 and L07868 respectively) were cloned and expressed in the baculovirus/Sf21 system. Lysates were prepared from these cells by treatment with ice-cold lysis buffer (20 mM N-2-hydroxyethylpiperizine-N′-2-ethanesulfonic acid (HEPES) pH 7.5, 150 mM NaCl, 10% glycerol, 1% Triton X-100, 1.5 mM MgCl2, 1 mM ethylene glycol-bis(β-aminoethyl ether) N′,N′,N′,N′-tetraacetic acid (EGTA), plus protease inhibitors and then cleared by centrifugation. Constitutive kinase activity of these recombinant proteins was determined by their ability to phosphorylate a synthetic peptide (made up of a random co-polymer of Glutamic Acid, Alanine and Tyrosine in the ratio of 6:3:1). Specifically, Maxisorb™ 96-well immunoplates were coated with synthetic peptide (0.2 μg of peptide in a 200 μl phosphate buffered saline (PBS) solution and incubated at 4° C. overnight). Plates were washed in 50 mM HEPES pH 7.4 at room temperature to remove any excess unbound synthetic peptide. EGFR or erbB2 activities were assessed by incubation in peptide coated plates for 20 minutes at room temperature in 100 mM HEPES pH 7.4 at room temperature, adenosine trisphosphate (ATP) at Km concentration for the respective enzyme, 10 mM MnCl2, 0.1 mM Na3VO4, 0.2 mM DL-dithiothreitol (DTT), 0.1% Triton X-100 with test compound in DMSO (final concentration of 2.5%). Reactions were terminated by the removal of the liquid components of the assay followed by washing of the plates with PBS-T (phosphate buffered saline with 0.5% Tween 20). The immobilised phospho-peptide product of the reaction was detected by immunological methods. Firstly, plates were incubated for 90 minutes at room temperature with anti-phosphotyrosine primary antibodies that were raised in the mouse (4G10 from Upstate Biotechnology). Following extensive washing, plates were treated with Horseradish Peroxidase (HRP) conjugated sheep anti-mouse secondary antibody (NXA931 from Amersham) for 60 minutes at room temperature. After further washing, HRP activity in each well of the plate was measured colorimetrically using 22′-Azino-di-[3-ethylbenzthiazoline sulfonate (6)] diammonium salt crystals (ABTS™ from Roche) as a substrate. Quantification of colour development and thus enzyme activity was achieved by the measurement of absorbance at 405 nm on a Molecular Devices ThermoMax microplate reader. Kinase inhibition for a given compound was expressed as an IC50 value. This was determined by calculation of the concentration of compound that was required to give 50% inhibition of phosphorylation in this assay. The range of phosphorylation was calculated from the positive (vehicle plus ATP) and negative (vehicle minus ATP) control values. b) EGFR Driven KB Cell Proliferation Assay This assay measures the ability of a test compound to inhibit the proliferation of KB cells (human naso-pharangeal carcinoma obtained from the American Type Culture Collection (ATCC)). KB cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% foetal calf serum, 2 mM glutamine and non-essential amino acids at 37° C. in a 7.5% CO2 air incubator. Cells were harvested from the stock flasks using Trypsin/ethylaminediaminetetraacetic acid (EDTA). Cell density was measured using a haemocytometer and viability was calculated using trypan blue solution before being seeded at a density of 1.25×103 cells per well of a 96 well plate in DMEM containing 2.5% charcoal stripped serum, 1 mM glutamine and non-essential amino acids at 37° C. in 7.5% CO2 and allowed to settle for 4 hours. Following adhesion to the plate, the cells are treated with or without EGF (final concentration of 1 ng/ml) and with or without compound at a range of concentrations in dimethylsulfoxide (DMSO) (0.1% final) before incubation for 4 days. Following the incubation period, cell numbers were determined by addition of 50 μl of 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (stock 5 mg/ml) for 2 hours. MTT solution was then tipped off, the plate gently tapped dry and the cells dissolved upon the addition of 100 μl of DMSO. Absorbance of the solubilised cells was read at 540 nm using a Molecular Devices ThermoMax microplate reader. Inhibition of proliferation was expressed as an IC50 value. This was determined by calculation of the concentration of compound that was required to give 50% inhibition of proliferation. The range of proliferation was calculated from the positive (vehicle plus EGF) and negative (vehicle minus EGF) control values. c) Clone 24 phospho-erbB2 Cell Assay This immunofluorescence end point assay measures the ability of a test compound to inhibit the phosphorylation of erbB2 in a MCF7 (breast carcinoma) derived cell line which was generated by transfecting MCF7 cells with the full length erbB2 gene using standard methods to give a cell line that overexpresses full length wild type erbB2 protein (hereinafter ‘Clone 24’ cells). Clone 24 cells were cultured in Growth Medium (phenol red free Dulbecco's modified Eagle's medium (DMEM) containing 10% foetal bovine serum, 2 mM glutamine and 1.2 mg/ml G418) in a 7.5% CO2 air incubator at 37° C. Cells were harvested from T75 stock flasks by washing once in PBS (phosphate buffered saline, pH 7.4, Gibco No. 10010-015) and harvested using 2 mls of Trypsin (1.25 mg/ml)/ethylaminediaminetetraacetic acid (EDTA) (0.8 mg/ml) solution. The cells were resuspended in Growth Medium. Cell density was measured using a haemocytometer and viability was calculated using Trypan Blue solution before being further diluted in Growth Medium and seeded at a density of 1×104 cells per well (in 100 ul) into clear bottomed 96 well plates (Packard, No. 6005182). 3 days later, Growth Medium was removed from the wells and replaced with 100 ul Assay Medium (phenol red free DMEM, 2 mM glutamine, 1.2 mg/ml G418) either with or without erbB inhibitor compound. Plates were returned to the incubator for 4 hrs and then 20 μl of 20% formaldehyde solution in PBS was added to each well and the plate was left at room temperature for 30 minutes. This fixative solution was removed with a multichannel pipette, 100 μl of PBS was added to each well and then removed with a multichannel pipette and then 50 μl PBS was added to each well. Plates were then sealed and stored for up to 2 weeks at 4° C. Immunostaining was performed at room temperature. Wells were washed once with 200 μl PBS/Tween 20 (made by adding 1 sachet of PBS/Tween dry powder (Sigma, No. P3563) to 1 L of double distilled H2O) using a plate washer then 200 μl Blocking Solution (5% Marvel dried skimmed milk (Nestle) in PBS/Tween 20) was added and incubated for 10 minutes. Blocking Solution was removed using a plate washer and 200 μl of 0.5% Triton X-100/PBS was added to permeabalise the cells. After 10 minutes, the plate was washed with 200 μl PBS/Tween 20 and then 200 μl Blocking Solution was added once again and incubated for 15 minutes. Following removal of the Blocking Solution with a plate washer, 30 μl of rabbit polyclonal anti-phospho ErbB2 IgG antibody (epitope phospho-Tyr 1248, SantaCruz, No. SC-12352-R), diluted 1:250 in Blocking Solution, was added to each well and incubated for 2 hours. Then this primary antibody solution was removed from the wells using a plate washer followed by two 200 μl PBS/Tween 20 washes using a plate washer. Then 30 μl of Alexa-Fluor 488 goat anti-rabbit IgG secondary antibody (Molecular Probes, No. A-11008), diluted 1:750 in Blocking Solution, was added to each well. From now onwards, wherever possible, plates were protected from light exposure, at this stage by sealing with black backing tape. The plates were incubated for 45 minutes and then the secondary antibody solution was removed from the wells followed by two 200 ul PBS/Tween 20 washes using a plate washer. Then 100 μl PBS was added to each plate, incubated for 10 minutes and then removed using a plate washer. Then a further 100 μl PBS was added to each plate and then, without prolonged incubation, removed using a plate washer. Then 50 μl of PBS was added to each well and plates were resealed with black backing tape and stored for up to 2 days at 4° C. before analysis. The Fluorescence signal is each well was measured using an Acumen Explorer Instrument (Acumen Bioscience Ltd.), a plate reader that can be used to rapidly quantitate features of images generated by laser-scanning. The instrument was set to measure the number of fluorescent objects above a pre-set threshold value and this provided a measure of the phosphorylation status of erbB2 protein. Fluorescence dose response data obtained with each compound was exported into a suitable software package (such as Origin) to perform curve fitting analysis. Inhibition of erbB2 phosphorylation was expressed as an IC50 value. This was determined by calculation of the concentration of compound that was required to give 50% inhibition of erbB2 phosphorylation signal. d) In vivo Xenograft Assay This assay measures the ability of a test compound to inhibit the growth of a LoVo tumour (colorectal adenocarcinoma obtained from the ATCC) in Female Swiss athymic mice (Alderley Park, nu/nu genotype). Female Swiss athymic (nu/nu genotype) mice were bred and maintained in Alderley Park in negative pressure Isolators (PFI Systems Ltd.). Mice were housed in a barrier facility with 12 hr light/dark cycles and provided with sterilised food and water ad libitum. All procedures were performed on mice of at least 8 weeks of age. LoVo tumour cell (colorectal adenocarcinoma obtained from the ATCC) xenografts were established in the hind flank of donor mice by sub cutaneous injections of 1×107 freshly cultured cells in 100 μl of serum free media per animal. On day 5 post-implant, mice were randomised into groups of 7 prior to the treatment with compound or vehicle control that was administered once daily at 0.1 ml/10 g body weight. Tumour volume was assessed twice weekly by bilateral Vernier calliper measurement, using the formula (length×width)×√(length×width)×(π/6), where length was the longest diameter across the tumour, and width was the corresponding perpendicular. Growth inhibition from start of study was calculated by comparison of the mean changes in tumour volume for the control and treated groups, and statistical significance between the two groups was evaluated using a Students t test. Although the pharmacological properties of the compounds of the Formula I vary with structural change as expected, in general activity possessed by compounds of the Formula I, may be demonstrated at the following concentrations or doses in one or more of the above tests (a), (b), (c) and (d): Test (a): IC50 in the range, for example, 0.001-1 μM; Test (b): IC50 in the range, for example, 0.001-5 μM; Test (c): IC50 in the range, for example, 0.01-5 μM; Test (d): activity in the range, for example, 1-200 mg/kg/day; No physiologically unacceptable toxicity was observed in Test (d) at the effective dose for compounds tested of the present invention. Accordingly no untoward toxicological effects are expected when a compound of Formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore is administered at the dosage ranges defined hereinafter. By way of example, using Test (a) (for the inhibition of EGFR tyrosine kinase protein phosphorylation) and Test (b) (the KB cell assay) described above, representative compounds described in the Examples herein gave the IC50 results shown below in Table A: TABLE A IC50 (nM) Test (a) (Inhibition of EGFR IC50 (nM) Test (b) tyrosine kinase protein (EGFR driven KB cell Compound of Example phosphorylation) proliferation assay) 2 76 112 3 41 55 4[1] 30 37 4[3] 65 84 4[4] 52 109 According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof, as defined hereinbefore in association with a pharmaceutically acceptable diluent or carrier. The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. The size of the dose for therapeutic or prophylactic purposes of a quinazoline derivative of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. In using a quinazoline derivative of the formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration is however preferred, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention. We have found that the compounds of the present invention possess anti-proliferative properties such as anti-cancer properties that are believed to arise from their erbB family receptor tyrosine kinase inhibitory activity, particularly inhibition of the EGF receptor (erbB1) tyrosine kinase. Furthermore, certain of the compounds according to the present invention possess substantially better potency against the EGF receptor tyrosine kinase, than against other tyrosine kinase enzymes, for example erbB2, VEGF or KDR receptor tyrosine kinases. Such compounds possess sufficient potency against the EGF receptor tyrosine kinase that they may be used in an amount sufficient to inhibit EGF receptor tyrosine kinase whilst demonstrating little, or significantly lower, activity against other tyrosine kinase enzymes such as erbB2. Such compounds are likely to be useful for the selective inhibition of EGF receptor tyrosine kinase and are likely to be useful for the effective treatment of, for example EGF driven tumours. Accordingly, the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by erbB receptor tyrosine kinases (especially EGF receptor tyrosine kinase), i.e. the compounds may be used to produce an erbB receptor tyrosine kinase inhibitory effect in a warm-blooded animal in need of such treatment. Thus the compounds of the present invention provide a method for the treatment of malignant cells characterised by inhibition of one or more of the erbB family of receptor tyrosine kinases. Particularly the compounds of the invention may be used to produce an anti-proliferative and/or pro-apoptotic and/or anti-invasive effect mediated alone or in part by the inhibition of erbB receptor tyrosine kinases. Particularly, the compounds of the present invention are expected to be useful in the prevention or treatment of those tumours that are sensitive to inhibition of one or more of the erbB receptor tyrosine kinases, such as EGF and/or erbB2 and/or erbB4 receptor tyrosine kinases (especially EGF receptor tyrosine kinase) that are involved in the signal transduction steps which drive proliferation and survival of these tumour cells. Accordingly the compounds of the present invention are expected to be useful in the treatment of psoriasis, benign prostatic hyperplasia (BPH), atherosclerosis and restenosis and/or cancer by providing an anti-proliferative effect, particularly in the treatment of erbB receptor tyrosine kinase sensitive cancers. Such benign or malignant tumours may affect any tissue and include non-solid tumours such as leukaemia, multiple myeloma or lymphoma, and also solid tumours, for example bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial, gastric, head and neck, hepatic, lung (particularly non-small-cell lung), neuronal, oesophageal, ovarian, pancreatic, prostate, renal, skin, testicular, thyroid, uterine and vulval cancers. According to this aspect of the invention there is provided a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, for use as a medicament. According to a further aspect of the invention there is provided a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, for use in the production of an anti-proliferative effect in a warm-blooded animal such as a human. Thus according to this aspect of the invention there is provided the use of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as a human. According to a further feature of this aspect of the invention there is provided a method for producing an anti-proliferative effect in a warm-blooded animal, such as a human, in need of such treatment which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as hereinbefore defined. According to a further aspect of the invention there is provided the use of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of erbB receptor tyrosine kinases, such as EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinases, that are involved in the signal transduction steps which lead to the proliferation of tumour cells. According to a further feature of this aspect of the invention there is provided a method for the prevention or treatment of those tumours in a warm-blooded animal such as a human which are sensitive to inhibition of one or more of the erbB family of receptor tyrosine kinases, such as EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinases, that are involved in the signal transduction steps which lead to the proliferation and/or survival of tumour cells which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined hereinbefore. According to a further feature of this aspect of the invention there is provided a compound of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, for use in the prevention or treatment of those tumours in a warm-blooded animal such as a human which are sensitive to inhibition of erbB receptor tyrosine kinases, such as EGFR and/or erbB2 and/or erbB4 (especially EGFR) tyrosine kinases, that are involved in the signal transduction steps which lead to the proliferation of tumour cells. According to a further aspect of the invention there is provided the use of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a EGFR and/or erbB2 and/or erbB4 (especially a EGFR) tyrosine kinase inhibitory effect in a warm-blooded animal such as a human. According to a further feature of this aspect of the invention there is provided a method for providing a EGFR and/or an erbB2 and or an erbB4 (especially a EGFR) tyrosine kinase inhibitory effect in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined hereinbefore. According to a further feature of this aspect of the invention there is provided a compound of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, for use in providing a EGFR and/or erbB2 and/or erbB4 (especially a EGFR) tyrosine kinase inhibitory effect in a warm-blooded animal such as a human. According to a further feature of the present invention there is provided the use of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal such as a human. According to a further feature of this aspect of the invention there is provided a method for providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined hereinbefore. According to a further feature of this aspect of the invention there is provided a compound of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, for use in providing a selective EGFR tyrosine kinase inhibitory effect in a warm-blooded animal such as a human. By “a selective EGFR kinase inhibitory effect” is meant that the quinazoline derivative of Formula I is more potent against EGF receptor tyrosine kinase than it is against other kinases. In particular some of the compounds according to the invention are more potent against EGF receptor kinase than it is against other tyrosine kinases such as other erbB receptor tyrosine kinases such erbB2. For example a selective EGFR kinase inhibitor according to the invention is at least 5 times, preferably at least 10 times more potent against EGF receptor tyrosine kinase than it is against erbB2 tyrosine kinase, as determined from the relative IC50 values in suitable assays. For example, by comparing the IC50 value from the KB cell assay (a measure of the EGFR tyrosine kinase inhibitory activity) with the IC50 value from the Clone 24 phospho-erbB2 cell assay (a measure of erb-B2 tyrosine kinase inhibitory activity) for a given test compound as described above. According to a further aspect of the present invention there is provided the use of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of a cancer (for example a cancer selected from leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial, gastric, head and neck, hepatic, lung (particularly non-small-cell lung), neuronal, oesophageal, ovarian, pancreatic, prostate, renal, skin, testicular, thyroid, uterine and vulval cancer) in a warm-blooded animal such as a human. According to a further feature of this aspect of the invention there is provided a method for treating a cancer (for example a cancer selected from leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial, gastric, head and neck, hepatic, lung (particularly non-small-cell lung), neuronal, oesophageal, ovarian, pancreatic, prostate, renal, skin, testicular, thyroid, uterine and vulval cancer) in a warm-blooded animal, such as a human, in need of such treatment, which comprises administering to said animal an effective amount of a quinazoline derivative of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, as defined hereinbefore. According to a further aspect of the invention there is provided a compound of the Formula I, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable ester thereof, for use in the treatment of a cancer (for example selected from leukaemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectal, endometrial, gastric, head and neck, hepatic, lung (particularly non-small-cell lung), neuronal, oesophageal, ovarian, pancreatic, prostate, renal, skin, testicular, thyroid, uterine and vulval cancer) in a warm-blooded animal such as a human. As mentioned above the size of the dose required for the therapeutic or prophlyactic treatment of a particular disease will necessarily be varied depending upon, amongst other things, the host treated, the route of administration and the severity of the illness being treated. The anti-proliferative treatment/tyrosine kinase inhibitory effect/anti-cancer treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents: (i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function); (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbb1 antibody cetuximab [C225]) , farnesyl transferase inhibitors, MEK inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example other inhibitors of the epidermal growth factor family (for example other EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin); (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and WO02/08213; (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. (x) Cell cycle inhibitors including for example CDK inhibitiors (eg flavopiridol) and other inhibitors of cell cycle checkpoints (eg checkpoint kinase); inhibitors of aurora kinase and other kinases involved in mitosis and cytokinesis regulation (eg mitotic kinesins); and histone deacetylase inhibitors Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range. According to this aspect of the invention there is provided a pharmaceutical product comprising a quinazoline derivative of the Formula I as defined hereinbefore and an additional anti-tumour agent as defined hereinbefore for the conjoint treatment of cancer. Although the compounds of the Formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of the erbB receptor tyrosine protein kinases. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. The invention will now be illustrated by the following non limiting examples in which, unless stated otherwise: (i) temperatures are given in degrees Celsius (° C.); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25° C.; (ii) organic solutions were dried over anhydrous magnesium sulfate or sodium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperature of up to 60° C.; (iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; (iv) in general, the course of reactions was followed by TLC and/or analytical LCMS, and reaction times are given for illustration only; (v) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data; (vi) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at the operating frequency of the NMR apparatus used (300 or 400 MHz), using perdeuterio dimethyl sulfoxide (DMSO-d6) as solvent unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad; (viii) chemical symbols have their usual meanings; SI units and symbols are used; (ix) solvent ratios are given in volume:volume (v/v) terms; (x) mass spectra (MS) were run using a Waters or Micromass electrospray LC-MS in positive or negative ion mode; values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is (MH)+; (xi) where a synthesis is described as being analogous to that described in a previous example the amounts used are the millimolar ratio equivalents to those used in the previous example; (xii) where compounds were purified using Mass-Triggered Preparative LCMS the following conditions were used: Column: ThermoHypersil Keystone B-Basic 5 μ21 mm×100 mm Eluant: 7.5 minutes Gradient from 20% to 95% of acetonitrile in water (buffer 2 g/l of (NH4)2CO3, pH 8.9). Flow rate: 25 ml/min; (xiii) melting points (mp) were measured using a Buchi B-545 Automated melting point apparatus; (xiv) unless stated otherwise compounds containing an asymmetrically substituted carbon atom were not resolved; and (xv) the following abbreviations have been used: HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-Tetramethyluronium Hexafluoro-Phosphate; DIPEA: diisopropylethylamine; DMA: N,N-dimethylacetamide; DMF: N,N-dimethylformamide; DCM dichloromethane; DMSO: dimethylsulfoxide EtOAc: ethyl acetate; IPA: isopropyl alcohol; TBTU: O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium tetrafluoroborate; TFA: trifluoroacetic acid; and THF: tetrahydrofuran. EXAMPLE 1 N-(3-Chloro-2-fluorophenyl)-7-({1-[(dimethylamino)acetyl]piperidin-4-yl}oxy)-6-methoxyquinazolin-4-amine N,N-Dimethylaminoacetyl chloride hydrochloride (100 mg) was added portionwise to a stirred solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (250 mg, 0.57 mmol) and diisopropylethylamine (300 μl) in methylene chloride (25 ml) at 0° C. The reaction mixture was allowed to stir for 2 hours to room temperature. The reaction mixture was washed with saturated sodium bicarbonate solution (25 ml), dried (MgSO4), filtered and evaporated. The residues were purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 90/10), followed by methylene chloride/methanol (saturated with ammonia) (90/10). The fractions containing the desired product were combined and evaporated under vacuum to give the title product as a white foam (0.125 g, 45%); 1H NMR Spectrum: (DMSO d6) 1.50-1.65 (m, 1H); 1.65-1.80 (m, 1H); 1.95-2.15 (m, 2H); 2.25 (s, 6H); 3.10-3.50 (m, 4H); 3.75-4.05 (m, 2H); 3.95 (s, 3H); 4.90 (m, 1H); 7.30 (m, 1H); 7.35 (s, 1H); 7.40-7.60 (m, 2H); 7.85 (s, 1H); 8.40 (s, 1H); 9.65 (s, 1H); Mass Spectrum: (M+H)+ 488. The N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride used as starting material was prepared as follows: 4.0 M HCl in Dioxane (4.0 ml) was added to a stirred suspension of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (CAS Registry No162364-72-9, prepared as described in WO98/13354, Example 1) (60 g, 0.2 mol) and 3-chloro-2-fluoroaniline (31.96 g, 0.22 mol) in acetonitrile (1200 ml). The reaction mixture was heated at 80° C. for 1 hour then left to stand overnight. Acetonitrile (500 ml) was added and the resulting precipitate filtered, washed with acetonitrile (3×500 ml) and dried under vacuum to give 7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine hydrochloride as a beige solid (85.45 g, 96%); 1H NMR Spectrum: (DMSO d6) 4.02 (s, 3H), 5.35 (s, 2H), 7.30-7.60 (m, 9H), 7.65 (m, 1H), 8.38 (s, 1H), 8.85 (s, 1H), 11.8 (s, 1H); Mass Spectrum: (M+H)+ 410. A solution of 7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine hydrochloride (85.45 g, 0.192 mol) in trifluoroacetic acid (300 ml) was heated at 80° C. for 1 hour. The reaction mixture was the evaporated to dryness and the residues re-dissolved in methanol (200 ml). This solution was then added dropwise to a stirred aqueous solution of saturated sodium bicarbonate (500 ml). The resulting precipitate was collected by filtration, washed with acetonitrile and dried under vacuum. The resulting solids were then purified by hot (100° C.) trituration with a mixture of butanone (500 ml) and MeOH (100 ml), filtered and dried to 4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-ol as a cream solid (45 g, 73%); 1H NMR Spectrum: (DMSO d6): 3.98 (s, 3H), 7.10 (s, 1H), 7.25-7.30 (m, 1H), 7.40-7.50 (m, 1H), 7.50-7.60 (m, 1H), 7.80 (s, 1H), 8.30 (s, 1H), 9.55 (s, 1H), 10.32 (s, 1H); Mass Spectrum: (M+H)+ 320. 4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-ol (500 mg, 1.565 mmol) was dissolved in DMA (20 ml). tert-Butyl (4-methanesulfonyloxy)piperidine-1-carboxylate (436.6 mg, 1.565 mmol) and cesium fluoride (236.3 mg, 1.565 mmol) were added, and the mixture was heated to 60° C. with stirring. After 18 hours, tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate and cesium fluoride were again added in the same quantities to the reaction mixture and heating was continued at 60° C. for a further 18 hours. The solvent was evaporated, and the residue was partitioned between saturated aqueous sodium bicarbonate solution (50 ml) and EtOAc (2×50 ml). The organics were combined, dried over MgSO4 and evaporated. The resulting product was then purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/EtOAc (100/0 to 0/100). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate as a colourless foam (757 mg, 96%); 1H NMR Spectrum: (DMSO-d6): 1.52 (s, 9H), 1.60-1.80 (m, 2H), 2.02-2.20 (m, 2H), 3.20-3.45 (m, 2H), 3.75-3.92 (m, 2H), 4.05 (s, 3H), 4.95 (m, 1H), 7.32-7.45 (m, 2H), 7.55-7.70 (m, 2H), 7.92 (s, 1H), 8.50 (s, 1H), 9.73 (s, 1H); Mass Spectrum: (M+H)+ 503. Trifluoroacetic acid (50 ml) was added to a solution of tert-butyl 4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate (750 mg, 1.49 mmol) in methylene chloride (1 ml) and triethylsilane (1 ml) and the solution stirred for 1 hour. The reaction mixture was then evaporated under reduced pressure and the residues re-dissolved in EtOAc (5 ml). This solution was then treated with 1M HCl/diethylether (1 ml) followed by more diethylether (50 ml) to give a white precipitate. The resulting solids were collected following centrifugation and dried under vacuum to give N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride as a white solid (750 mg); 1H NMR Spectrum: (DMSO-d6): 2.00-2.20 (m, 2H), 2.25-2.45 (m, 2H), 3.15-3.50 (m, 4H), 4.15 (s, 3H), 5.02 (m, 1H), 7.48 (m, 1H), 7.60-7.85 m, 3H), 8.35 (s, 1H), 8.85 (s, 1H), 9.56 (bs, 2H); Mass Spectrum: (M+H)+ 403. EXAMPLE 2 N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2-methoxyethoxy)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 2-(2-methoxyethoxy)acetyl chloride (0.105 g) were stirred in methylene chloride (9 ml) for 2.5 hours. Methylene chloride (20 ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.110 g); 1H NMR Spectrum: (DMSO d6 373K) 1.73 (m, 2H), 2.02 (m, 2H), 3.29 (s, 3H), 3.42 (m, 2H), 3.51 (t, J=7 Hz, 2H), 3.60 (t, J=9 Hz, 2H), 3.78 (m, 2H), 3.96 (s, 3H), 4.17 (s, 2H), 4.87 (m, 1H), 7.27 (m, 1H), 7.33 (s, 1H), 7.42 (m, 1H), 7.58 (m, 1H), 7.85 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H); Mass Spectrum: (M+H)+ 519; melting point 110 to 111° C. EXAMPLE 3 N-(3-Chloro-2-fluorophenyl)-6methoxy-7-{[1-(methoxyacetyl)piperidin-4-yl]oxy}quinazolin-4-amine HATU (0.24 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (250 mg), diisopropylethylamine (0.37 ml) and methoxyacetic acid (0.054 g) in methylene chloride (9 ml) and the mixture was stirred at room temperature for 2.5 hours. Methylene chloride (20 ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) to give a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.200 g); 1H N Spectrum: (DMSO d6 373K) 1.73 (m, 2H), 2.02 (m, 2H), 3.37 (s, 3H), 3.41 (m, 2H), 3.77 (m, 2H), 3.98 (s, 3H), 4.09 (s, 2H), 4.85 (m, 1H), 7.26 (m, 1H), 7.30 (s, 1H), 7.39 (m, 1H), 7.59 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.34 (br s, 1H); Mass Spectrum: (M+H)+ 475. EXAMPLE 4 Using a similar procedure to that described in Example 3, N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride was coupled with the appropriate carboxylic acid to give the compounds shown in Table I: TABLE 1 No. and Note R [1] hydroxyacetyl [2] ethoxyacetyl [3] 3-methoxypropanoyl [4] 3-hydroxypropanoyl [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] Notes: [1] 2-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol (0.170 g); 1H NMR Spectrum: (DMSO d6 373K) 1.78 (m, 2H), 2.02 (m, 2H), 3.42 (m, 2H), 3.75 (m, 2H), 3.97 (s, 3H), 4.11 (s, 2H), 4.84 (m, 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.40 (m, 1H), 7.50-7.67 (m, 2H), 7.82 (s, 1H), 8.38 (s, 1H), 9.31 (br s, 1H); Mass Spectrum: (M+H)+ 461. [2] N-(3-Chloro-2-fluorophenyl)-7-{[1-(ethoxyacetyl)piperidin4-yl]oxy}-6-methoxyquinazolin-4-amine as a white solid (0.185 g); 1H NMR Spectrum: (DMSO d6 373K) 1.18 (t, J=8 Hz, 3H), 1.74 (m, 2H), 2.03 (m, 2H), 3.41 (m, 2H), 3.52 (q, J=8 Hz, 2H), 3.79 (m, 2H), 3.98 (s, 3H), 4.12 (s, 2H), 4.84 (m, 1H), 7.23 (m, 1H), 7.32 (s, 1H), 7.42 (m, 1H), 7.58 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.30 (br s, 1H); Mass Spectrum: (M+H)+ 489; melting point 160 to 161° C. [3] N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-{[1-(3-methoxypropanoyl)piperidin-4-yl]oxy}quinazolin-4-amine (0.155 g); 1H NMR Spectrum: (DMSO d6 373K) 1.73 (m, 2H), 2.01 (m, 2H), 2.62 (t, J=9 Hz, 2H), 3.28 (s, 3H), 3.41 (m, 2H), 3.60 (t, J=9 Hz, 2H), 3.79 (m, 2H), 3.97 (s, 3H), 4.82 (m, 1H), 7.24 (m, 1H), 7.30 (s, 1H), 7.40 (m, 1H), 7.58 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.30 (br s, 1H); Mass Spectrum: (M+H)+ 489; melting point 184 to 185° C. [4] 3-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol (0.061 g); 1H NMR Spectrum: (DMSO d6 373K) 1.72 (m, 2H), 2.01 (m, 2H), 2.62 (t, J=8 Hz, 2H), 3.40 (m, 2H), 3.71 (m, 2H), 3.80 (m, 2H), 3.96 (s, 3H), 4.13 (t, J=5 Hz, 1H), 4.83 (m, 1H), 7.28 (m, 1H), 7.31 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H); Mass Spectrum: (M+H)+ 475; melting point 128 to 132° C. [5] Following the coupling reaction between (2S)-2-hydroxypropanoic acid and N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride the product was purified by flash column chromatography eluting with methylene chloride/7N ammonia solution in methanol (98.6/1.4) to give a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol as an amorphous white solid (0.092 g) (melting point 107 to 111° C). Recrystallisation from acetonitrile gave a crystalline solid (melting point 189 to 191° C.); 1H NMR Spectrum: (DMSO d6) 1.19 (d, 3H), 1.48-1.75 (m, 2H), 1.94-2.13 (m, 2H), 3.21-3.53 (m, 2H), 3.93 (s, 3H), 3.78-4.06 (m, 2H), 4.40-4.52 (m, 1H), 4.83-4.99 (m, 2H), 7.28 (dd, 1H), 7.33 (s, 1H), 7.42-7.55 (m, 2H), 7.81 (s, 1H), 8.36 (s, 1H), 9.62 (s, 1H); Mass Spectrum: (M+H)+ 475. [6] Following the coupling reaction, the product was purified by flash column chromatography eluting with methylene chloride/7N ammonia solution in methanol (98/2) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give (2S,3S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-methyl-1-oxopentan-2-ol as a white solid (0.244 g); 1H NMR Spectrum: (DMSO d6) 0.78 (d, J=7 Hz, 3H), 0.91 (t, J=7 Hz, 3H), 1.21 (m, 1H), 1.44 (m, 1H), 1.61 (m, 3H), 2.05 (m, 2H), 3.40 (m, 2H), 3.79 (m, 1H), 3.95 (s, 3H), 4.00 (m, 1H), 4.28 (m, 1H), 4.43 (m, 1H), 4.93 (m, 1H), 7.29 (m, 1H), 7.36 (s, 1H), 7.48 (m, 1H), 7.53 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.63 (br s, 1H); Mass Spectrum: (M+H)+ 517; melting point 114 to 118° C. [7] Following the coupling reaction, the product was purified by flash column chromatography eluting with methanol (4%) and methylene chloride (96%) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give 4-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-methyl-4-oxobutan-2-ol as a white solid (0.232 g); 1H NMR Spectrum: (DMSO d6) 1.20 (s, 6H), 1.54-1.77 (m, 2H), 2.04 (m, 2H), 2.49 (s, 2H), 3.30 (m, 1H), 3.45 (m, 1H), 3.86 (m, 1H), 3.96 (s, 3H), 4.00 (m, 1H), 4.88 (s, 1H), 4.91 (1H, m), 7.28 (m, 1H), 7.35 (s, 1H), 7.47 (m, 1H), 7.54 (m, 1H), 7.83 (s, 1H), 8.40 (s, 1H), 9.63 (br s, 1H); Mass Spectrum: (M+H)+ 503; melting point 196 to 199° C. [8] Following the coupling reaction, the product was purified by flash column chromatography eluting with methylene chloride/7N ammonia solution in methanol (98/2) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]oxy}quinazolin-4-amine as a white solid (0.260 g); 1H NMR Spectrum: (DMSO d6 373K) 1.73 (m, 2H), 1.99 (m, 2H), 2.05 (m, 3H), 2.14 (m, 1H), 3.48 (m, 2H), 3.83 (m, 4H), 3.99 (s, 3H), 4.69 (t, J=7 Hz, 1H), 4.89 (1H, m), 7.29 (m, 1H), 7.37 (s, 1H), 7.43 (m, 1H), 7.60 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.33 (br s, 1H); Mass Spectrum: (M+H)+ 501; melting point 199 to 201° C. [9] Following the coupling reaction, the product was purified by flash column chromatography eluting with methanol (4%) and methylene chloride (96%) gave a foam. his was re-precipitated by stirring in diethyl ether (20 ml) to give 3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2,2-dimethyl-3-oxopropan-1-ol as a white solid (0.244 g). 1H NMR Spectrum: (DMSO d6) 1.10 (s, 6H), 1.64 (m, 2H), 2.03 (m, 2H), 3.39 (m, 2H), 3.45 (m, 2H), 3.95 (s, 3H), 3.98 (m, 2H), 4.54 (t, J=6 Hz, 1H), 4.91 (1H, m), 7.29 (m, 1H), 7.35 (s, 1H), 7.48 (m, 1H), 7.53 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.64 (br s, 1H); Mass Spectrum: (M+H)+ 503; melting point 111 to 115° C. [10] (3R,5S)-1-Acetyl-5-{[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7- yl}oxy)piperidin-1-yl]carbonyl}pyrrolidin-3-ol (0.160 g); 1H NMR Spectrum: (DMSO d6 373K) 1.65-1.87 (m, 3H), 1.93 (s, 3H), 2.04 (m, 3H), 3.44-3.64 (m, 4H), 3.81 (m, 2H), 3.98 (s, 3H), 4.28-4.39 (m, 1H), 4.71 (m, 1H), 4.89 (m, 2H), 7.23 (m, 1H), 7.32 (s, 1H), 7.40 (m, 1H), 7.59 (m, 1H), 7.81 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H); Mass Spectrum: (M+H)+ 558; melting point 183 to 187° C. [11] Following the coupling reaction, the product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) to give a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxobutan-2-ol (0.108 g) as a white solid; 1H NMR Spectrum: (DMSO d6 373K) 0.91 (t, J=9 Hz, 3H), 1.52 (m, 1H), 1.70 (m, 3H), 2.05 (m, 2H), 3.40 (m, 2H), 3.84 (m, 2H), 3.94 (s, 3H), 4.28 (m, 1H), 4.40 (m, 1H), 4.88 (m, 1H), 7.26 (m, 1H), 7.32 (s, 1H), 7.42 (m, 1H), 7.60 (m, 1H), 7.80 (s, 1H), 8.38 (s, 1H), 9.30 (br s, 1H); Mass Spectrum: (M+H)+ 489; melting point 152 to 153° C. [12] Following the coupling reaction, the product was purified by flash column chromatography eluting with methylene chloride/7N ammonia solution in methanol (98/2) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.142 g); 1H NMR Spectrum: (DMSO d6 373K) 1.73 (m, 2H), 1.99 (m, 2H), 2.05 (m, 3H), 2.14 (m, 1H), 3.48 (m, 2H), 3.83 (m, 4H), 3.99 (s, 3H), 4.69 (t, J=7 Hz, 1H), 4.89 (1H, m), 7.29 (m, 1H), 7.37 (s, 1H), 7.43 (m, 1H), 7.60 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H); Mass Spectrum: (M+H)+ 501; melting point 198 to 199° C. [13] Following the coupling reaction, the product was purified by flash column chromatography eluting with methylene chloride/7N ammonia solution in methanol (98/2) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-tetrahydrofuran-2-ylcarbonyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.212 g); 1H N Spectrum: (DMSO d6 373K) 1.73 (m, 2H), 1.99 (m, 2H), 2.05 (m, 3H), 2.14 (m, 1H), 3.48 (m, 2H), 3.83 (m, 4H), 3.99 (s, 3H), 4.69 (t, J=7 Hz, 1H), 4.89 (1H, m), 7.29 (m, 1H), 7.37 (s, 1H), 7.43 (m, 1H), 7.60 (m, 1H), 7.83 (s, 1H), 8.39 (s, 1H), 9.29 (br s, 1H); Mass Spectrum: (M+H)+ 501; melting point 193 to 194° C. [14] Following the coupling reaction, the product was purified by flash column chromatography eluting with methanol (2.5%) and methylene chloride (97.5%) to give a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3,3-dimethyl-1-oxobutan-2-ol (0.026 g) as a white solid; 1H NMR Spectrum: (DMSO d6 373K) 0.94 (s, 9H), 1.72 (m, 2H), 2.03 (m, 2H), 3.49 (m, 2H), 3.90 (m, 2H), 3.96 (s, 3H), 4.17 (m, 1H), 4.24 (m, 1H), 4.86 (m, 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.40 (m, 1H), 7.59 (m, 1H), 7.82 (s, 1H), 8.38 (s, 1H), 9.29 (br s, 1H); Mass Spectrum: (M+H)+ 517; melting point 205 to 206° C. [15] 7-({1-[(1-acetylpiperidin-4-yl)carbonyl]piperidin-4-yl}oxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine; 1H NMR Spectrum: (DMSO+CD3COOD): 1.33-1.46 (m, 1H); 1.50-1.62 (m, 1H): 1.62-1.74 (m, 3H); 1.75-1.85 (m, 1H); 2.00-2.18 (m, 2H); 2.02 (s, 3H); 2.62-2.71 (m, 1H); 2.92-3.00 (m, 1H); 3.13 (dd, 1H); 3.30-3.43 (m, 1H); 3.47-3.57 (m, 1H); 3.80-3.98 (m, 3H); 4.02 (s, 3H); 4.39 (d, 1H); 4.93 (bs, 1H); 7.41 (dd, 1H); 7.49 (s, 1H); 7.58 (dd, 1H); 7.68 (dd, 1H); 8.11 (s, 1H); 8.92 (s, 1H); Mass Spectrum: (M+H)+ 556. [16] N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]oxy}quinazolin-4-amine; 1H NMR Spectrum: (DMSO+CD3COOD): 11.64-1.74 (m, 1H); 1.74-1.84 (m, 1H); 2.01-2.17 (m, 4H); 3.33-3.55 (m, 3H); 3.66-3.80 (m, 3H); 3.80-3.99 (m, 3H); 4.03 (s, 3H); 3.93 (bs, 1H); 7.41 (dd, 1H); 7.48 (s, 1H); 7.58 (dd, 1H); 7.67 (dd, 1H); 8.12- (s, 1H); 8.92 (s, 1H); Mass Spectrum: (M+H)+ 501. [17] Following the coupling reaction, the product was purified by flash column chromatography eluting with methanol (5%) and methylene chloride (95%) to give a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give 1-{[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]carbonyl}cyclopropanol as a white solid (0.125 g); 1H NMR Spectrum: (DMSO d6 373K) 0.80 (m, 2H), 0.95 (m, 2H), 1.72 (m, 2H), 2.02 (m, 2H), 3.54 (m, 2H), 3.96 (s, 3H), 4.00 (m, 2H), 4.87 (m, 1H), 5.90 (s, 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.40 (m, 1H), 7.58 (m, 1H), 7.80 (s, 1H), 8.38 (s, 1H), 9.30 (br s, 1H); Mass Spectrum: (M+H)+ 487; melting point 177 to 178° C. EXAMPLE 5 N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[(3S)-1-(methoxyacetyl)piperidin-3-yl]oxy}quinazolin-4-amine HATU (0.24 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-amine dihydrochloride (250 mg), diisopropylethylamine (0.37 ml) and methoxyacetic acid (0.054 g) in methylene chloride (9 ml) and the mixture was stirred at room temperature for 2.5 hours. Methylene chloride (20 ml) was added and the organic layer was washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) gave a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.202 g); 1H NMR Spectrum: (DMSO d6 373K) 1.60 (m, 1H), 1.88 (m, 2H), 2.10 (m, 1H), 3.32 (s, 3H), 3.51 (m, 2H), 3.62 (m, 1H), 3.87 (m, 1H), 3.98 (s, 3H), 4.02 (d, J=14 Hz, 1H), 4.12 (d, J=14 Hz, 1H), 4.66 (m, 1H), 7.26 (m, 1H), 7.33 (s, 1H), 7.43 (m, 1H), 7.62 (m, 1H), 7.83 (s, 1H), 8.40 (s, 1H), 9.34 (br s, 1H); Mass Spectrum: (M+H)+ 475. The N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-amine dihydrochloride used as starting material was prepared as follows: Diethylazodicarboxylate (3.73 g) was added dropwise to a mixture of tert-butyl (3R)-3-hydroxypiperidine-1-carboxylate (4.29 g), 4-chloro-6-methoxyquinazolin-7-ol (3.00 g) and triphenylphosphine (5.61 g) in methylene chloride (75 ml). The solution was then heated to 0° C. and stirred for 3 hours. After cooling the mixture was filtered and then purified by flash column chromatography eluting with isohexane/acetone/triethylamine (80/20/1) to give tert-butyl (3S)-3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate as a colourless oil (3.29 g) which was used directly; Mass Spectrum: (M+H)+ 394. 4.0M HCl in dioxane (6.0 ml) was added to a stirred suspension of tert-butyl (3S)-3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate (3.21 g) and 3-chloro-2-fluoroaniline (0.98 ml) in acetonitrile (50 mL). The reaction mixture was heated at 80° C. and left at this temperature overnight. The solvent was evaporated and the residue purified by flash column chromatography eluting with increasingly polar mixtures of methylene chloride/7N ammonia solution in methanol (97/3 to 95/5) to give N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-amine dihydrochloride as a solid (3.20 g); 1H NMR Spectrum: (DMSO d6) 1.56 (m, 2H), 1.72 (m, 1H), 2.12 (m, 1H), 2.48-2.59 (m, 2H), 2.82 (m,1H), 3.20 (m, 1H), 3.95 (s, 3H), 4.49 (m, 1H), 7.26 (s, 1H), 7.28 (m, 1H), 7.47 (m, 1H), 7.53 (m, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.63(s, 1H); Mass Spectrum: (M+H)+ 403. EXAMPLE 6 2-[(3S)-3-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-oxoethanol Using an analogous procedure to that described in Example 5 N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-amine dihydrochloride (250 mg) was coupled with glycolic acid (0.045 g). The resulting product was purified by flash column chromatography eluting with methanol (3%) and methylene chloride (97%) to give a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.105 g); 1H NMR Spectrum: (DMSO d6 373K) 1.59 (m, 1H), 1.87 (m, 2H), 2.09 (m, 1H), 3.40-3.60 (m, 4H), 3.86 (m, 1H), 3.98 (s, 3H), 4.044.18 (m, 2H), 4.66 (m, 1H), 7.24 (m, 1H), 7.31 (s, 1H), 7.40 (m, 1H), 7.60 (m, 1H), 7.80 (s, 1H), 8.38 (s, 1H), 9.30 (br s, 1H); Mass Spectrum: (M+H)+ 461. EXAMPLE 7 N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-({(3S)-1-[(4-methylpiperazin-1-yl)acetyl]piperidin-3-yl}oxy)quinazolin-4-amine Chloroacetyl chloride (47 μl) was added to a solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-[(3S)-piperidin-3-yloxy]quinazolin-4-amine dihydrochloride (250 mg) and diisopropylethylamine (373 μl) in methylene chloride (10 ml) and the mixture was stirred at ambient temperature for 1 hour. 1-Methylpiperazine (228 mg) was added, and the solution stirred for 1 hour before being washed with aqueous sodium hydroxide (2M, 10 ml) and water (10 ml). The organics were then purified by flash column chromatography eluting with methylene chloride/7N ammonia solution in methanol (97/3) to give a foam. This was re-precipitated by stirring in diethyl ether (20 ml) to give the title product as a white solid (0.135 g); 1H NMR Spectrum: (DMSO d6) 1.42-1.67 (m, 1H), 1.70-1.95 (m, 2H), 1.98-2.48 (m, 9H), 2.18 (s, 3H), 2.82-3.05 (m, 1H), 3.20-4.02 (m, 8H), 4.68 (m, 1H,), 7.30 (m, 1H), 7.34 (s, 1H), 7.44-7.60 (m, 2H), 7.82 (m, 1H), 8.38 (s, 1H), 9.64 (m, 1H); Mass Spectrum: (M+H)+ 543; melting point 120 to 121° C. EXAMPLE 8 N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-({1-[(4-methylpiperazin-1-yl)acetyl]piperidin-4-yl}oxy)quinazolin-4-amine Using an analogous procedure to that described in Example 7 N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (250 mg) was reacted with chloroacetyl chloride (47 μl), followed by 1-Methylpiperazine (228 mg) and purification to give the title product as a white solid (0.110 g); 1H NMR Spectrum: (DMSO d6) 1.57 (m, 1H), 1.72 (m, 1H), 1.96-2.12 (m, 2H), 2.15 (s, 3H), 2.27-2.48 (m, 8H), 3.08-3.52 (m, 4H), 3.86-4.04 (m, 2H), 3.95 (s, 3H), 4.90 (m, 1H,), 7.30 (m, 1H), 7.37 (s, 1H), 7.47-7.58 (m, 2H), 7.83 (s, 1H), 8.38 (s, 1H), 9.63 (s, 1H); Mass Spectrum: (M+H)+ 543. EXAMPLE 9 (2R)-1-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (a)) A suspension of a hydrochloride salt of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine (4.87 g, 11.1 mmol, prepared using an analogous process to that described in Example 1) in 1-methyl-2-pyrrolidinone (40 ml) was stirred and cooled in a bath of ice/water. Triethylamine (4.7 mls, 33.7 mmol), N,N-diisopropylethylamine (1.9 ml, 11 mmol) and D-(−)-lactic acid (1.5 g, 16.7 mmol) were added. HATU (5.27 g, 13.87 mmol) was then added portionwise such that the internal temperature remained less than 12° C. The reaction mixture was stirred at room temperature overnight and partitioned between saturated aqueous sodium bicarbonate solution (NaHCO3) and ethyl acetate (EtOAc). The combined organic layers were washed with saturated aqueous ammonium chloride (×2), 50% aqueous brine (×2) and brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated. The residues were purified by column chromatography eluting with dichloromethane/7N ammonia in methanol (96/4). Fractions containing the desired product were evaporated to a gum which was triturated with diethylether/isohexane (1:1). This solid was then crystallised from acetonitrile to give the title product as a white powder (2.93 g, 55.6%); 1H NMR Spectrum (DMSO d6) 1.20 (d, 3H), 1.50-1.80 (m, 2H), 1.93-2.13 (m, 2H), 3.15-3.53 (m, 2H), 3.94 (s, 3H), 3.72-4.08 (m, 2H), 4.35-4.55 (m, 1H), 4.80-5.00 (m, 2H), 7.27(dd, 1H); 7.34 (s, 1H); 7.40-7.60 (m, 2H); 7.80 (s, 1H); 8.38 (s, 1H); 9.63 (s, 1H); Mass Spectrum: (M+H)+ 475; melting point: 189 to 189.5° C. EXAMPLE 10 N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-(methylamino)propanoyl]piperidin-4-yl}oxy)quinazolin-4-amine (Process (a)) tert-butyl {(1R)-2-[4-({4-[(3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-methyl-2-oxoethyl}methylcarbamate (2.22 g, 3.77 mmol) was dissolved in acetonitrile (20 ml) and treated with 4M HCl in dioxane (3.8 ml, 15.2 mmol) at 80° C. for 5 minutes. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organics were washed with brine (×1), dried over sodium sulfate, filtered and evaporated. The residues were purified by column chromatography eluting with dichloromethane/7N ammonia in methanol (92/8). Fractions containing the desired product were evaporated to give a gum which was triturated with diethyl ether/isohexane (1:1) to give the title product as a white powder. (1.55 g, 84.1%); 1H NMR Spectrum: (DMSO d6 +CD3CO2D) 1.35 (d, 3H), 1.61-1.81 (m, 2H), 1.98-2.15 (m, 2H), 2.48 (s, 3H), 3.26-3.51 (m, 2H), 3.65-3.79 (m, 1H), 3.92 (s, 3H), 3.84-4.08 (m, 1H), 4.32-4.42 (m, 1H), 4.85-4.99 (m, 1H), 7.20-7.29 (m, 1H), 7.36 (s, 1H), 7.42-7.54 (m, 2H), 7.81 (s, 1H), 8.35 (s, 1H); Mass Spectrum: (M+H)+ 488. The tert-butyl {(1R)-2-[4-({4-[(3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-methyl-2-oxoethyl}methylcarbamate starting material was prepared as follows: A hydrochloride salt of N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine (2.0 g, 4.55 mmol) was coupled with N-tert-butoxycarbonyl-N-methyl-D-alanine according to the method described in Example 9. The product was purified using column chromatography eluting with dichloromethane/7N ammonia in methanol (98/2) to give tert-butyl {(1R)-2-[4-({4-[(3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl)-1-methyl-2-oxoethyl}methylcarbamate as a foam. (2.34 g, 87.6%); 1H NMR Spectrum: (CDCl3) 1.29 (d, 3H), (1.48) (s, 9H), 1.75-1.89 (m, 1H), 1.89-2.04 (m, 2H), 2.07-2.22 (m, 1H), 2.75 (s, 3H), 3.26-3.42 (m, 1H), 3.50-3.85 (m, 2H), 4.02 (s, 3H), 3.91-4.28 (m, 1H), 4.65-4.93 (m, 1H), 5.10-5.21 (m, 1H), 7.05 (s, 1H), 7.13-7.21 (m, 2H), 7.28-7.33 (m, 2H), 8.44-8.54 (m, 1H), 8.69 (s, 1H); Mass Spectrum: (M+H)+ 588 EXAMPLE 11 N-(3-Chloro-2-fluorophenyl)-7-({1-[(2R)-2-(dimethylamino)propanoyl]piperidin-4-yl}oxy)-6-methoxyquinazolin-4-amine (Process (d)) A mixture of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-(methylamino)propanoyl]piperidin-4-yl}oxy)quinazolin-4-amine (0.5 g, 1.03 mmol (Example 10), paraformaldehyde (0.3 g, 10.0 mmol) and anhydrous magnesium sulfate (0.25 g, 2.08 mmol) in methanol (5 ml) was treated with 4M hydrogen chloride in dioxane (257 μl, 1.03 mmol). Sodium cyanoborohydride (0.26 g, 4.12 mmol) was added and the mixture heated to 40° C. for 3 hours. The reaction mixture was then partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organics were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with dichloromethane/7N ammonia in methanol (96/4). Fractions containing the desired product were evaporated to give a gum which was triturated with diethyl ether/isohexane (1:1) to give the title product as a white powder (0.415 g, 80.7%); 1H NMR Spectrum: (DMSO d6 +CD3CO2D) 1.18-1.25 (m, 3H), 1.52-1.80 (m, 2H), 1.95-2.15 (m, 2H), 2.48 (s, 6H), 3.18-3.54 (m, 2H), 3.73-3.91 (m, 1.5H), 3.92 (s, 3H), 4.00-4.14 (m, 1.5H), 4.83-4.95 (m, 1H), 7.21-7.29 (m, 1H), 7.35 (s, 1H), 7.41-7.55 (m, 2H), 7.80 (s, 1H), 8.35 (s, 1H); Mass Spectrum: (M+H)+ 502. EXAMPLE 12 N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2S)-2-methoxypropanoylpiperidin-4-yl}oxy)quinazolin-4-amine (Process (a)) Solid TBTU (285 mg, 0.75 mmol) was added to a stirred solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine (200 mg, 0.50 mmol), DIPEA (0.261 ml, 1.50 mmol) and (S)-(−)-2-methoxypropionoic acid (57 mg, 0.55 mmol) in methylene chloride (3 ml). The resulting solution was allowed to stir at room temperature overnight, diluted with methylene chloride (20 ml), washed with 2N sodium hydroxide (2×5 ml), water (5 ml), dried (MgSO4), filtered and evaporated. The resulting foams were purified using flash chromatograpy on silica eluting with increasingly polar mixtures of methanol/methylene chloride (0/100-3/97) to give the title compound as a white solid (100%); 1H NMR Spectrum: 1.34 (d, 3H), 1.64-1.72 (m, 2H), 2.04-2.07 (m, 2H), 3.20 (s, 3H), 3.25-3.47 (m, 2H), 3.86-3.97 (m, 2H), 4.03 (s, 3H), 4.21-4.23 (m, 1H), 4.88-4.91 (m, 1H), 7.28(dd, 1H), 7.33 (s, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.92 (s, 1H), 8.38 (s, 1H), 9.67 (s, 1H); Mass Spectrum: (M+H)+ 489. The N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine starting material was obtained from the corresponding dihydrochloride salt (Example 1) by a basic aqueous work-up at pH=11.5 and extraction of the aqueous layer by dichloromethane. The organic layer was dried on magnesium sulfate and concentrated to give the free amine as a white foam; 1H NMR Spectrum: (CDCl3) 1.78-1.85 (m, 2H+1NH), 2.18 (m, 2H), 2.80 (m, 2H), 3.22 (m, 2H), 4.03 (s, 3H), 4.61 (m, 1H), 7.03 (s, 1R), 7.15 (m, 2H), 7.29 (s, 1H), 7.31 (m, 1H), 8.50 (m, 1H), 8.69 (s, 1NH); Mass Spectrum: (M+H)+ 403. EXAMPLE 13 N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-({1-[(2R)-2-methoxypropanoyl]piperidin-4-yl}oxy)quinazolin-4-amine (Process (a)) The method described in Example 12 was repeated using (R)-(+)-2-methoxypropionic acid (57 mg, 0.55 mmol) to give the title compound as a white solid (82%); 1H NMR Spectrum: 1.24 (d, 3H), 1.57-1.67 (m, 2H), 2.04-2.09 (m, 2H), 3.22 (s, 3H), 3.22-3.47 (m, 2H), 3.87-3.97 (m, 2H), 3.97 (s, 3H), 4.22-4.27 (m, 1H), 4.92-4.95 (m, 1H), 7.27-7.30 (dd, 1H), 7.35 (s, 1H), 7.47 (dd, 1H), 7.60 (dd, 1H), 7.82 (s, 1H), 8.37 (s, 1H), 9.67 (s, 1H); Mass Spectrum: (M+H)+ 489. EXAMPLE 14 (2R)-2-Amino-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol (Process (a)) TBTU (709 mg, 1.87 mmol) was added to a stirred solution of N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine (500 mg, 1.24 mmol), DIPEA (0.648 ml, 3.72 mmol) and N-(tert-butoxycarbonyl)-D-serine (280 mg, 1.36 mmol) in methylene chloride (3 ml). The resulting solution was allowed to stir at room temperature overnight, diluted with methylene chloride (20 ml), washed with 2N NaOH (2×5 ml), water (5 ml), dried (MgSO4) and evaporated. The resulting foam was dissolved in methylene chloride (5 ml) and treated with trifluoroacetic acid (5 ml). The resulting solution was left to stand at room temperature for 1 hour, concentrated and purified by mass-triggered preparative LCMS to give the title compound (42.5%); 1H NMR Spectrum: 1.58-1.72 (m, 2H), 2.01-2.08 (m, 2H), 3.24-3.44 (m, 2H), 3.80-4.03 (m, 4H), 3.95 (s, 3H), 4.77 (m, 1H), 4.91-4.94 (m, 1H), 7.27(dd, 1H), 7.35 (s, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.82 (s, 1H), 8.38 (s, 1H), 9.67 (s, 1H); Mass Spectrum: (M+H)+ 490. EXAMPLE 15 (2S)-2-Amino-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol The method described in Example 14 was repeated but using N-(tert-butoxycarbonyl)-L-serine (280 mg, 1.36 mmol) to give the title product (32%); 1H NMR Spectrum: 1.58-1.73 (m, 2H), 2.01-2.08 (m, 2H), 3.24-3.44 (m, 2H), 3.80-4.00 (m, 4H), 3.97 (s, 3H), 4.74 (m, 1H), 4.93-4.96 (m, 1H), 7.28(dd, 1H), 7.35 (s, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.82 (s, 1H), 8.37 (s, 1H), 9.67 (s, 1H); Mass Spectrum: (M+H)+ 490. EXAMPLE 16 (2S)-3-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-(dimethylamino)-3-oxopropan-1-ol (Process(d)) Solid NaCNBH3 (38.3 mg, 0.614 mmol) was added to a stirred solution of (2S)-2-amino-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol (150 mg, 0.307 mmol, Example 15), sodium acetate trihydrate (251 mg, 3.07 mmol), formaldehyde 37% (aq) (2.5 ml) and acetic acid (184 mg, 3.07 mmol) at 0-5° C. The resulting solution was allowed to warm to room temperature and stir for 1 hour. The mixture was then evaporated and the resulting yellow residue was purified by flash chromatography on silica gel eluting with increasingly polar mixtures of dichloromethane/7N ammonia in methanol (100/0-85/15). Fractions containing the desired product were combined and evaporated to give the title compound as a white solid (26%); 1H NMR Spectrum: 1.52-1.69 (m, 2H), 1.94-2.07 (m, 2H), 2.28-2.30 (2 x s, 6H), 3.15-3.22 (m, 2H), 3.53-3.76 (m, 4H), 3.94 (s, 3H), 4.02 (m, 1H), 4.49 (m, 1H), 4.92-4.94 (m, 1H), 7.27(dd, 1H), 7.34 (s, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.65 (s, 1H); Mass Spectrum: (M+H)+ 518. EXAMPLE 17 (2R)-3-[4-({4-[3-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-2-(dimethylamino)-3-oxopropan-1-ol (Process(d)) The process described in Example 16 was repeated using (2R)-2-amino-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol (150 mg, 0.307 mmol, Example 14) to give the title compound (32%); 1H NMR Spectrum: 1.58-1.69 (m, 2H), 1.93-2.06 (m, 2H), 2.26-2.28 (2×s, 6H), 3.17-3.20 (m, 2H), 3.53-3.74 (m, 4H), 3.94 (s, 3H), 4.04 (m, 1H), 4.47 (m, 1H), 4.91 (m, 1H), 7.26 (dd, 1H), 7.35 (s, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.81 (s, 1H), 8.37 (s, 1H), 9.66 (s, 1H); Mass Spectrum: (M+H)+ 518. EXAMPLE 18 (2S)-1-(4-{[4-[3-Chloro-2-fluoroanilino]-6-(2-pyrrolidin-1-ylethoxy)quinazolin-7-yl]oxy}piperidin-1-yl)-1-oxopropan-2-ol (Process (b)) (S)-(−)-2-Acetoxyproprionyl chloride (0.131 g, 0.87 mmol) was added to a stirred solution of N-(3-chloro-2-fluorophenyl)-7-(piperidin-4-yloxy)-6-(2-pyrrolidin-1-ylethoxy)quinazolin-4-amine trihydrochloride (220 mg, 0.395 mmol) and triethylamine (0.110 ml, 0.79 mmol) in methylene chloride (10 ml) at −10° C. The resulting solution was allowed to warm to room temperature and stirred for 30 minutes. The resulting yellow solution was diluted with methylene chloride (10 ml) and washed with water (3×5 ml), dried (MgSO4) and evaporated. The resulting foam was dissolved in THF (1 ml) and pyrrolidine (1 ml) was added. The mixture was heated at 70° C. for 3 hours, evaporated and the residues purified by flash chromatography on silica gel eluting with dichloromethane/7N ammonia in methanol (95/5). Fractions containing the desired product were combined and evaporated to give the title product as a white solid. (0.099 g, 45.6%); 1H NMR Spectrum: (DMSO-d6): δ1.20 (d, 3H), 1.52-1.82 (m, 6H), 1.86-2.08 (m, 4H), 3.24-3.50 (m, 4H), 3.74-3.86 (m, 2H), 4.28 (m, 2H), 4.45 (m, 1H), 4.89-4.95 (m, 3H), 7.27 (dd, 1H), 7.36 (s, 1H), 7.48 (dd, 1H), 7.53 (dd, 1H), 7.87 (s, 1H), 8.38 (s, 1H), 9.65 (s, 1H); Mass Spectrum: (M+H)+ 558. The N-(3-chloro-2-fluorophenyl)-7-(piperidin-4-yloxy)-6-(2-pyrrolidin-1-ylethoxy)quinazolin-4-amine trihydrochloride used as a starting material (1) was prepared as follows: 1,2-Dichloroethane (5 ml) was added to a stirred suspension of 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline 6 (2.0 g, 6.27 mmol, prepared as described in Reference Example 2 of WO03/082831) and potassium carbonate (1.39 g, 10.0 mmol) in DMF (10 ml), and the resulting suspension was heated at 60° C. for 48 hours. The reaction mixture was diluted with methylene chloride (50 ml) and washed with water (3×20 ml), dried (MgSO4) and evaporated to dryness to afford 5 (2.39 g, 100%) as a brown oil which was used without further purification; Mass Spectrum: (M+H)+ 382. Pyrrolidine (4.44 g, 5.13 ml, 62.5 mmol) was added to a stirred solution of 5 (2.38 g, 6.25 mmol) in DMF (30 ml) and the resulting pale brown solution was heated at 90° C. for 2 hours. The reaction mixture was evaporated to dryness using a rotary evaporator and under high vacuum to afford 4 (2.6 g, 100%) as a brown foam; Mass Spectrum: (M+H)+ 417. Intermediate 4 (2.60 g, 6.3 mmol) was added to neat liquid pyridinium hydrochloride (3.6 g, 31.3 mmol) at 170° C. over a period of 5 minutes. The reaction mixture was allowed to stir at 170° C. for 1 hour. The reaction mixture was cooled to room temperature and the resulting solid was suspended in water (30 ml) and the resulting black precipitate eliminated by filtration. The pH of the filtrate was increased to 7 with concentrated aqueous ammonia and the resulting solution was evaporated to dryness. The resulting beige solid was purified by flash chromatography on silica gel eluting with increasingly polar mixtures of dichloromethane/7N ammonia in methanol (100/0-85/15). Fractions containing the desired product were combined and evaporated to give 3 as a pale green foam (1.62 g, 64%). Mass Spectrum: (M+H)+ 403. Di-tert-butylazodicarboxylate (0.571 g, 2.48 mmol) was added to a stirred solution of 3 (500 mg, 1.24 mmol), 4-hydroxy-1-tert-butoxycarbonylpiperidine (374 mg, 1.86 mmol) and triphenylphosphine (660 mg, 2.48 mmol) in THF (10 ml) at 0° C. over 5 minutes. The resulting yellow solution was allowed to warm to room temperature and subsequently heated at 70° C. for 1 hour. The reaction mixture was concentrated and the residues were purified by flash chromatography on silica gel eluting with increasingly polar mixtures of methylene chloride/7N ammonia in methanol (100/0-95/5). Fractions containing the desired product were combined and evaporated to give a 2 as a pale green oil (0.52 g, 72%); Mass Spectrum: (M+H)+ 586. TFA (1 ml) was added to a stirred solution of 2 (220 mg, 0.395 mmol) in methylene chloride (1 ml) at 0° C. over 5 minutes. The resulting yellow solution was allowed to warm to room temperature and stir for 1 hour. The reaction mixture was evaporated to dryness and the residues re-dissolved in methylene chloride (10 ml). Ethyl ether (10 ml) was added followed by a 4.0 M solution of HCl in dioxane (2 ml). The resulting thick white precipitate was collected by filtration, washed with Ethyl ether (3×2 ml) and dried to a constant weight to give N-(3-chloro-2-fluorophenyl)-7-(piperidin-4-yloxy)-6-(2-pyrrolidin-1-ylethoxy)quinazolin-4-amine trihydrochloride (1) as a white solid which was used without further purification (0.48 g, 100%); Mass Spectrum: (M+H)+ 486. EXAMPLE 19 (2S)-1-(4-{[4-[3-Chloro-2-fluoroanilino]-6-(2-methoxyethoxy)quinazolin-7-yl]oxy}piperidin-1-yl)-1-oxopropan-2-ol (Process (a)) TBTU (200 mg, 0.525 mmol) was added to a stirred solution of N-(3-chloro-2-fluorophenyl)-6-(2-methoxyethoxy)-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (180 mg, 0.404 mmol), L-(+)-lactic acid (37 mg, 0.44 mmol) and DIPEA (0.091 ml, 0.525 mmol) in methylene chloride (10 ml). The resulting solution was stirred at room temperature for 2 hours then diluted with methylene chloride (10 ml). This solution was washed with 2N NaOH (2×5 ml), dried (MgSO4), filtered and evaporated. The residues were purified by flash chromatography on silica gel eluting with methylene chloride/7N ammonia in methanol (95/5) to give the title product as a white solid (89 mg, 42.6%); 1H NMR Spectrum: (DMSO-d6): δ1.21 (d, 3H), 1.64-1.72 (m, 2H), 1.86-2.07 (m, 2H), 3.37-3.46 (m, 2H), 3.77-3.92 (m, 5H), 4.27 (m, 2H), 4.46 (m, 1H), 4.90-4.92 (m, 3H), 7.29 (dd, 1H), 7.36 (s, 1H), 7.48 (dd, 1H), 7.52 (dd, 1H), 7.86 (s, 1H), 8.38 (s, 1H), 9.63 (s, 1H); Mass Spectrum : (M+H)+ 519. The N-(3-chloro-2-fluorophenyl)-6-(2-methoxyethoxy)-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (intermediate 7 in the reaction scheme below) used as starting material was prepared as follows: Solid 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline 6 (1.00 g, 3.13 mmol) was added to neat liquid pyridinium hydrochloride (3.62 g, 31.3 mmol) at 170° C. over a period of 10 minutes. The reaction mixture was stirred at 170° C. for 2 hours then cooled to room temperature. The mixture was then suspended in water (30 ml) and the resulting precipitate was collected by filtration, washed with acetonitrile (5 ml) diethyl ether (5 ml) and dried to a constant weight in a vacuum oven at 50° C. to afford 10 as a beige solid (0.71 g, 77%); Mass Spectrum: (M+H)+ 306. Acetic anhydride (117 mg, 1.15 mmol) and a solution NaOH (46 mg, 1.15 mmol) in water (3 ml) was added to a stirred suspension of 10 (350 mg, 1.15 mmol) in THF (3 ml) at −10° C. The resulting two-phase mixture was stirred at room temperature for 2 hours. The organic phase was retained, dried (MgSO4) and evaporated to dryness. The resulting beige foam was triturated with acetonitrile (3 ml), cooled to 0° C. and the resulting precipitate was collected by filtration and dried to a constant weight at 40° C. in a vacuum oven to give 9 as a beige solid (232 mg, 68%); Mass Spectrum: (M+H)+ 348. Solid di-tert-butylazodicarboxylate (364 mg, 1.58 mmol) was added to a stirred solution of 9 (250 mg, 0.72 mmol), triphenylphosphine (420 mg, 1.58 mmol) and 4-hydroxy-1-tert-butoxycarbonylpiperidine (289 mg, 1.44 mmol) in THF (10 ml) at room temperature over 5 minutes. The resulting yellow solution was stirred at room temperature for 2 hours and concentrated to afford a yellow foam. The foam was dissolved in 7N NH3 in MeOH (5 ml) and left to stand for 1 hour. The solution was concentrated and purified by flash chromatography on silica gel (elution with a mixture of DCM-MeOH 95/5) to give 8 (138 mg, 39%) as a beige foam; Mass Spectrum: (M+H)+ 489. Solid di-tert-butylazodicarboxylate (166 mg, 0.72 mmol) was added to a stirred solution of 8 (115 mg, 0.24 mmol), triphenylphosphine (0.191 g, 0.72 mmol) and 2-methoxyethanol (55 mg, 0.72 mmol) in THF (2 ml) at room temperature over 5 minutes. The resulting yellow solution was stirred at room temperature for 2 hours then concentrated to a yellow foam. This was dissolved in DCM (1 ml), treated with trifluoroacetic acid (1 ml) and left to stand for 1 hour. The solution was concentrated and purified by mass-triggered preparative LCMS to give N-(3-chloro-2-fluorophenyl)-6-(2-methoxyethoxy)-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (7) as a white solid (80 mg, 77%); Mass Spectrum: (M+H)+ 447.13. EXAMPLE 20 4-[3-chloro-2-fluoroanilino]-7-({1-[(2S)-2-hydroxypropanoyl]piperidin-4-yl}oxy)quinazolin-6-ol Solid lithium iodide (2.11 g, 15.8 mmol) was added to stirred neat 2,4,6-collidine (5 ml) at 130° C. The resulting yellow solution was heated at 130° C. for 1 hour. Solid (2S)-1-[4-({4-[(3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (1.5 g, 3.17 mmol, Example 4[5]) over a period of 10 minutes. The resulting solution was stirred at 130° C. for 16 hours to give a dark brown solid precipitate. The liquid was decanted and the solid was purified by mass-triggered preparative LCMS to give the title product as a brown solid (1.30 g, 87%); 1H NMR Spectrum: (DMSO-d6): δ1.21 (d, 3H), 1.61-1.77 (m, 2H), 1.95-2.08 (m, 2H), 3.41-3.51 (m, 2H), 3.86-3.92 (m, 2H), 4.47 (m, 1H), 4.91 (m, 1H), 7.26 (m, 1H), 7.32 (s, 1H), 7.45 (m, 1H), 7.53 (m, 1H), 7.70 (s, 1H), 8.33 (s, 1H), 9.45 (s, 2H); Mass Spectrum: (M+H)+ 461. EXAMPLE 21 (2S)-1-[4-({4-[3-Chloro-2-fluoroanilino]-6-isopropoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (f)) Solid di-tert-butylazodicarboxylate (225 mg, 0.98 mmol) was added to a stirred solution of 2-propanol (0.074 ml, 0.98 mmol) and triphenylphosphine (260 mg, 0.98 mmol) in THF (1 ml) at 0° C. over 5 minutes. The resulting yellow solution was allowed to warm to room temperature and 4-[3-chloro-2-fluoroanilino]-7-({1-[(2S)-2-hydroxypropanoyl]piperidin-4-yl}oxy)quinazolin-6-ol (250 mg, 0.33 mmol, Example 20) was added. The mixture was heated at 80° C. for 3 hours, cooled and evaporated. The residues were purified by mass-triggered preparative LCMS to give the title compound as a white solid (75 mg, 45.7%); 1H NMR Spectrum: (CDCl3): δ1.37 (d, 3H), 1.43 (d, 6H), 1.61-1.72 (m, 2H), 1.95-2.07 (m, 2H), 3.38-3.50 (m, 2H), 3.78-3.88 (m, 2H), 4.49 (m, 1H), 4.66 (m, 1H), 4.82 (m, 1H), 7.15 (m, 3H), 7.31 (s, 1H), 8.52 (s, 1H), 8.69 (s, 1H); Mass Spectrum: (M+H)+ 503. EXAMPLE 22 (2S)-1-[4-({4-[(3-Chloro-4-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol. (Process (a)) HATU (190 mg, 0.5 mmol) was added to a stirred solution of N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride (200 mg, 0.456 mmol), L-(+)-lactic acid (45 mg, 0.5 mmol) and N-methyl morpholine (0.15 ml, 1.39 mmol) in DMF (10 ml) at room temperature. After 2 hours the mixture was evaporated to dryness and the residues were purified by column chromatography on silica eluting with increasingly polar mixtures of dichloromethane/methanol (99/1-90/10). Fractions containing the desired product were evaporated to a gum. This was triturated with diethylether (10 ml) and the resulting solid was collected by filtration and dried under high vacuum to give the title product as a white powder. (54.2 mg, 25%); 1H NMR Spectrum: (DMSO d6) 1.1-1.3 (m, 3H), 1.5-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.0-3.60 (m, 2H +H2O), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.43 (m, 1H), 4.95 (m, 2H), 7.32 (s, 1H), 7.47 (dd, 1H), 7.7-7.8 (m, 1H), 7.83 (s, 1H), 8.0-8.1 (m, 1H), 8.58 (s, 1H), 9.87 (bs, 1H); Mass Spectrum: (M+H)+ 475. The N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride used as the starting material was prepared as follows: Di-tert-butylazodicarboxylate (1.64 g, 7.14 mmol) in methylene chloride (20 ml) was added slowly to a stirred suspension of 4-Chloro-6-methoxyquinazolin-7-ol (1.0 g, 4.76 mmol, prepared as described in WO2004041829, Example 1 therein (preparation of starting materials)), 4-hydroxy-1-tert-butoxycarbonylpiperidine (1.44 g, 7.14 mmol) and triphenylphosphine (1.87 g, 7.14 mmol) in methylene chloride (50 ml) at 5° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 18 hours. The reaction mixture was then filtered and purified by flash chromatography on silica eluting with increasingly polar mixtures of isohexane/ethyl acetate/triethylamine (75/24/1 followed by 0/99/1). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate as a white solid (1.75 g, 93.4%); 1H NMR Spectrum: (DMSO d6) 1.40 (s, 9H), 1.5-1.7 (m, 2H), 1.9-2.1 (m, 2H), 3.1-3.3 (m, 2H), 3.60-3.80 (m, 2H), 3.95 (s, 3H), 4.92 (m, 1H), 7.38 (s, 1H), 7.58 (s, 1H), 8.83 (s, 1H); Mass Spectrum: (M+H)+ 394. 4.0M HCl in Dioxane (1 ml) was added to a suspension of tert-butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate (331 mg, 0.84 mmol) and 3-chloro-4-fluoroaniline (134.5 mg) in acetonitrile (10 ml). The reaction mixture was stirred and heated at 70° C. for 4 hours. The resulting precipitate was filtered hot, washed with acetonitrile and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride (566 mg); Mass Spectrum: (M+H)+ 403. EXAMPLE 23 (2R)-1-[4-({4-[3-Chloro-4-fluoroanilino]-6methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (a)) D-Lactic acid was coupled with N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride using the same conditions as those described in Example 22 to give the title product; 1H NMR Spectrum: (DMSO d6) 1.2 (d, 3H), 1.5-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.50 (m, 2H+H2O), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.45 (pent, 1H), 4.8-5.8 (m, 2H), 7.32 (s, 1H), 7.45 (dd, 1H), 7.7-7.85 (m, 2H), 8.1 (dd, 1H), 8.5 (s, 1H), 9.55 (s, 1H); Mass Spectrum: (M+H)+ 475; melting point 143.6° C. EXAMPLE 24 (2S)-1-[4-({4-[3-Bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (a)) N-(3-Bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride was coupled with L-(+)-lactic acid using an analogous process to that described in Example 22 to give the title product as a white powder; 1H NMR Spectrum: (DMSO d6) 1.2 (d, 3H), 1.5-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.60 (m, 2H+H2O), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.45 (m, 1H), 4.8-5.0 (m, 2H), 7.2-7.4 (m, 3H), 7.8-7.9 (m, 2H), 8.13 (s, 1H), 8.5 (s, 1H), 9.5 (s, 1H); Mass Spectrum: (M+H)+ 501,503. The N-(3-bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride starting material was prepared as follows. tert-Butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate was coupled with 3-bromoaniline using an analogous process to that described in Example 21 (preparation of starting materials) for the preparation of N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride, to give N-(3-bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride; 1H NMR Spectrum: (DMSO d6): 1.8-2.1 (m, 2H), 2.1-2.3 (m, 2H), 3.0-3.35 (m, 4H), 4.05 (s, 3H), 4.88 (m, 1H), 7.38-7.52 (m, 2H), 7.6 (s, 1H), 7.8 (d, 1H), 8.05 (s, 1H), 8.5 (s, 1H), 8.87 (s, 1H), 9.2 (bs, 2H), 11.7 (s, 1H); Mass Spectrum: (M+H)+ 431. EXAMPLE 25 (2R)-1-[4-({4-[3-Bromoanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (a)) N-(3-bromophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride was coupled with D-lactic acid using an analogous process to that described in Example 22 to give the title product as a white powder; 1H NMR Spectrum: (DMSO d6) 1.2 (d, 3H), 1.5-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+H2O), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.43 (m, 1H), 4.8-5.0 (m, 2H), 7.2-7.4 (m, 3H), 7.8-7.9 (m, 2H), 8.15 (s, 1H), 8.5 (s, 1H), 9.5 (s, 1H); Mass Spectrum: (M+H)+ 501,503. EXAMPLE 26 (2S)-1-[4-({4-[5-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (a)) N-(5-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride was coupled with L-(+)-lactic acid using an analogous process to that described in Example 22 to give the title product as a white powder; 1H NMR Spectrum: (DMSO d6) 1.2 (d, 3H), 1.5-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.60 (m, 2H+H2O), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.45 (m, 1H), 4.8-5.0 (m, 2H), 7.3-7.45 (m, 3H), 7.7 (d, 1H), 7.85 (s, 1H), 8.5 (s, 1H), 9.95 (s, 1H); Mass Spectrum: (M+H)+ 475. The N-(5-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride starting material was prepared as follows. tert-butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate was coupled with 2-fluoro-5-chloroaniline using an analogous process to that described in Example 22 (preparation of starting materials) for the preparation of N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride, to give N-(5-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride; 1H NMR Spectrum: (DMSO d6) 1.8-2.1 (m, 2H), 2.1-2.35 (m, 2H), 3.0-3.35 (m, 4H), 4.05 (s, 3H), 4.8-5.0 (m, 1H), 7.4-7.55 (m, 2H), 7.55-7.75 (m, 2H), 8.45 (s, 1H), 8.82 (s, 1H), 9.22 (bs, 2H), 11.94 (s, 1H); Mass Spectrum: (M+H)+ 403. EXAMPLE 27 (2R)-1-[4-({4-[5-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (a)) N-(5-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride was coupled with D-lactic acid using an analogous process to that described in Example 22 to give the title product as a white powder; 1H NMR Spectrum: (DMSO d6) 1.2 (d, 3H), 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+H2O), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.25-7.45 (m, 3H), 7.7 (dd, 1H), 7.8 (s, 1H), 8.4 (s, 1H), 9.55 (s, 1H); Mass Spectrum: (M+H)+ 475. EXAMPLE 28 (2S)-1-[4-({4-[3-Ethynylanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (a)) N-(3-Ethynylphenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride was coupled with L-(+)-lactic acid using an analogous process to that described in Example 22 to give the title product as a white powder; 1H NMR Spectrum: (DMSO d6) 1.2 (d, 3H), 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+H2O), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.18 (s, 1H), 4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.2 (d, 1H), 7.33 (s, 1H), 7.39 (dd, 1H), 7.83 (s, 1H), 7.89 (d, 1H), 7.97 (s, 1H), 8.5 (s, 1H), 9.48 (s, 1H); Mass Spectrum: (M+H)+ 447. The N-(3-ethynylphenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride used as starting material was prepared as follows: tert-butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate was coupled with 3-ethynylaniline using an analogous process to that described in Example 22 (preparation of starting materials) for the preparation of N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride, to give N-(3-ethynylphenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride 1H NMR Spectrum: (DMSO d6) 1.85-2.1 (m, 2H), 2.1-2.3 (m, 2H), 3.0-3.35 (m, 4H), 4.05 (s, 3H), 4.25 (s, 1H), 4.8-4.95 (m, 1H), 7.39 (d, 1H), 7.47 (dd, 1H), 7.6 (s, 1H), 7.8 (d, 1H), 7.89 (s, 1H), 8.5 (s, 1H), 8.83(s, 1H), 9.22 (bs, 2H), 11.68 (s, 1H); Mass Spectrum: (M+H)+ 375. EXAMPLE 29 (2R)-1-[4-({4-[(3-Ethynylanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (a)) N-(3-Ethynylphenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride was coupled with D-lactic acid using an analogous process to that described in Example 28 to give the title product as a white powder; 1H NMR Spectrum: (DMSO d6) 1.2 (d, 3H), 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+H2O), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.18 (s, 1H), 4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.2 (d, 1H), 7.33 (s, 1H), 7.39 (dd, 1H), 7.83 (s, 1H), 7.89 (d, 1H), 7.97 (s, 1H), 8.48 (s, 1H), 9.47 (s, 1H); Mass Spectrum: (M+H)+ 447. EXAMPLE 30 (2S)-1-[4-({4-[3-Bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (a)) N-(3-Bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride was coupled with L-(+)-lactic acid using an analogous process to that described in Example 22 to give the title product as a white powder; 1H NMR Spectrum: (DMSO d6) 1.2 (d, 3H), 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+H2O), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.21 (dd, 1H), 7.32 (s, 1H), 7.48-7.65 (m, 2H), 7.8 (s, 1H), 8.37 (s, 1H), 9.6 (s, 1H); Mass Spectrum: (M+H)+ 521. The N-(3-Bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride starting material was prepared as follows: tert-Butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate was coupled with tert-butyl (3-bromo-2-fluorophenyl)carbamate using an analogous process to that described in Example 22 (preparation of starting materials) for the preparation of N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride, to give N-(3-bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride; 1H NMR Spectrum: (DMSO d6) 1.85-2.1 (m, 2H), 2.1-2.32 (m, 2H), 3.0-3.35 (m, 4H), 4.02 (s, 3H), 4.83-5.0 (m, 1H), 7.3 (dd, 1H), 7.5-7.65 (m, 2H), 7.75 (dd, 1H), 8.45 (s, 1H), 8.8(s, 1H), 9.15 (bs, 2H), 11.86 (s, 1H); Mass Spectrum: (M+H)+ 447.12. The tert-butyl (3-bromo-2-fluorophenyl)carbamate starting material was prepared as follows. Triethylamine (0.6 ml) was added to a stirred solution of 3-bromo-2-fluorobenzoic acid (438 mg, 2 mmol) in tert-butanol (10 ml). Diphenyl phosphoryl azide (1 ml, 4.6 mmol) was then added and the reaction mixture was heated under reflux overnight. The solution was evaporated to dryness and azeotroped with toluene. The residues were then purified by flash chromatography on silica eluting with ethyl acetate/i-hexane (10/90). Fractions containing the required product were combined and evaporated to give tert-butyl (3-bromo-2-fluorophenyl)carbamate as a white solid (330 mg); 1H NMR Spectrum: (CDCl3) 1.5 (s, 9H), 6.4 (s, 1H), 7.1-7.25 (m, 1H), 7.7 (dd, 1H). EXAMPLE 31 (2R)-1-[4-({4-[3-Bromo-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (a)) N-(3-Bromo-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride was coupled with D-lactic acid using an analogous process to that described in Example 22 to give the title product as a white powder; 1H NMR Spectrum: (DMSO d6) 1.2 (d, 3H), 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+H2O), 3.7-4.1 (m, 2H), 3.95 (s, 3H), 4.45 (pent, 1H), 4.8-5.0 (m, 2H), 7.22 (dd, 1H), 7.32 (s, 1H), 7.48-7.65 (m, 2H), 7.8 (s, 1H), 8.37 (s, 1H), 9.62 (s, 1H); Mass Spectrum: (M+H)+ 521. EXAMPLE 32 (2S)-1-[4-({4-[(4-Chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (a)) N-(4-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride was coupled with L-(+)-lactic acid using an analogous process to that described in Example 22 to give the title product as a white powder; 1H NMR Spectrum: (DMSO d6) 1.2 (d, 3H), 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+H2O), 3.7-4.1 (m, 2H), 3.93 (s, 3H), 4.44 (pent, 1H), 4.8-5.0 (m, 2H), 7.25-7.4 (m, 2H), 7.45-7.65 (m, 2H), 7.8 (s, 1H), 8.33 (s, 1H), 9.5 (s, 1H); Mass Spectrum: (M+H)+ 475; melting point 149° C. The N-(4chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride starting material was prepared as follows: 4-[(4-chloro-2-fluorophenyl)amino]-6-methoxyquinazolin-7-ol (5 g, 15.65 mmol, prepared as described in WO 2001/077085) was dissolved in DMA (200 ml). tert-Butyl (4-methanesulfonyloxy)piperidine-1-carboxylate (6.55 g, 23.5 mmol) and cesium fluoride (7.09 g, 46.95 mmol) were added, and the mixture was heated to 60° C. with stirring. The solvent was evaporated, and the residue was partitioned between water (200 ml) and EtOAc (200 ml). The organics were washed with water (2×100 ml) and brine (100 ml), dried over MgSO4 and evaporated to give tert-butyl 4-({4-[4-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate (7.23 g, 91.9%); 1H NMR Spectrum: (DMSO-d6): 1.4 (d, 9H), 1.5-1.7 (m, 2H), 1.8-2.1 (m, 2H), 3.1-3.3 (m, 2H), 3.65-3.85 (m, 2H), 3.91 (s, 3H), 4.75-4.9 (m, 1H), 7.3 (s, 1H), 7.32 (dd, 1H), 7.54 (dd, 1H), 7.57 (dd, 1H), 7.80 (s, 1H), 8.32 (s, 1H), 9.5 (s, 1H); Mass Spectrum: (M+H)+ 503. A solution of 4M hydrogen chloride in dioxane (100 ml) was added to a stirred solution of tert-butyl 4-({4-[4-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate (7.23 g, 14.4 mmol) in acetonitrile (100 ml). The reaction mixture was heated at 70° C. for 1 hour then concentrated to ½ volume. The resulting precipitate was collected by filtration, washed with acetonitrile and dried under vacuum to give N-(4-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride as a white solid (4.42 g, 76.3%); 1H NMR Spectrum: (DMSO-d6): 1.90-2.10 (m, 2H), 2.10-2.32 (m, 2H), 3.00-3.35 (m, 4H), 4.02 (s, 3H), 4.90 (m, 1H), 7.36-7.50 (m, 1H), 7.50-7.70 (m, 3H), 8.48 (s, 1H), 8.80(s, 1H), 9.30(bs, 2H), 11.90 (bs, 1H); Mass Spectrum: (M+H)+ 403. EXAMPLE 33 (2R)-1-[4-({4-[4-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process)a)) N-(4-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride was coupled with D-lactic acid using an analogous process to that described in Example 22 to give the title product as a white powder; 1H NMR Spectrum: (DMSO d6) 1.2 (d, 3H), 1.45-1.8 (m,2H), 1.9-2.15 (m, 2H), 3.1-3.55 (m, 2H+H2O), 3.7-4.1 (m, 2H), 3.93 (s, 3H), 4.43 (pent, 1H), 4.80-4.98 (m, 2H), 7.25-7.4 (m, 2H), 7.45-7.65 (m, 2H), 7.8 (s, 1H), 8.35 (s, 1H), 9.5 (s, 1H); Mass Spectrum: (M+H)+ 475; melting point 118° C. EXAMPLE 34 N-(3-chloro-2-fluorophenyl)-6-methoxy-7-{[1-(1-methyl-L-prolyl)piperidin-4-yl]oxy}quinazolin-4-amine (Process) a)) N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride was coupled with N-methyl-L-proline using an analogous process to that described in Example 2 to give the title product as a white powder; 1H NMR Spectrum: (DMSO d6) 1.4-1.9 (m,5H), 1.9-2.20 (m, 7H), 2.9-3.05 (m, 1H), 3.05-3.25 (m, 2H), 3.25-3.65 (m, 1H+H2O), 3.75-4.2 (m, 2H), 3.95 (s, 3H), 4.75-5.0 (m, 1H), 7.2-7.4 (m, 2H), 7.4-7.6 (m, 2H), 7.8 (s, 1H), 8.37 (s, 1H), 9.65 (s, 1H); Mass Spectrum: (M+H)+ 514; melting point 193° C. EXAMPLE 35 (2S)-1-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-1-oxopropan-2-ol (Process (b)) N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine (500 mg, 1.05 mmol) and 4-dimethylaminopyridine (128 mg, 1.05 mmol) were stirred in acetonitrile (2.5 ml) and diisopropylethylamine (0.366 ml, 2.10 mmol) was added. The mixture was cooled to 0° C. and a solution of (S)-(−)-2-acetoxypropionyl chloride (0.166 ml, 1.31 mmol) in acetonitrile (0.5 ml) was added drop-wise. The reaction mixture was then stirred at this temperature for 0.5 hours. Water (1.0 ml) and potassium hydroxide (0.641 ml of a 49% w/w solution in water) were added and the mixture stirred at room temperature over night. The layers were separated and the organic layer diluted with ethyl acetate (2.5 ml). Water was added followed by glacial acetic acid (0.210 ml). The mixture was stirred and partitioned. The organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title product (215 mg, 43%) as a white solid; 1H NMR Spectrum: (DMSO d6) 1.19 (d, 3H), 1.48-1.75 (m, 2H), 1.94-2.13 (m, 2H), 3.21-3.53 (m, 2H), 3.93 (s, 3H), 3.78-4.06 (m, 2H), 4.40-4.52 (m, 1H), 4.83-4.99 (m, 2H), 7.28 (dd, 1H), 7.33 (s, 1H), 7.42-7.55 (m, 2H), 7.81 (s, 1H), 8.36 (s, 1H), 9.62 (s, 1H); Mass Spectrum: (M+H)+ 475. EXAMPLE 36 N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-{[-(3-methoxypropanoyl)piperidin-4-yl]oxy}quinazolin-4-amine (Process (b)) N-(3-Chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine was coupled with 3-methoxypropionyl chloride using an analogous process to that described in Example 35 except that following addition of the water and potassium hydroxide at the completion of the coupling reaction, the layers were separated directly and the product was extracted and isolated as described in Example 35 to give the title product; 1H NMR Spectrum: (DMSO d6) 1.59 (m, 1H); 1.69 (m, 1H); 2.04 (m, 2H); 2.61 (t, 2H); 3.21 (s, 3H); 3.26 (m, 1H); 3.41 (m, 1H); 3.57 (t, 2H); 3.77 (m, 1H); 3.95 (m, 4H); 4.90 (m, 1H); 7.29 (m, 1H); 7.35 (s, 1H); 7.48 (m, 1H); 7.53 (m, 1H); 7.83 (s, 1H); 8.39 (s, 1H); 9.63 (s, 1H). Mass Spectrum: (M+H)+ 489. EXAMPLE 37 Pharmaceutical Compositions The following illustrates representative pharmaceutical dosage forms of the invention as defined herein (the active ingredient being termed “Compound X”) which may be prepared, for therapeutic or prophylactic use in humans: (a) Tablet I mg/tablet Compound X 100 Lactose Ph. Eur 182.75 Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate 3.0 (b) Injection I (50 mg/ml) Compound X 5.0% w/v 1M Sodium hydroxide solution 15.0% v/v 0.1M Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100%. The above compositions may be prepared by conventional procedures well known in the pharmaceutical art. For example, Tablet I may be prepared by blending the components together and compressing the mixture into a tablet.

20060315

20090804

20070222

94734.0

A61K3133

TRUONG, TAMTHOM NGO

QUINAZOLINE DERIVATIVES AS TYROSINE KINASE INHIBITORS

UNDISCOUNTED

ACCEPTED

A61K

ACCEPTED

Method for bisulfite treatment

The invention is related to the detection of a methylated cytosine in a nucleic acid wherein guanidinium hydrogen sulfite is used for the preparation of a solution containing guanidinium ions and sulfite ions and subsequent modification of the nucleic acid. Thereby, a non-methylated cytosine is converted to uracil. The invention further discloses kits for performing the methods of the invention.

1. Method for the conversion of a cytosine base, in a nucleic acid to an uracil base comprising: a) providing a solution that contains a nucleic acid, b) providing guanidinium hydrogen sulfite and preparing a solution comprising guanidinum and sulfite ions, c) mixing the solutions from step a) and b), d) incubating the solution obtained in step c) containing the nucleic acid and guanidinium and sulfite ions whereby the nucleic acid is deaminated, e) incubating the deaminated nucleic acid under alkaline conditions whereby the deaminated nucleic acid is desulfonated, and f) isolating the deaminated nucleic acid. 2. The method according to claim 1, wherein the concentration of guanidinium ions and sulfite ions is between 0.1 to 8 M. 3. The method according to claim 1, wherein the pH of the solutions in step b) and c) is less than 7.0. 4. The method according to claim 1, characterized in that the incubation temperature in step d) and e) is between 0° C. and 90° C. 5. The method according to claim 1, wherein the incubation time in step d) is between 30 min and 48 hours. 6. The method according to claim 1, wherein step e) is performed by adding an alkaline solution or buffer, or a solution containing ethanol, sodium chloride and sodium hydroxide. 7. The method according to claim 1, wherein the incubation temperature in step e) is between 0° C. and 90° C. 8. The method according to claim 1, wherein the incubation time in step e) is between 5 min and 60 min. 9-12. (canceled) 13. A kit containing guanidinium hydrogen sulfite and plasticware for performing a reaction in which a cytosine base in a nucleic acid is converted to a uracil base. 14. (canceled)

FIELD OF THE INVENTION The invention is related to the detection of a methylated cytosine in a nucleic acid wherein guanidinium hydrogen sulfite is used for the preparation of a solution containing guanidinium ions and sulfite ions and subsequent modification of the nucleic acid. Thereby, a non-methylated cytosine is converted to uracil. The invention further discloses uses of guanidinium hydrogen sulfite and kits containing it. BACKGROUND OF THE INVENTION Genes constitute only a small proportion of the total mammalian genome, and the precise control of their expression in the presence of an overwhelming background of noncoding desoxyribonucleic acid (DNA) presents a substantial problem for their regulation. Noncoding DNA, containing introns, repetitive elements, and potentially active transposable elements requires effective mechanisms for its long term silencing. Mammals appear to have taken advantage of the possibilities afforded by cytosine methylation to provide a heritable mechanism for altering DNA-protein interactions to assist in such silencing. DNA methylation is essential for the development of mammals; and plays a potential role during aging and cancer. The involvement of methylation in the regulation of gene expression and as an epigenetic modification marking imprinted genes is well established. In mammals, methylation occurs only at cytosine residues and more specifically only on cytosine residues adjacent to a guanosine residue, i.e. at the sequence CG. The detection and mapping of DNA methylation sites are essential steps towards understanding the molecular signals which indicate whether a given sequence is methylated. This is currently accomplished by the so-called bisulfite method described by Frommer, M., et al., Proc. Natl. Acad. Sci. USA 89 (1992) 1827-1831) for the detection of 5-methyl-cytosines. The bisulfite method of mapping 5-methylcytosine uses the effect that sodium hydrogen sulfite reacts with cytosine but not or only poorly with 5-methyl-cytosine. Cytosine reacts with bisulfite to form a sulfonated cytosine reaction intermediate being prone to deamination resulting in a sulfonated uracil which can be desulfonated to uracil under alkaline conditions. It is common knowledge that uracil has the base pairing behavior of thymine different to the educt cytosine whereas 5-methylcytosine has the base pairing behavior of cytosine. This makes the discrimination of methylated or non-methylated cytosines possible by e.g. bisulfite genomic sequencing (Grigg, G., and Clark, S., Bioessays 16 (1994) 431-436; Grigg, G. W., DNA Seq. 6 (1996) 189-198) or methylation specific PCR (MSP) disclosed in U.S. Pat. No. 5,786,146. There are various documents addressing specific aspects of the bisulfite reaction (Benyajati, C., et al., Nucleic Acids Res. 8 (1980) 5649-5667) make general investigations to the bisulfite modification of 5-methyl-deoxycytosine and deoxycytosine (Olek, A., et al., Nucleic Acids Res. 24 (1996) 5064-5066) disclose a method for bisulfite base sequencing whereby bisulfite treatment and subsequent PCR steps are performed on material embedded in agarose beads. In the bisulfite method as disclosed by Clark, S. J., et al., Nucleic Acids Res. 22 (1994) 2990-2997, the sample is desalted after deamination. Raizis, A. M., et al., Anal. Biochem. 226 (1995) 161-166 disclose a bisulfite method of 5-methylcytosine mapping that minimizes template degradation. They investigate the influence of pH, temperature and time of reaction. Similar investigations have been made by Grunau, C., et al., Nucleic Acids Res. 29 (2001) E65-5 or Warnecke, P. M., et al., Methods 27 (2002) 101-107. Different additional components in the bisulfite mixture are disclosed by WO 01/98528 or by Paulin, R., et al., Nucleic Acids Res. 26 (1998) 5009-5010. An additional bisulfite step after bisulfite treatment and PCR is disclosed in WO 02/31186. Komiyama, M., and Oshima, S., Tetrahedron Letters 35 (1994) 8185-8188) investigate the catalysis of bisulfite-induced deamination of cytosine in oligodeoxyribonucleotides. Kits for performing bisulfite treatments are commercially available from Intergen, distributed by Serologicals Corporation, Norcross, Ga., USA, e.g. CpGenome™ DNA modification kit. A variation of the bisulfite genomic sequencing method is disclosed by Feil, R., et al., Nucleic Acids Res. 22 (1994) 695-696, whereby the genomic DNA is bound to glass beads after deamination and washed. After elution the nucleic acid is desulfonated. It is known that nucleic acids can be isolated by the use of their binding behavior to glass surfaces, e.g. adsorption to silica gel or diatomic earths, adsorption to magnetic glass particles (MGPs) or organo silane particles under chaotropic conditions. Extraction using solid phases usually contains the steps of adding the solution with the nucleic acids to the solid phase under conditions allowing binding of the substance of interest to the solid phase, removal of the remainder of the solution from the solid phase bound nucleic acids and subsequent release of the nucleic acids from the solid phase into a liquid eluate (sometimes called elution). The result of the such process is usually a solution containing the substance of interest in dissolved state. Guanidinium hydrogen sulfite is known from various documents. U.S. Pat. No. 2,437,965 discloses a method for relaxing keratinous fibers using guanidinium hydrogen sulfite. U.S. Pat. No. 2,654,678 discloses the antistatic treatment of shaped articles using guanidinium salts. U.S. Pat. No. 4,246,285 discloses skin conditioning compositions containing guanidine inorganic salts. DE19527313 discloses guanidine derivatives and cosmetic articles containing them. All prior art methods for the bisulfite treatment have disadvantages. Therefore, the problem to be solved by the present invention was to provide a method wherein guanidinium hydrogen sulfite is used. SUMMARY OF THE INVENTION The invention is related to a method for the conversion of a cytosine base in a nucleic acid to an uracil base comprising the steps of a) providing a solution that contains a nucleic acid, b) providing guanidinium hydrogen sulfite and preparing a solution comprising guanidinium and sulfite ions, c) mixing the solutions from step a) and b) d) incubating the solution obtained in step c) containing the nucleic acid and guanidinium and sulfite ions whereby the nucleic acid is deaminated, e) incubating the deaminated nucleic acid under alkaline conditions whereby the deaminated nucleic acid is desulfonated, f) isolating the deaminated nucleic acid. In a further embodiment of the invention, guanidinium hydrogen sulfite is used for chemically modifying a nucleic acid, particularly in a method wherein a cytosine base in a nucleic acid is converted to an uracil base. In another embodiment of the invention, guanidinium hydrogen sulfite is used to prepare a solution comprising guanidinium and sulfite ions, particularly the solution is used for converting a cytosine base in a nucleic acid to an uracil base. In another embodiment of the invention, a kit containing guanidinium hydrogen sulfite is provided and uses of the kit according to the invention for a reaction wherein a cytosine base in a nucleic acid is converted to an uracil base in the presence of bisulfite ions. According to the invention the term a “bisulfite reaction”, “bisulfite treatment” or “bisulfite method” shall mean a reaction for the conversion of a cytosine base, in particular cytosine bases, in a nucleic acid to an uracil base, or bases, preferably in the presence of bisulfite ions whereby preferably 5-methyl-cytosine bases are not significantly converted. This reaction for the detection of methylated cytosines is described in detail by Frommer et al., supra and Grigg and Clark, supra. The bisulfite reaction contains a deamination step and a desulfonation step which can be conducted separately or simultaneously (see FIG. 1; Grigg and Clark, supra). The statement that 5-methyl-cytosine bases are not significantly converted shall only take the fact into account that it cannot be excluded that a small percentage of 5-methyl-cytosine bases is converted to uracil although it is intended to convert only and exclusively the (non-methylated) cytosine bases (Frommer et al., supra). DETAILED DESCRIPTION OF THE INVENTION The invention is related to a method for the conversion of a cytosine base in a nucleic acid to an uracil base comprising the steps of a) providing a solution, preferably a sample, that contains a nucleic acid, b) providing guanidinium hydrogen sulfite and preparing a solution comprising guanidinum and sulfite ions, c) mixing the solutions from step a) and b) or preferably the sample from step a) and the solution from step b), d) incubating the solution obtained in step c) containing the nucleic acid and guanidinium and sulfite ions whereby the nucleic acid is deaminated, e) incubating the deaminated nucleic acid under alkaline conditions whereby the deaminated nucleic acid is desulfonated, f) isolating the deaminated nucleic acid. Guanidinium hydrogen sulfite is a salt and used in solid form, i.e. it should be primarily in dry form and not contain water although minor amounts of water, including crystal water may be present. Guanidinium hydrogen sulfite may be produced as described in the invention (see Example 1) or as described in U.S. Pat. No. 2,437,965, U.S. Pat. No. 2,654,678, U.S. Pat. No. 4,246,285 or DE 19527313. The preparation of the solution comprising guanidinium and sulfite ions is accomplished by methods known to the expert skilled in the art, particularly by combining water or a buffered solution and the guanidinium hydrogen sulfite and mechanically agitation by e.g. shaking, stirring, pipetting the solution up and down or any other suitable means known to the expert skilled in the art. As said above, the guanidinium hydrogen sulfite may also be dissolved in a buffered solution which may be an aequeous buffer, may contain further substances as organic substances, salts and buffering constituents known to the expert in the field as phosphate, Tris, HEPES or other suitable buffers. The expert skilled in the art knows how to perform the bisulfite reaction, e.g. by referring to Frommer et al., supra or Grigg and Clark, supra who disclose the principal parameters of the bisulfite reaction. From Grunau et al., supra, it is known to the expert in the field what variations of the bisulfite method are possible. The influence of incubation time and temperature on deamination efficiency and parameters affecting DNA degradation is disclosed. In summary, in the deamination step a buffer containing bisulfite ions and chaotropic agents and optionally further reagents as an alcohol or stabilizers as hydroquinone are employed and the pH is in the acidic range. The concentration of bisulfite is between 0.1 to 6 M bisulfite, preferably 1 M to 5.5 M, the concentration of the chaotropic agent is between 1 to 8 M, whereby in general preferably guanidinium salts are employed but guanidinium hydrogen sulfite according to the invention as described herein, the pH is in the acidic range, preferably between 4.5 to 6.5, the temperature is between 0° C. to 90° C., preferably between room temperature (25° C.) to 90° C., and the reaction time is between 30 min to 24 hours or 48 hours or even longer, but preferably between 1 hour to 24 hours. The desulfonation step is performed by adding an alkaline solution or buffer as e.g. a solution only containing a hydroxide, e.g. sodium hydroxide, or a solution containing ethanol, sodium chloride and sodium hydroxide (e.g. 38% EtOH, 100 mM NaCl, 200 mM NaOH) and incubating at room temperature or elevated temperatures for several min, preferably 5 min to 60 min. Therefore, in an embodiment of the invention, in the method according to the invention, the concentration of guanidinium ions and sulfite ions is 0.1 to 8 M, preferably 2 to 8 M. In an embodiment of the invention, the pH of the solutions in step b) and c) of the method according to the invention is in the acidic range, preferably between 4.5 to 6.5. In an embodiment of the method according to the invention, the incubation temperature in step d) and e) of the method according to the invention is between 0° C. to 90° C., preferably between 18° C. to 90° C. In an embodiment of the method according to the invention, the incubation time in step d) is between 30 min to 48 hours, preferably 24 hours. In an embodiment of the invention, the step e) in the method according to the invention is performed by adding an alkaline solution or buffer, preferably a solution containing a hydroxide, preferably sodium hydroxide, or a solution containing ethanol, sodium chloride and sodium hydroxide, preferably a solution containing 38% (volume/volume) ethanol, 100 mM NaCl, 200 mM NaOH. In an embodiment of the invention, in the method according to the invention, the incubation temperature in step e) is between 0° C. to 90° C., preferably between 18° C. to 90° C. The incubation time in step e) of the method according to the invention is between 5 min to 60 min. In another embodiment of the invention, the incubation parameters as described in EP03001854.3 may be used, wherein the nucleic acid is incubated in a solution for a time period of 1.5 to 3.5 hours at a temperature between 70 and 90° C., whereby the concentration of bisulfite in the solution is between 3 M and 6.25 M and whereby the pH value of the solution is between 5.0 and 6.0 whereby the nucleic acid is deaminated. Desalting of the nucleic acid can be performed using magnetic glass particles as described in WO96/41811 or desulfonation and/or desalting can be performed as described in EP 1 394 172. In general, the method of the invention can be performed on solid surfaces as described in EP 1 394 172 or under the special conditions as described in EP 1 443 052. In an embodiment of the invention, the nucleic acid is desoxyribonucleic acid (DNA), in particular genomic DNA or nucleic acid, i.e. the DNA or nucleic acid which is found in the organism's genome and is passed on to offspring as information necessary for survival. The phrase is used to distinguish between other types of DNA, such as found within plasmids. The source of the nucleic acid may be eukaryotic or prokarytic, preferably from vertebrates, particularly from mammalians, most preferred from animals or humans. The solution that contains a nucleic acid is preferably a sample that contains a nucleic acid. Other compounds may be present but it is preferred that the solution containing the nucleic acid is as pure as possible. In another embodiment, the solution contains other insoluble components, i.e. it is a suspension preferably containing material comprising glass as e.g. magnetic glass particles as described in EP 1 394 172. In an embodiment of the invention the solution or the sample containing the nucleic acid is obtained from a biological sample using e.g. solid phases (see e.g. WO96/41811 or WO01/37291 or the MagNAPure® System available from Roche Diagnostics, Mannheim Germany) or other methods known to the expert in the field (see e.g. Sambrook et al.: Molecular Cloning, A Laboratory Manual, 2nd Addition, Cold Spring Harbour Laboratory Press, Cold Spring Harbour, N.Y. and Ausubel et al.: Current Protocols in Molecular Biology 1987, J. Wiley and Sons, NY or commercial DNA isolation kits available e.g. from Qiagen, Hilden Germany). The biological sample comprises cells from multicellular organisms as e.g. human and animal cells such as Leucocytes, and immunologically active low and high molecular chemical compounds such as haptens, antigens, antibodies and nucleic acids, blood plasma, cerebral fluid, sputum, stool, biopsy specimens, bone marrow, oral rinses, blood serum, tissues, urine or mixtures thereof. In a preferred embodiment of the invention the biological sample is a fluid from the human or animal body. The biological sample may be blood, blood plasma, blood serum or urine. The biological sample comprising the nucleic acid is lysed to create a mixture of biological compounds comprising nucleic acids and other components. Procedures for lysing biological samples are known by the expert and can be chemical, enzymatic or physical in nature. A combination of these procedures is applicable as well. For instance, lysis can be performed using ultrasound, high pressure, shear forces, alkali, detergents or chaotropic saline solutions, or proteases or lipases. For the lysis procedure to obtain nucleic acids, special reference is made to Sambrook et al.: Molecular Cloning, A Laboratory Manual, 2nd Addition, Cold Spring Harbour Laboratory Press, Cold Spring Harbour, N.Y. and Ausubel et al.: Current Protocols in Molecular Biology 1987, J. Wiley and Sons, NY. Then the nucleic acids are isolated from the lysis mixture using the methods and solid phases according to the invention and can then be subjected to the methods according to the invention, i.e. the bisulfite treatment according to the invention. Chaotropic agents are also used to lyse cells to prepare a mixture between nucleic acids and other biological substances (see e.g. Sambrook et al. (1989) or EP 0 389 063). Afterwards the material comprising glass or silica may be added and a purification effect results from the behavior of DNA or RNA to bind to material with a glass surface under these conditions i.e. in the presence of certain concentrations of a chaotropic agent, higher concentrations of organic solvents or under acidic conditions. Alternative methods may be used as well. In another embodiment of the invention, a method is provided for the conversion of a cytosine base in a nucleic acid to an uracil base comprising the steps of a) providing guanidinium hydrogen sulfite and preparing a solution comprising guanidinum and sulfite ions, b) mixing the solution from step a) with a solution, preferably a sample, containing a nucleic acid, c) incubating the solution obtained in step b) containing the nucleic acid and guanidinium and sulfite ions whereby the nucleic acid is deaminated, d) incubating the deaminated nucleic acid under alkaline conditions whereby the deaminated nucleic acid is desulfonated, e) isolating the deaminated nucleic acid. After the steps of the method according to the invention, further steps may be performed. In a preferred embodiment of the invention, the nucleic acid is amplified with the polymerase chain reaction (PCR; EP 0 201 184, EP-A-0 200 362, U.S. Pat. No. 4,683,202). The amplification method may also be the ligase Chain Reaction (LCR, Wu, D. Y., and Wallace, R. B., Genomics 4 (1989) 560-569 and Barany, F., Proc. Natl. Acad. Sci. USA 88 (1991) 189-193; Polymerase Ligase Chain Reaction (Barany, F., PCR Methods Appl. 1 (1991) 5-16); Gap-LCR(PCT Patent Publication No. WO 90/01069); Repair Chain Reaction (European Patent Publication No. EP 439,182 A2), 3SR (Kwoh, D. Y., et al., Proc. Natl. Acad. Sci. USA 86 (1989) 1173-1177; Guatelli, J. C., et al., Proc. Natl. Acad. Sci. USA 87 (1990) 1874-1878; PCT Patent Publication No. WO 92/0880A), and NASBA (U.S. Pat. No. 5,130,238). Further, there are strand displacement amplification (SDA), transciption mediated amplification (TMA), and Qβ-amplification (for a review see e.g. Whelen, A. C., and Persing, D. H., Annu. Rev. Microbiol. 50 (1996) 349-373; Abramson, R. D., and Myers, T. W., Curr. Opin. Biotechnol. 4 (1993) 41-47). Particularly preferred amplification methods according to the invention are the methylation specific PCR method (MSP) disclosed in U.S. Pat. No. 5,786,146 which combines bisulfite treatment and allele-specific PCR (see e.g. U.S. Pat. No. 5,137,806, U.S. Pat. No. 5,595,890, U.S. Pat. No. 5,639,611). The bisulfite treatment may be performed according to the invention. In a preferred embodiment, the method may further comprise the step of detecting the amplified nucleic acid. The amplified nucleic acid may be determined or detected by standard analytical methods known to the person skilled in the art and described e.g. in Sambrook, et al., Molecular Cloning, Cold Spring Harbor University Press (1989), Lottspeich and Zorbas, in “Bioanalytik” (1998), Eds. L. a. Zorbas, Spektrum Akademischer Verlag, Heidelberg, Berlin, Germany, or in Ausubel, F., et al., in “Current protocols in molecular biology” (1994), Eds. F. Ausubel, R. Brent and K. R. E., Wiley & Sons Verlag, New York. There may be also further purification steps before the target nucleic acid is detected e.g. a precipitation step. The detection methods may include but are not limited to the binding or intercalating of specific dyes as ethidium bromide which intercalates into the double-stranded DNA and changes its fluorescence thereafter. The purified nucleic acids may also be separated by electrophoretic methods optionally after a restriction digest and visualized thereafter. There are also probe-based assays which exploit the oligonucleotide hybridisation to specific sequences and subsequent detection of the hybrid. It is also possible to sequence the target nucleic acid after further steps known to the expert in the field. Other methods apply a diversity of nucleic acid sequences to a silicon chip to which specific probes are bound and yield a signal when a complementary sequences bind. In a particularly preferred embodiment of the invention, the nucleic add is detected by measuring the intensity of fluorescence light during amplification. This method entails the monitoring of real time fluorescence. A particularly preferred method exploiting simultaneous amplification and detection by measuring the intensity of fluorescent light is the TaqMan® method disclosed in WO 92/02638 and the corresponding US patents U.S. Pat. No. 5,210,015, U.S. Pat. No. 5,804,375, U.S. Pat. No. 5,487,972. This method exploits the exonudease activity of a polymerase to generate a signal. In detail, the nucleic acid is detected by a process comprising contacting the sample with an oligonucleotide containing a sequence complementary to a region of the target nucleic acid and a labeled oligonucleotide containing a sequence complementary to a second region of the same target nucleic acid strand, but not including the nucleic acid sequence defined by the first oligonucleotide, to create a mixture of duplexes during hybridization conditions, wherein the duplexes comprise the target nucleic acid annealed to the first oligonucleotide and to the labeled oligonucleotide such that the 3′-end of the first oligonucleotide is adjacent to the 5′-end of the labeled oligonucleotide. Then this mixture is treated with a template-dependent nucleic acid polymerase having a 5′ to 3′ nuclease activity under conditions sufficient to permit the 5′ to 3′ nuclease activity of the polymerase to cleave the annealed, labeled oligonucleotide and release labeled fragments. The signal generated by the hydrolysis of the labeled oligonucleotide is detected and/or measured. TaqMan® technology eliminates the need for a solid phase bound reaction complex to be formed and made detectable. In more general terms, the amplification and/or detection reaction of the method according to the invention is a homogeneous solution-phase assay. Further preferred method are the formats used in the LightCycler® instrument (see e.g. U.S. Pat. No. 6,174,670). Particularly preferred is the use of bisulfite treatment, amplification with or without methylation specific primers in the presence of a methylation-specific probe and real-time fluorescence detection as described in U.S. Pat. No. 6,331,393. In a preferred embodiment of the present invention, the method is automated, i.e. the method carries out an automatable process as e.g. described in WO 99/16781. Automatable process means that the steps of the process are suitable to be carried out with an apparatus or machine capable of operating with little or no external control or influence by a human being. Automated method means that the steps of the automatable method are carried out with an apparatus or machine capable of operating with little or no external control or influence by a human being. Only the preparation steps for the method may have to be done by hand, e.g. the storage containers have to filled up and put into place, the choice of the samples has to be done by a human being and further steps known to the expert in the field, e.g. the operation of the controlling computer. The apparatus or machine may e.g. add automatically liquids, mix the samples or carry out incubation steps at specific temperatures. Typically, such a machine or apparatus is a robot controlled by a computer which carries out a program in which the single steps and commands are specified. In a preferred embodiment of the invention, the method is in a high-throughput format, i.e. the automated methods is carried out in a high-throughput format which means that the methods and the used machine or apparatus are optimized for a high-throughput of samples in a short time. Preferably the method according to the invention is used in diagnostics, for diagnostic analysis or for bioanalytics, or for the screening of tissue or fluids from the human or even animal body for the presence of certain methylation pattern. Further, the method according to the invention is used to enhance the speed, accuracy or sensitivity of the detection of methylation sites in nucleic acids. In an embodiment of the invention, guanidinium hydrogen sulfite is used for chemically modifying a nucleic acid, preferably wherein a cytosine base in a nucleic acid is converted to an uracil base. In another embodiment of the invention, guanidinium hydrogen sulfite is used to prepare a solution comprising guanidinum and sulfite ions. Preferably, the solution is used for converting a cytosine base in a nucleic acid to an uracil base. In another preferred embodiment, the present invention is directed to a kit for performing a bisulfite reaction containing guanidinium hydrogen sulfite or a solution comprising bisulfite ions and guanidinium prepared from guanidinium hydrogen sulfite. Generally, kits known in the art further comprise plastics ware which may be used during the bisulfite procedure as e.g. microtiter-plates in the 96 or 384 well format or reaction tubes manufactured e.g. by Eppendorf, Hamburg, Germany. Further, additional reagents may be present which contain buffers suitable for use in the present invention, primers, probes, a DNA polymerase, preferably a thermostabile DNA polymerase and possibly nucleotides. Therefore, in an embodiment of the invention a kit is provided comprising guanidinium hydrogen sulfite, primers, probes, a DNA polymerase and nucleotides. Preferably, the kit according to the invention is used for a reaction wherein a cytosine base, preferably cytosine bases, in a nucleic acid is converted to an uracil base, preferably uracil bases, in the presence of bisulfite ions whereby preferably 5-methyl-cytosine bases are not significantly converted. The following examples, references and figures are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims. It is understood that modifications can be made in the procedures set forth without departing from the spirit of the invention. DESCRIPTION OF THE FIGURES FIG. 1: The steps of the bisulfite method FIGS. 2 to 4: HPLC profiles of the reaction mixtures after certain time periods as indicated in the examples FIG. 2a) 1 M sodium hydrogensulfite, 30 min FIG. 2b) 1 M guanidinium hydrogensulfite, 30 min FIG. 3a) 2 M sodium hydrogensulfite, 30 min FIG. 3b) 2M guanidinium hydrogensulfite, 30 min FIG. 4a) 2 M sodium hydrogensulfite, 60 min FIG. 4b) 2 M guanidinium hydrogensulfite, 60 min EXAMPLES 1 Production of Guanidinium Hydrogen Sulfite 130 g (722 mmol) of guanidine carbonate (Fluka 50930) was dissolved in 700 ml of water at room temperature. A stream of SO2 was bubbled through this solution for several hours until pH 2-3 was measured. The yellow solution was lyophilised. The yield of the colorless product was 184 g. 1H-NMR ([D6] DMSO, 300 MHz): δ=7.12 (s, 6H). 13C-NMR ([D6] DMSO, 75 MHz): δ=158.3. Elementary analysis yielded data as expected. 2 Desamination Reaction with an Oligonucleotide 2.1.1 Experimental Design: A double stranded nucleic acid formed from two oligonucleotides (“GSTP1 ds”) is treated with sodium disulfite or guanidinium hydrogensulfite in different molar concentrations. After this procedure the GSTP1 ds is desulfonated and desalted. The purified GSTP1 ds is analysed by HPLC (see FIGS. 2 to 4). The two oligonucleotides forming the double-stranded nucleic acid (“GSTP1 ds”) are described below and have the sequences SEQ ID NO: 1 and 2. 2.1.2 Method 2.1.2.1 Oligonucleotides Oligo 1: 5′-GGG ACT CCA GGG CGC CCC TC-3′ (SEQ ID NO: 1) MW = 6079.97 Da 1OD = 5.04 nmol Oligo 2: 5′-GAG GGG CGC CCT GGA GTC CC-3′ (SEQ ID NO: 2) MW = 6159.99 Da 1OD 4.83 nmol 2.1.2.2 Deamination of GSTP1 ds Using Sodium Disulfite: 5 nmol (MW 12239.96 Da) of GSTP1 ds are mixed with 200 μl of bisulfite reagent (1-2M, pH 5.5) and incubated for several minutes (30 min-60 min) at 80° C. 2.1.2.3 Deamination of GSTP1 ds Using Guanidinium Hydrogensulfite: 5 nmol (MW 12239.96 Da) of GSTP1 ds are mixed with 200 ul of bisulfite reagent (1-2M, pH 5.5) and incubated for several minutes (30 min-60 min) at 80° C. 2.1.2.4 Desulfonation and Desalting: 200 μl of the deaminated GSTP1 ds are mixed with 500 μl of 2N KOH and left for 30 minutes at room temperature. Thereafter a gel filtration with water on Sephadex G -25M (Pharmacia, Code No. 17-0851-01, Lot. No. QG 11018, bed volume 9 ml) takes place. The solvent is removed and the residue dissolved in 200 μl of water. 40 μl are used for the HPLC. 2.1.2.5 HPLC: Column: Dionex DNAPac PA-100SEL, 4×250 mm with precolumn: Product No. SP3816 Serial No. 0440 Solvent A: 0.2 M NaCl in 0.01 M NaOH Solvent B: 1 M NaCl in 0.01 M NaOH Gradient: 0 min: 50% A/50% B 25 min: 100% B, 1 ml/min The kinetic of the bisulfite reaction is analysed via HPLC. It is shown that under the same conditions the kinetic of the deamination process is much faster with relative low concentrations (2 M) of guanidinium hydrogensulfite in comparison with the standard reagent sodiumhydrogensulfite (see FIGS. 2 to 4). This shows clearly at relative low bisulfite concentration the advantages of the chaotropic guanidinium cation over sodium. The chromatogram of the 1 M bisulfite reaction is an example of the status shortly after starting the bulfite reaction. As later the elution the more the deamination reaction is completed. 3 Establishment of a LC-PCR Specific for Bisulphite Treated DNA General The fact that the bisulfite reaction has worked and converted non-methylated cytosines to uracil can be demonstrated by a polymerase chain reaction whereby primers are used which are specific to a region of the nucleic acid sequence wherein non-methylated cytosines have been converted to uracils, i.e. the base adenine in the primer is opposite to the uracil being the bisulfite reaction product from non-methylated cytosines. In case of incomplete conversion, the primer could not hybridize to this region as there would be cytosines not matching the adenine bases in the primer. This would have the effect that no PCR product would be obtained. An improved method to perform rapid polymerase chain reactions is disclosed e.g. in U.S. Pat. No. 6,174,670 and is used in the LightCycler® instrument (Roche, Mannheim, Germany). In this method, two labeled probes can come into close proximity in an amplificate dependent manner so that the two labels can perform a fluorescence energy transfer (FRET). The amount of the amplificate thereby correlates with the intensity of the emitted light of a certain wavelength. This specific PCR method can therefore be used to analyze whether a complete conversion of non-methylated cytosines was obtained, by e.g. analyzing the promoter region of the glutathion-S-transferase π gene (see e.g. SEQ ID NO: 3 for the full length sequence of this gene and the promoter, U.S. Pat. No. 5,552,277, Genbank accession code M24485 and Morrow, C. S., et al., Gene 75 (1989) 3-11) using suitable probes and primers. However, the expert skilled in the art knows that other methods can be used for this evaluation as well. Fluorescence measurements are normalized by dividing by an initial fluorescence measurement, i.e., the background fluorescence, obtained during a cycle early in the reaction while the fluorescence measurements between cycles appear to be relatively constant. The cycle number chosen for the initial fluorescence measurement is the same for all reactions compared, so that all measurements represent increases relative to the same reaction cycle. In the early cycles of a polymerase chain reaction amplification, the number of target molecules can be described by the geometric equation Ni=No×(1+E)i, where No=the number of target molecules at the start of the reaction, Ni=the number of target molecules at the completion of the i-th cycle, E=the efficiency of the amplification (0=<E=<1). During this geometric growth phase of the amplification, the number of cycles required to reach a particular threshold value (CT value or crossing point) is inversely proportional to the logarithm of (1+E). Thus, the CT value represents a measure of the reaction efficiency that allows comparisons between reactions. A decrease in the CT value, which means that the reaction reached the threshold value in fewer cycles, indicates an increase in reaction efficiency. As the increase in amplification product is monitored by measuring the increase in reaction fluorescence, the CT is defined herein as the number of amplification cycles carried out until the fluorescence exceeded an arbitrary fluorescence level (AFL). The AFL was chosen close to the baseline fluorescence level, but above the range of random fluctuations in the measured fluorescence, so that the reaction kinetics were measured during the geometric growth phase of the amplification. Accumulation of amplified product in later cycles inhibits the reaction and eventually leads to a reaction plateau. An AFL of 1.5 was chosen for all reactions. Because a PCR amplification consists of discrete cycles and the fluorescence measurements are carried out once per cycle, the measured fluorescence typically increases from below the AFL to above the AFL in a single cycle. To improve the precision of the measurements, an “exact” number of cycles to reach the AFL threshold, referred to herein as the CT value or crossing point, was calculated by interpolating fluorescence measurements between cycles. General Methodology The following experiment demonstrates that the described PCR on the LightCycler® instrument can be used as an evaluation tool for bisulfite treated DNA. It shows that the designed primer/probe combination gives positive results only with DNA after bisulfite treatment. Bisulfite treated DNA (in this case bisulfite DNA was treated according to the protocol described in example 2) and untreated DNA were amplified in parallel using the same template concentrations (20 ng and 1 ng per PCR). PCR analysis on the LightCycler® instrument 3.1.1 Composition of Mastermix: LC FastStart DNA Master HybridizationProbe 1×, 2 mM MgCl2, forward Primer 0.5 μM, reversed Primer 0.5 μM, donor probe 250 nM, acceptor probe 250 nM, template 10 μl, total PCR volume 20 μl. 3.1.2 PCR-Conditions: Denaturation 10 min/95° C. 55 cycles 95° C./10 s 65° C./10 s−signal acquisition 72° C./10 s Ramp time 20° C./s 3.1.3 Result MDNA/PCR Bisulphite treatment CT-Value or Crossingpoint 20 ng Yes 30.55 29.72 29.95 30.06 1 ng yes 34.7 35.8 34.07 33.86 20 ng No No growth curve No growth curve No growth curve No growth curve 1 ng No No growth curve No growth curve No growth curve No growth curve The result shows crossing points only for bisulfite treated DNA. Therefore this PCR is suitable in evaluating bisulfite methods. For those skilled in the art it is clear that any PCR might be used as an evaluation tool if it is guaranteed that the primer/probe combination does not react with DNA before bisulfite treatment. 4 Gua-Hydrogen-Sulfite can Replace the Standard Deamination Reagent Sodium-Bisulfite During Analysis of DNA Methylation Experimental Design: Methylated DNA is spiked in unmethylated DNA, denatured and then treated in parallel with sodium bisulfite or guanidinium hydrogen sulfite. Thereafter, the DNA is desalted using magnetic glass particles, desulfonated and again desalted. The purified DNA is analysed using a real time kinetic PCR protocol that detects only bisulfite treated methylated DNA. 4.1.1 Denaturation of DNA: 100 μl of methylated DNA (Serologicals Corporation, Norcross, Ga., USA; Cat S 7821) dilution (50 ng/assay spiked in 1000 ng HDNA background, Roche Cat.1691112; 5 replicates per method), and 11 μl 2 M NaOH are mixed and incubated for 10 min at 37° C. 4.1.2 Deamination of DNA: Method 1 Using Standard Reagent Sodium-Bisulfite 111 μl of the denatured DNA are mixed with 200 μl bisulfite reagent (2.5M sodium bisulfite=5M sulfite solution, 125 mM hydroquinone, pH 5.5) and incubated for 2 h at 80° C. 4.1.3 Deamination of DNA: Method 2 Using Reagent Guanidinium-Hydrogen-Sulfite 111 μl of the denatured DNA are mixed with 200 μl bisulfite reagent (5M guanidinium hydrogen sulfite, pH 5.5) and incubated for 2 h at 80° C. 4.1.4 Processing Using MGPs 311 μl of the deaminated DNA are mixed with 600 μl binding buffer (MagNAPure DNA Isolation Kit I, Roche Cat. Nr. 3 003 990) and 75 μl magnetic glass particle solution (MagNAPure DNA Isolation Kit I) and incubated for 15 min/room temperature with continuous mixing. Thereafter, the magnetic glass particles are washed three times with 1 ml 70% Ethanol. Bound free separation is done in a magnetic separator (Roche Cat.1641794). Thereafter, desulphonation takes place by adding 250 μl 90% EtOH/20 mM NaOH to the DNA bound to the MGPs; the mixture is incubated for 10 min at room temperature with mixing. Thereafter the MGPs are washed two times with 90% Ethanol. To remove ethanol rests the MGPs are heated for 15 min./60° C. in a thermomixer with open lid. Thereafter the DNA is eluted with 50 μl 10 mM Tris/0.1 mM EDTA pH 7.5 (15 min/60° C.). 10 μl of the eluted DNA is used for subsequent PCR analysis. Analysis of Deaminated DNA on the LightCyler® Instrument 4.1.5 Composition of Mastermix LightCycler® FastStart DNA Master HybridizationProbe 1× (Roche 2239272), 3 mM MgCl2, forward Primer 0.4 μM, reversed Primer 0.4 μM, donor probe 200 nM, acceptor probe 200 nM, template 10 μl, total PCR volume 20 μl. 4.1.6 PCR-Conditions Denaturation 10 min/95° C. 55 cycles 95° C./10 s 62° C./10 s−signal acquisition 72° C./10 s Ramp time 20° C./s Results: Guanidinium Sodium bisulfite hydrogensulfite Methylated reagent reagent replicates DNA/PCR CT-Values or Crossing points 1 10 ng 30.24 29.22 2 10 ng 29.68 29.85 3 10 ng 30.20 29.64 4 10 ng 29.89 29.74 5 10 ng 29.81 29.18 Mean value 29.96 29.53 The CT-values or crossing points calculated during real time PCR are almost identical for both sulfite reagents used, for guanidinium hydrogensulfite the mean value is even lower; i.e. that guanidinium hydrogensulfite can replace the standard deamination reagent showing a somewhat better performance. 5 Use of Guanidinium Hydrogen Sulfite Without Prior Denaturation of DNA for Methylation Analysis Experimental Design: Methylated DNA is spiked in unmethylated DNA, denatured or not denatured and then treated in parallel with sodium bisulfite or guanidinium hydrogen sulfite. Thereafter, the DNA is desalted using magnetic glass particles, desulfonated and again desalted. The purified DNA is analysed using a real time kinetic PCR protocol that detects only bisulfite treated methylated DNA. 5.1.1 Denaturation of DNA: 100 μl of methylated DNA (Serologicals Corporation, Norcross, Ga., USA; Cat S 7821) dilution (50 ng/assay spiked in 1000 ng hDNA background, Roche Cat.1691112; 4 replicates per method), and 11 μl 2 M NaOH are mixed and incubated for 10 min at 37° C. 5.1.2 Deamination of DNA: Method 1 Using Standard Reagent Sodium-Bisulfite 111 μl of the denatured DNA or 100 μl of not denatured DNA are mixed with 200 μl bisulfite reagent (2.5M sodium bisulfite, 125 mM hydroquinone, pH 5.5) and incubated for 2 h at 80° C. 5.1.3 Deamination of DNA: Method 2 Using Reagent Guanidinium-Hydrogen-Sulfite 111 μl of the denatured DNA or 100 μl of not denatured DNA are mixed with 200 μl bisulfite reagent (5M guanidinium hydrogen sulfite, pH 5.5) and incubated for 2 h at 80° C. 5.1.4 Processing Using MGPs 311 μl of the deaminated DNA are mixed with 600 μl binding buffer (MagNAPure DNA Isolation Kit I, Roche Cat. Nr. 3 003 990) and 75 μl magnetic glass particle solution (MagNAPure DNA Isolation Kit I) and incubated for 15 min/room temperature with continuous mixing. Thereafter, the magnetic glass particles are washed three times with 1 ml 70% Ethanol. Bound free separation is done in a magnetic separator (Roche Cat.1641794). Thereafter, desulphonation takes place by adding 250 μl 90% EtOH/20 mM NaOH to the DNA bound to the MGPs; the mixture is incubated for 10 min at room temperature with mixing. Thereafter the MGPs are washed two times with 90% Ethanol. To remove residual ethanol the MGPs are heated for 15 min/60° C. in a thermomixer with open lid. Thereafter the DNA is eluted with 50 μl 10 mM Tris/0.1 mM EDTA pH 7.5 (15 min./60° C.). 10111 of the eluted DNA is used for subsequent PCR analysis. Analysis of Deaminated Treated DNA on the LightCycler® Instrument 5.1.5 Composition of Mastermix LightCycler® FastStart DNA Master HybridizationProbe 1× (Roche 2239272), 3 mM MgCl2, forward Primer 0.4 μM, reversed Primer 0.4 μM, donor probe 200 nM, acceptor probe 200 nM, template 10 μl, total PCR volume 20 μl. 5.1.6 PCR-Conditions Denaturation 10 min/95° C. 55 cycles 95° C./10 s 62° C./10 s−signal acquisition 72° C./10 s Ramp time 20° C./s Results: Guanidinium Sodium Guanidinium Sodium disulfite hydrogensulfite disulfite hydrogensulfite reagent reagent reagent reagent With With Without Without Methylated denaturation denaturation denaturation denaturation replicates DNA/PCR CT-Values or Crossing points 1 10 ng 29.74 29.06 34.35 33.62 2 10 ng 29.48 29.85 35.17 33.92 3 10 ng 29.66 29.86 33.64 33.60 4 10 ng 29.80 29.86 33.10 33.63 Mean 29.67 29.66 34.07 33.69 value The result shows that the Bisulfite reaction does work without prior denaturation of DNA; the novel reagent guanidinium hydrogen sulfite is more efficient because the median of the crossing points is lower than that of the standard bisulfite reagent. 6 Guanidinium Hydrogensulfit can be Used in Lower Molar Concentrations for Methylation Analysis Experimental Design: Methylated DNA is spiked in unmethylated DNA, denatured and then treated in parallel with sodium disulfite or guanidinium hydrogen sulfite in different molar concentrations. Thereafter, the DNA is desalted using magnetic glass particles, desulfonated and again desalted. The purified DNA is analysed using a real time kinetic PCR protocol that detects only bisulfite treated methylated DNA. 6.1.1 Denaturation of DNA: 100 μl of methylated DNA (Serologicals Corporation, Norcross, Ga., USA; Cat S 7821) dilution (50 ng/assay spiked in 1000 ng HDNA background, Roche Cat.1691112; 4 replicates per method), and 11 μl 2 M NaOH are mixed and incubated for 10 min at 37° C. 6.1.2 Deamination of DNA: Method 1 Using Standard Reagent Sodium-Bisulfite 111 μl of the denatured DNA or 100 μl of not denatured DNA are mixed with 200 μl bisulfite reagent (2.5M-1.5M-0.5M sodium disulfite, 125 mM hydroquinone, pH 5.5) and incubated for 2 h at 80° C. (Comment: a 2.5M solution of sodium disulfite is 5M regarding sulfite ions) 6.1.3 Deamination of DNA: Method 2 Using Reagent Guanidinium-Hydrogen-Sulfite 111 μl of the denatured DNA or 100 μl of not denatured DNA are mixed with 200 μl bisulfite reagent (5M-3M-1M guanidinium hydrogen sulfite, pH 5.5) and incubated for 2 h at 80° C. 6.1.4 Processing Using MGPs 311 μl of the deaminated DNA are mixed with 600 μl binding buffer (MagNAPure DNA Isolation Kit I, Roche Cat. Nr. 3 003 990) and 75 μl magnetic glass particle solution (MagNAPure DNA Isolation Kit I) and incubated for 15 min/room temperature with continuous mixing. Thereafter, the magnetic glass particles are washed three times with 1 ml 70% Ethanol. Bound free separation is done in a magnetic separator (Roche Cat.1641794). Thereafter, desulphonation takes place by adding 250 μl 90% EtOH/20 mM NaOH to the DNA bound to the MGPs; the mixture is incubated for 10 min at room temperature with mixing. Thereafter the MGPs are washed two times with 90% Ethanol. To get rid of ethanol rests the MGPs were heated for 15 min./60° C. in a thermomixer with open lid. Thereafter the DNA is eluted with 50 μl 10 mM Tris/0.1 mM EDTA pH 7.5 (15 min./60° C.). 10 μl of the eluted DNA is used for subsequent PCR analysis. Analysis of Deaminated Treated DNA on the Lightycler® Instrument 6.1.5 Composition of Mastermix LightCycler® FastStart DNA Master HybridizationProbe 1× (Roche 2239272), 3 mM MgCl2, forward Primer 0.4 μM, reversed Primer 0.4 μM, donor probe 200 nM, acceptor probe 200 nM, template 10 μl, total PCR volume 20 μl. 6.1.6 PCR-Conditions Denaturation 10 min/95° C. 55 cycles 95° C./10 s 62° C./10 s−signal acquisition 72° C./10 s Ramp time 20° C./s Results: Sodium Guanidinium Amount of disulfite hydrogensulfite sulfite during reagent reagent Methylated deamination CT-Values or Replicates DNA/PCR reaction Crossing points 1 10 ng 5M 29.24 28.56 2 10 ng 5M 29.36 29.35 3 10 ng 5M 29.19 28.87 4 10 ng 5M 29.61 28.94 Mean value 29.35 28.93 1 10 ng 3M 30.67 29.76 2 10 ng 3M 30.20 29.68 3 10 ng 3M 30.61 30.59 10 ng 3M 31.10 30.53 Mean value 30.65 30.14 1 10 ng 1M — — 2 10 ng 1M — — 3 10 ng 1M — — 4 10 ng 1M 41.64 — Mean value The results show that desamination is also possible with a lower molar concentration of sulfite ions, but the sensitivity drops; a concentration of 1M is too low. The novel reagent is somewhat more efficient because the difference in crossing points between 5M and 3M is 1.21, whereas for the standard reagent it is 1.3. 7 GuaSulfit can be Used for Solid Phase Deamination in DNA Methylation analysis Experimental Design Methylated DNA is spiked in unemthylated DNA, denatured in solution and transfer to silica solid phase (column). Deamination is done in parallel with sodium disulfite or guanidinium hydrogen sulfite. Thereafter the DNA is desalted, desulfonated and again desalted. The purified DNA is analysed using a real time kinetic PCR protocol that detects only bisulfite treated methylated DNA. 7.1.1 Denaturation of DNA: 100 μl of methylated DNA (Serologicals Corporation, Norcross, Ga., USA; Cat S 7821) dilution (50 ng/assay spiked in 1000 ng HDNA background, Roche Cat.1691112; 3 replicates per method), and 11 μl 2 M NaOH are mixed and incubated for 15 min at 37° C. 7.1.2 Solid Phase Deamination of DNA: Method 1 Using Standard Reagent Sodium-Bisulfite 111 μl of the denatured DNA are mixed with 300 μl bisulfite reagent (2.5M sodium bisulfite=5M sulfite in solution, pH 5.5) and 100 μl ethanol and loaded on to a silica column (from High Pure Template Preparation Kit, Roche, 1796828); incubation is overnight at 50° C. 7.1.3 Solid Phase Deamination of DNA: Method 2 Using Reagent Guanidinium-Hydrogen-Sulfite 111 μl of the denatured DNA are mixed with 300 μl bisulfite reagent (5M guanidinium hydrogensulfite, pH 5.5) and 1001 μl ethanol and loaded on to a silica column (from High Pure Template Preparation Kit, Roche, 1796828); incubation is overnight at 50° C. 7.1.4 Processing on Silica Columns After overnight incubation columns are centrifuged 1 min/800 rpm (Eppendorf bench top centrifuge) and two times washed with 500 μl 70% ethanol. Desulfonation is performed by adding 500 μl reagent (38% ethanol/100 mM EDTA/200 mM NaOH) and incubation for 20 min. at room temperature. After short centrifugation the columns are washed twice with 500 μl 90% ethanol each. To remove the entire ethanol the columns are centrifuged for 20 sec at 14000 rpm. Bound DNA is eluted by adding 100 μl prewarmed (70° C.) PCR grade water. The columns are centrifuged again and the supernatant is used for subsequent PCR analysis Analysis of Deaminated Treated DNA on the LightCycler® Instrument 7.1.5 Composition of Mastermix LightCycler® FastStart DNA Master HybridizationProbe 1× (Roche 2239272), 3 mM MgCl2, forward Primer 0.4 μM, reversed Primer 0.4 μM, donor probe 200 nM, acceptor probe 200 nM, template 10 μl, total PCR volume 20 μl. 7.1.6 PCR-Conditions Denaturation 10 min/95° C. 55 cycles 95° C./10 s 62° C./10 s−signal acquisition 72° C./10 s Ramp time 20° C./s Results: Solid phase Solid phase desamination with desamination with Guanidinium Sodium disulfite reagent hydrogensulfite reagent Replicates CT-Values or Crossing points 1 32.72 31.68 2 32.85 31.64 3 32.47 31.75 Mean value 32.68 31.69 The results show that solid phase desamination is possible with both sulfite reagents, but the efficiency for the novel reagent is significantly higher: the resulting crossing points are 1 cycle earlier corresponding to a twofold better yield of bisulfite treated DNA. 8 GuaSulfit can be Used for Combined Process SP+BIS Experimental Design A clinical sample is directly contacted with the bisulfite reagent (GuaSulfit or Na-Bisulfit) without prior purification of the DNA. After incubation the processing of the converted DNA is done using the magnetic glass particles as usual. The purified DNA is analysed using a real time kinetic PCR protocol that detects only bisulfite treated DNA. 8.1.1 Combined SP and BIS Process: 200 μl of normal human serum or normal human serum spiked with 0.2 μg of nucleosomal DNA (3 replicates each) are mixed with 50 μl Proteinase K (Roche) and 600 μl BIS reagent (either 6M Guanidiniumhydrogen-Sulfit or 5M Sodiumbisulfite); pH is adjusted to 5.5 with 5M NaOH. Then the mixture is incubated for 2 h at 80° C. in a thermomixer. 8.1.2 Processing Using MGPs Thereafter 6 mg magnetic glass particles ((MagNAPure DNA Isolation Kit I, Roche Cat. Nr. 3 003 990) in 600 μl isopropanol are added, and the solution is mixed thoroughly and incubated for 15 min/room temperature with continuous mixing. Thereafter, the magnetic glass particles are washed three times with 1 ml 70% Ethanol. Bound free separation is done in a magnetic separator (Roche Cat. 1641794). Thereafter, desulphonation takes place by adding 250 μl 90% EtOH/20 mM NaOH to the DNA bound to the MGPs; the mixture is incubated for 10 min at room temperature with mixing. Thereafter the MGPs are washed two times with 90% Ethanol. To get rid of ethanol rests the MGPs were heated for 15 min./60° C. in a thermomixer with open lid. Thereafter the DNA is eluted with 500 μl 10 mM Tris/0.1 mM EDTA pH 7.5 (15 min./60° C.). 10 μl of the eluted DNA is used for subsequent PCR analysis. Analysis of Deaminated Treated DNA on the LightCycler® Instrument 8.1.3 Composition of Mastermix LightCycler® FastStart DNA Master HybridizationProbe 1× (Roche 2239272), 2 mM MgCl2, forward Primer 0.5 μM, reversed Primer 0.5 μM, donor probe 300 nM, acceptor probe 300 nM, template 10 μl, total PCR volume 20 μl. 8.1.4 PCR-Conditions Denaturation 10 min/95° C. 55 cycles 95° C./10 s 62° C./10 s−signal acquisition 72° C./10 s Ramp time 20° C./s Results: Sodium disulfite Guanidinium reagent hydrogensulfite reagent Sample CT-Values or Crossing points NS No growth curve 43.04 NS No growth curve 37.67 NS No growth curve 40.96 Mean value — 40.56 NS + DNA 36.75 35.37 NS + DNA 37.56 34.40 NS + DNA 37.55 36.26 Mean value 37.29 35.34 The results show that the new format “combination of Sample preparation and BIS-Treatment” results in converted, amplifiable DNA. For the standard BIS reagent positive results are seen only for the spiked samples; that means that the overall efficiency of the process is still quite limited. In contrast however using the novel BIS reagent results in positive results for the unspiked serum as well as the spiked serum, indicating that the novel BIS reagent can be used more efficiently for the combined SP-BIS format than the standard reagent. 9 GuaSulfit can be Used as Binding Reagent for DNA Isolation on Silica Surfaces Experimental Design 50 ng human genomic DNA, Roche 1691112 is spiked in 2001 μl normal negative serum. Then the DNA is isolated using the High Pure Template preparation kit (Roche 1796828) either with the recommended binding buffer or with 5M Guanidinium hydrogensulfit pH 5.5 or 5M Sodium Bisulfite pH 5.5 as binding buffer (3 replicates each). The purified DNA is then quantified in a real time kinetic PCR using the LC Control Kit (Roche 2015102) that detects β Globin DNA. Results 5M Sodium 5M Guanidinium Original Binding Bisulfite as Hydrogensulfite as Buffer Binding buffer Binding buffer ng ng ng Replicates cp DNA cp DNA cp DNA 1 26.6 50.2 28.97 9.56 29.61 6.11 2 26.59 50.4 28.72 11.4 29.36 7.32 3 26.74 45.6 28.95 9.74 29.56 6.34 Mean value 26.64 48.7 28.88 10.2 29.51 6.6 The results show that the original binding buffer in the kit gives the best performance, but both sulfite reagents might be used also as binding buffers; the novel reagent is somewhat less efficient and some more optimization might be needed. LIST OF REFERENCES Abramson, R. D., and Myers, T. W., Curr. Opin. Biotechnol. 4 (1993) 41-47 Alderton, R. P., et al., Anal. Biochem. 201 (1992) 166-169 Ausubel, F., et al., in “Current protocols in molecular biology” (1994), Eds. F. Ausubel, R. Brent and K. R. E., Wiley & Sons Verlag, New York Barany, F., PCR Methods Appl. 1 (1991) 5-16 Barany, F., Proc. Natl. Acad. Sci. USA 88 (1991) 189-193 Benyajati, C., et al., Nucleic Acids Res. 8 (1980) 5649-5667 Braunauer, in “The Adsorption of Gases and Vapors” (1943), Princeton University Press Clark, S. J., et al., Nucleic Acids Res. 22 (1994) 2990-2997 DE 3724442 EP 0200 362 EP0201 184 EP 0 389 063 EP 0 439 182 Feil, R., et al., Nucleic Acids Res. 22 (1994) 695-696 Frommer, M., et al., Proc. Natl. Acad. Sci. USA 89 (1992) 1827-1831 GB 91/00212 Grigg, G., and Clark, S., Bioessays 16 (1994) 431-436 Grigg, G. W., DNA Seq. 6 (1996) 189-198 Grunau, C., et al., Nucleic Acids Res. 29 (2001) E65-5 Guatelli, J. C., et al., Proc. Natl. Acad. Sci. USA 87 (1990) 1874-1878 Jakobi, R., et al., Anal. Biochem. 175 (1988) 196-201 Komiyama, M., and Oshima, S., Tetrahedron Letters 35 (1994) 8185-8188 Kwoh, D. Y., et al., Proc. Natl. Acad. Sci. USA 86 (1989) 1173-1177 Lottspeich, and Zorbas, in “Bioanalytik” (1998), Eds. L. a. Zorbas, Spektrum Akademischer Verlag, Heidelberg, Berlin, Germany Marko, M. A., et al., Anal. 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C., and Persing, D. H., Annu. Rev. Microbiol. 50 (1996) 349-373 WO 00/32762 WO 00/37291 WO 01/37291 WO 01/98528 WO 02/31186 WO 90/01069 WO 90/06045 WO 92/02638 WO 92/0880A WO 96/41811 WO 99/16781 WO 99/40098 Wu, D. Y., and Wallace, R. B., Genomics 4 (1989) 560-569

<SOH> BACKGROUND OF THE INVENTION <EOH>Genes constitute only a small proportion of the total mammalian genome, and the precise control of their expression in the presence of an overwhelming background of noncoding desoxyribonucleic acid (DNA) presents a substantial problem for their regulation. Noncoding DNA, containing introns, repetitive elements, and potentially active transposable elements requires effective mechanisms for its long term silencing. Mammals appear to have taken advantage of the possibilities afforded by cytosine methylation to provide a heritable mechanism for altering DNA-protein interactions to assist in such silencing. DNA methylation is essential for the development of mammals; and plays a potential role during aging and cancer. The involvement of methylation in the regulation of gene expression and as an epigenetic modification marking imprinted genes is well established. In mammals, methylation occurs only at cytosine residues and more specifically only on cytosine residues adjacent to a guanosine residue, i.e. at the sequence CG. The detection and mapping of DNA methylation sites are essential steps towards understanding the molecular signals which indicate whether a given sequence is methylated. This is currently accomplished by the so-called bisulfite method described by Frommer, M., et al., Proc. Natl. Acad. Sci. USA 89 (1992) 1827-1831) for the detection of 5-methyl-cytosines. The bisulfite method of mapping 5-methylcytosine uses the effect that sodium hydrogen sulfite reacts with cytosine but not or only poorly with 5-methyl-cytosine. Cytosine reacts with bisulfite to form a sulfonated cytosine reaction intermediate being prone to deamination resulting in a sulfonated uracil which can be desulfonated to uracil under alkaline conditions. It is common knowledge that uracil has the base pairing behavior of thymine different to the educt cytosine whereas 5-methylcytosine has the base pairing behavior of cytosine. This makes the discrimination of methylated or non-methylated cytosines possible by e.g. bisulfite genomic sequencing (Grigg, G., and Clark, S., Bioessays 16 (1994) 431-436; Grigg, G. W., DNA Seq. 6 (1996) 189-198) or methylation specific PCR (MSP) disclosed in U.S. Pat. No. 5,786,146. There are various documents addressing specific aspects of the bisulfite reaction (Benyajati, C., et al., Nucleic Acids Res. 8 (1980) 5649-5667) make general investigations to the bisulfite modification of 5-methyl-deoxycytosine and deoxycytosine (Olek, A., et al., Nucleic Acids Res. 24 (1996) 5064-5066) disclose a method for bisulfite base sequencing whereby bisulfite treatment and subsequent PCR steps are performed on material embedded in agarose beads. In the bisulfite method as disclosed by Clark, S. J., et al., Nucleic Acids Res. 22 (1994) 2990-2997, the sample is desalted after deamination. Raizis, A. M., et al., Anal. Biochem. 226 (1995) 161-166 disclose a bisulfite method of 5-methylcytosine mapping that minimizes template degradation. They investigate the influence of pH, temperature and time of reaction. Similar investigations have been made by Grunau, C., et al., Nucleic Acids Res. 29 (2001) E65-5 or Warnecke, P. M., et al., Methods 27 (2002) 101-107. Different additional components in the bisulfite mixture are disclosed by WO 01/98528 or by Paulin, R., et al., Nucleic Acids Res. 26 (1998) 5009-5010. An additional bisulfite step after bisulfite treatment and PCR is disclosed in WO 02/31186. Komiyama, M., and Oshima, S., Tetrahedron Letters 35 (1994) 8185-8188) investigate the catalysis of bisulfite-induced deamination of cytosine in oligodeoxyribonucleotides. Kits for performing bisulfite treatments are commercially available from Intergen, distributed by Serologicals Corporation, Norcross, Ga., USA, e.g. CpGenome™ DNA modification kit. A variation of the bisulfite genomic sequencing method is disclosed by Feil, R., et al., Nucleic Acids Res. 22 (1994) 695-696, whereby the genomic DNA is bound to glass beads after deamination and washed. After elution the nucleic acid is desulfonated. It is known that nucleic acids can be isolated by the use of their binding behavior to glass surfaces, e.g. adsorption to silica gel or diatomic earths, adsorption to magnetic glass particles (MGPs) or organo silane particles under chaotropic conditions. Extraction using solid phases usually contains the steps of adding the solution with the nucleic acids to the solid phase under conditions allowing binding of the substance of interest to the solid phase, removal of the remainder of the solution from the solid phase bound nucleic acids and subsequent release of the nucleic acids from the solid phase into a liquid eluate (sometimes called elution). The result of the such process is usually a solution containing the substance of interest in dissolved state. Guanidinium hydrogen sulfite is known from various documents. U.S. Pat. No. 2,437,965 discloses a method for relaxing keratinous fibers using guanidinium hydrogen sulfite. U.S. Pat. No. 2,654,678 discloses the antistatic treatment of shaped articles using guanidinium salts. U.S. Pat. No. 4,246,285 discloses skin conditioning compositions containing guanidine inorganic salts. DE19527313 discloses guanidine derivatives and cosmetic articles containing them. All prior art methods for the bisulfite treatment have disadvantages. Therefore, the problem to be solved by the present invention was to provide a method wherein guanidinium hydrogen sulfite is used.

<SOH> SUMMARY OF THE INVENTION <EOH>The invention is related to a method for the conversion of a cytosine base in a nucleic acid to an uracil base comprising the steps of a) providing a solution that contains a nucleic acid, b) providing guanidinium hydrogen sulfite and preparing a solution comprising guanidinium and sulfite ions, c) mixing the solutions from step a) and b) d) incubating the solution obtained in step c) containing the nucleic acid and guanidinium and sulfite ions whereby the nucleic acid is deaminated, e) incubating the deaminated nucleic acid under alkaline conditions whereby the deaminated nucleic acid is desulfonated, f) isolating the deaminated nucleic acid. In a further embodiment of the invention, guanidinium hydrogen sulfite is used for chemically modifying a nucleic acid, particularly in a method wherein a cytosine base in a nucleic acid is converted to an uracil base. In another embodiment of the invention, guanidinium hydrogen sulfite is used to prepare a solution comprising guanidinium and sulfite ions, particularly the solution is used for converting a cytosine base in a nucleic acid to an uracil base. In another embodiment of the invention, a kit containing guanidinium hydrogen sulfite is provided and uses of the kit according to the invention for a reaction wherein a cytosine base in a nucleic acid is converted to an uracil base in the presence of bisulfite ions. According to the invention the term a “bisulfite reaction”, “bisulfite treatment” or “bisulfite method” shall mean a reaction for the conversion of a cytosine base, in particular cytosine bases, in a nucleic acid to an uracil base, or bases, preferably in the presence of bisulfite ions whereby preferably 5-methyl-cytosine bases are not significantly converted. This reaction for the detection of methylated cytosines is described in detail by Frommer et al., supra and Grigg and Clark, supra. The bisulfite reaction contains a deamination step and a desulfonation step which can be conducted separately or simultaneously (see FIG. 1 ; Grigg and Clark, supra). The statement that 5-methyl-cytosine bases are not significantly converted shall only take the fact into account that it cannot be excluded that a small percentage of 5-methyl-cytosine bases is converted to uracil although it is intended to convert only and exclusively the (non-methylated) cytosine bases (Frommer et al., supra).

20060919

20090310

20070816

73656.0

C12Q168

CHUNDURU, SURYAPRABHA

METHOD FOR BISULFITE TREATMENT

UNDISCOUNTED

ACCEPTED

C12Q

ACCEPTED

Apparatus and method for establishing the positions of metal objects in an input stream

Apparatus (10) for establishing the positions of metal objects in a mixed input stream of both metal and non-metal objects, the apparatus comprising a differential metal-detecting coil (14A) having a first coil portion wound in a first sense and a second coil portion of generally similar shape and size to the first, wound in a second sense opposite to the first sense, and conveying means (11) for moving objects with respect to, and past, the differential metal-detecting coil in a plane and in a direction with unit vector â, characterised in that the second coil portion is displaced from the first coil portion by a displacement B having a component in the plane in a direction with unit vector {circumflex over (b)}, wherein 0<cos−1 â·{circumflex over (b)}<π/2, and in that the apparatus further comprises analysing means for analysing the form of the output voltage of the coil as a function of time to establish the position of said metal objects in a direction ĉ in the plane, where ĉ is defined by â·ĉ=0.

1. Apparatus for establishing the positions of metal objects in a mixed input stream of both metal and non-metal objects, the apparatus comprising a differential metal-detecting coil having a first coil portion wound in a first sense and a second coil portion of generally similar shape and size to the first, wound in a second sense opposite to the first sense, and conveying means for moving objects with respect to, and past, the differential metal-detecting coil in a plane and in a direction with unit vector â, characterised in that the second coil portion is displaced from the first coil portion by a displacement B having a component in the plane in a direction with unit vector {circumflex over (b)}, wherein 0<cos−1 â·{circumflex over (b)}<π/2, and in that the apparatus further comprises a signal processor for analysing the form of the output voltage of the coil as a function of time to establish the position of said metal objects in a direction ĉ in the plane, where ĉ is defined by â·ĉ=0. 2. Apparatus according to claim 1 wherein B·â≧t, where t is the dimension of a coil portion in the â direction, and s 2 ≤ B · c ^ ≤ s , where s is the dimension of a coil portion in a direction with unit vector ĉ defined by â·ĉ=0. 3. Apparatus according to claim 1 wherein the signal processor is arranged to distinguish voltages of different polarities, and to associate voltages of a first polarity with one coil portion and voltages of a second polarity, opposite to the first, with the other coil portion. 4. Apparatus according to claim 1 and comprising a plurality of differential metal-detecting coils arranged in a linear array substantially in the ĉ direction. 5. Apparatus according to claim 4 and further comprising a single transmitter coil arranged around the differential metal-detecting coils. 6. Apparatus according to claim 4 wherein the differential metal-detecting coils are each formed on a printed circuit board (PCB). 7. Apparatus according to claim 6 wherein the differential metal-detecting coils are formed on a single PCB. 8. Apparatus according to claim 7 wherein a single transmitter coil is formed on the PCB around the differential metal-detecting coils. 9. Apparatus according to claim 8 wherein the signal processor comprises electronic hardware co-located with said coils on the single PCB. 10-12. (canceled) 13. A method of establishing the positions of metal objects in a mixed input stream of both metal and non-metal objects, characterised in that the method comprises use of apparatus according to claim 1. 14. A metal-detector array system comprising a plurality of differential metal-detecting coils, the array extending in a direction with unit vector {circumflex over (x)}, and each metal-detecting coil having a first coil portion wound in a first sense and a second coil portion of generally similar shape and size to the first, wound in a second sense opposite to the first sense, characterised in that, in at least one metal-detecting coil, the second coil portion thereof is displaced from the first coil portion thereof by a displacement B such that the two coil portions are substantially in the same plane and 0<cos−1 {circumflex over (b)}·{circumflex over (x)}<π/2 where {circumflex over (b)} is a unit vector defined by B·{circumflex over (b)}=|B|, and in that the system further comprises, in respect of that or those metal-detecting coil or coils, a signal processor for analysing the form of the output voltage of the coil or coils as a function of time to establish the position, along the direction {circumflex over (x)}, of metal objects when said objects are moving past the array substantially in a direction with unit vector ŷ where {circumflex over (x)}·ŷ=0.

The present invention relates to apparatus for establishing the positions metal objects in a mixed input stream of both metal and non-metal objects, and particularly (although not exclusively) to establishing the positions of metal objects in a mixed-waste input stream. Mixed-waste streams are encountered, for example, during reclamation of recyclable objects from unsorted household waste. The removal of metallic content in a waste stream and sorting between ferrous and non-ferrous objects are important steps in the recovery of metals in material reclamation facilities (MRFs). In a known type of apparatus, establishment of the positions of metal objects in a mixed input stream on a moving conveyor, and subsequent separation of the metal objects, is achieved by use of one or more metal detectors to detect the metal objects, and a rejection mechanism which receives signals from the one or more metal detectors and effects separation in response to the signals. An example is the apparatus disclosed in U.S. Pat. No. 4,541,530. Various rejection mechanisms are known, for example air separators, flap gates, or means to stop or reverse the conveyor to allow removal of detected metal objects. Typically, a series of discrete metal detectors is arranged across the width of the conveyor, and output signals from the metal detectors are processed to give positional information on metal objects to be separated. Each detector has associated with it processing circuitry to interpret its output and to provide control signals to a rejection mechanism. To efficiently and accurately establish the position of metal objects in a mixed input stream, a high linear density of detectors across the conveyor is required, and consequently a large number of detectors and a large amount of electronic hardware is needed in order to process output signals from each of the detectors because the effective detecting width of a single detector is limited. This is disadvantageous both in terms of cost and complexity. It is an object of the invention to ameliorate the aforementioned problems. According a first aspect of the present invention, this object is achieved by apparatus according to claim 1 comprising a differential metal-detecting coil having a first coil portion wound in a first sense and a second coil portion of generally similar shape and size to the first, wound in a second sense opposite to the first sense, and conveying means for moving objects with respect to, and past, the differential metal-detecting coil in a plane and in a direction with unit vector â, characterised in that the second coil portion is displaced from the first coil portion by a displacement B having a component in the plane in a direction with unit vector {circumflex over (b)}, wherein 0<cos−1 â·{circumflex over (b)}<π/2, and in that the apparatus further comprises analysing means for analysing the form of the output voltage of the coil as a function of time to establish the position of said metal objects in a direction ĉ in the plane, where ĉ is defined by â·ĉ=0. A metal object passing one coil portion of a differential metal-detecting coil will induce a signal in the coil that is opposite in polarity to that produced if the metal had passed the other coil portion. A metal object passing both coil portions induces an EMF which changes polarity as it passes the coil. Analysis of the form of the signal induced in a given metal detector coil as a function of time when a metal object passes the detector therefore provides positional information relating to the metal object; such information may then be used in extracting the metal object from the waste stream, if required. A single differential metal detector coil is thus effectively used as two distinct receivers by displacing the coil portions of each coil as described above. The invention provides the advantage that the detecting width of a single receiver coil is increased without detriment to the quality of positional information generated by the coil, and hence in a system of the invention having a linear array of receiver coils, the number of such coils is reduced compared to prior art apparatus. Furthermore the amount of electronic processing hardware associated with the array is reduced compared to prior art apparatus, due to the reduced number of receiver coils. Preferably, B·â≧t, where t is the dimension of a coil portion in the â direction, and s 2 ≤ B · c ^ ≤ s , where s is the dimension of a coil portion in a direction with unit vector ĉ defined by â·ĉ=0, because this geometry provides a significant improvement in the detecting width of receiver coil, whilst at the same time providing for unambiguous signals to be induced in the receiver coils. Also, this avoids overlapping coil portions. Conveniently, the analysing means comprises means for identifying voltages of different polarities, and for ascribing voltages of a first polarity to one coil portion and voltages of a second polarity, opposite to the first, to the other coil portion. Preferably the apparatus comprises a plurality of such differential metal-detecting coils arranged in a linear array substantially in the ĉ direction, thus allowing an input stream of substantial width to be processed. The apparatus may incorporate a transmitter coil, if appropriate (e.g. non-ferrous objects must have eddy currents induced in them order that they may be detected by a receiver coil). If a transmitter coil is required, preferably a single coil is arranged around the one or more metal-detecting receiver coils, as this provides a simpler arrangement than is found in prior art systems, which employ a separate transmitter coils for each receiver coil. Multiple transmitter coils are difficult to synchronise in practice. Conveniently, the differential metal-detecting coils may be formed by metal tracks on individual printed circuits boards (PCBs). The differential metal-detecting coils may also be formed on a single PCB. A single PCB may support both the differential metal-detecting coils and a single transmitter coil, and also electronic hardware for analysing signals from the transmitter coils. A second aspect of the invention provides a metal-detector array comprising a plurality of differential metal-detecting coils, the array extending in a direction with unit vector {circumflex over (x)}, and each metal-detecting coil having a first coil portion (15) wound in a first sense and a second coil portion (16) of generally similar shape and size to the first, wound in a second sense opposite to the first sense, characterised in that, in at least one metal-detecting coil, the second coil portion thereof is displaced from the first coil portion thereof by a displacement B such that the two coil portions are substantially in the same plane and 0<cos−1 {circumflex over (b)}·{circumflex over (x)}<π/2 where {circumflex over (b)} is a unit vector defined by B·{circumflex over (b)}=|B|, and in that the system further comprises, in respect of that or those metal-detecting coil or coils, analysing means for analysing the form of the output voltage of those coil or coils as a function of time to establish the position, along the direction {circumflex over (x)}, of metal objects when said objects are moving past the array substantially in a direction with unit vector ŷ where {circumflex over (x)}·ŷ=0. Such an array has a reduced number of individual detecting coils compared to prior art arrays of differential metal-detecting coils, and is therefore cheaper and less complex than such prior art arrays whilst simultaneously being capable of yielding the same level of positional information regarding metal objects passing the array, or past which the array is moved. Embodiments of the invention are described below by way of example only and with reference to the accompanying drawings in which: FIG. 1 shows a plan view of an apparatus of the invention; FIG. 2 shows in detail a metal-detecting receiver coil of the FIG. 1 apparatus; FIG. 3 shows graphs of voltage against time for EMFs induced the FIG. 2 coil when metal objects move past the coil; FIG. 4 shows electronic processing hardware comprised in the FIG. 1 apparatus; FIG. 5 shows a software flow diagram illustrating processing steps implemented in software by the FIG. 4 hardware; FIG. 6 shows two possible arrangements of a differential metal-detecting coil for two other embodiments of the invention; FIGS. 6A, 6B indicate the arrangement of adjacent metal-detecting coils corresponding to the FIG. 6 configurations; and FIG. 7 shows two possible arrangements of a differential metal-detecting coil for two further embodiments of the invention. FIG. 1 shows a plan view of an apparatus of the invention, for separating metal objects from a mixed input stream of both metal and non-metal objects, indicated generally by 10. The apparatus 10 comprises a conveyor belt 11, operable to carry material 11A, such as unsorted household waste, in the plane of the conveyor belt 11 in a direction 12 having a unit vector â towards and past a series of substantially identical metal-detecting receiver coils 14A, 14B, 14C, 14D which are arranged across the width of the conveyor belt 11 and are positioned below the belt 11 to form a linear metal-detector array. The apparatus 10 further comprises electronic processing hardware (not shown in FIG. 1 but shown in FIG. 4) for processing signals from the metal-detector array and generating appropriate control signals corresponding to positions of metal objects on the conveyor 11. The apparatus 10 may further comprise rejection means (not shown) for effecting rejection of the metal objects from the mixed input stream in response to the control signals if it is desired to additionally carry out rejection/extraction of metal objects whose position in the input stream has been established. A direction normal to â is indicated in FIG. 1 by a unit vector ĉ in the plane of the belt 11. The component BP of B in the plane of the belt 11 is in a direction having unit vector {circumflex over (b)} (i.e. BP=BP{circumflex over (b)}). FIG. 2 shows receiver coil 14A in detail. The receiver coil 14A comprises two square coil portions 15, 16 of side s, one 15 of which is displaced with respect to the other 16 by a displacement B. The component of B in the plane of the conveyor belt 11 is BP (=BP{circumflex over (b)}). The coil portion 15 is displaced from the coil portion 16 in the â direction by a distance s+x, where x=s/4, and by a distance s in the ĉ direction, i.e BP·â=s+x=5s/4 and BP·ĉ=s. The two coil portions 15, 16 of the coil 14A are wound in opposite senses to form a differential coil. In this example apparatus 10, the receiver coils 14A, 14B, 14C, 14D are each formed by metal tracks on a printed circuit board (PCB) and the turns of the coils are in the surface plane of the PCB. Multi-layer PCBs with spiral tracks on each layer may be used to increase the number of turns for a given coil portion area, as shown, for example, in U.S. Pat. No. 6,429,763. As a further step of integration, all of the receiver coils 14A, 14B, 14C, 14D and all electronic processing hardware of the apparatus 10 may be co-located on a single PCB for simplicity and ease of construction. Referring again to FIG. 1, the apparatus 10 further comprises a transmitter coil 13 (positioned below the conveyor belt 11 and around the detecting coils 14A, 14B, 14C, 14D) and an oscillator 13A for generating a time-varying transmitted magnetic field in the region of the coils 14A, 14B, 14C, 14D. Together with the coils 14A, 14B, 14C, 14D, the transmitter coil 13 and the oscillator 13A form a linear array of differential metal-detectors, each of which has a substantially zero response to the transmitted field because EMFs generated in respective coil portions of a receiver coil, such as 14A, have substantially equal magnitude, but opposite polarity. However, the transmitted field induces eddy currents in metal objects on the conveyor belt 11 and near the transmitter coil 13A; magnetic fields associated with these eddy currents are detected by the receiver coils 14A, 14B, 14C, 14D, i.e. EMFs are induced in the receiver coils 14A, 14B, 14C, 14D. FIG. 3 shows graphs 18B, 19B, 20B of voltage against time for EMFs induced in the coil 14A when a metal object is conveyed over it along paths 18A, 19A, 20A respectively, as shown in FIG. 2. If the object passes along paths such as 18A or 19A shown in FIG. 2, i.e. directly underneath one of the coil portions 15, 16, then an EMF having a corresponding polarity is induced, as shown by graphs 18B and 19B respectively. Signal 19B occurs later in time than signal 18B due to the displacement of the coil portion 15 in the â direction with respect to the coil portion 16. If the object passes along a path such as 20A in FIG. 2, the temporal form of the induced EMF is as shown by graph 20B in FIG. 3. The peaks of pulses 18B, 19B, and those of graph 20B, have a temporal separation (s+x)/v, where v is the velocity of the belt 11. The other receiver coils 14B, 14C, 14D respond to metallic objects moving on the conveyor belt 11 in a similar manner. It will be appreciated that the temporal forms of EMFs induced in the receiver coils give information on the position of the metal object across the width of the conveyor belt 11 (i.e. in the ĉ direction.) Although the displacement of the coils portions within a detector coil in the â direction may be s (so that the coil portions are contiguous in that direction), in practice an additional displacement x is desirable as this provides a larger temporal displacement between signals arising between coil portions. This allows more accurate positional information to be obtained relating to the position of a metal object in the input stream. A useful range of values for x is 0 < x < s 2 . FIG. 4 schematically illustrates electronic processing hardware 100 comprised in the apparatus 10. The hardware 100 receives signals from the receiver coils 14A, 14B, 14C, 14D, processes them to establish the positions of metal objects on the conveyor belt 11 and provides corresponding control signals for controlling the rejection means of the apparatus 10. Referring to FIG. 4, output signals from the receiver coil 14A are passed to a circuit module 102A. Module 102A comprises a pre-amplifier 104, phase sensitive detectors (PSDs) 106, 107, and analogue-to-digital converters (ADC) 108, 109. Outputs 110A, 111A from ADCs 108, 109 respectively of the module 102A are input to a microprocessor 106. The hardware 100 comprises three further such circuit modules (not shown), associated with receiver coils 14B, 14C, 14D and having outputs 110B, 111B, 110C, 111C, 110D, 111D which are also input to the microprocessor 106. Signals for the transmitter coil 13 are digitally synthesised by a signal synthesiser 150 which has a first (0°) output 151A connected to the transmitter coil 13 via a digital-to-analogue converter (DAC) 152 and an amplifier 156. The signal synthesiser 13 has a second (90°) output 151B for providing a signal identical to that from the output 151A, except that it is phased-shifted with respect to the signal at 151A by 90°. The 90° output 151B is connected to a DAC 154. Analogue outputs 153A, 155A of the DACs 152, 154 are connected to PSDs 107, 106 respectively within the circuit module 102A. Further analogue outputs 153B, 153C, 153D and 155B, 155C, 155D are connected to PSDs such as 107, 106 within circuit modules (not shown) associated with receiver coils 14B, 14C, 14D. The electronic processing hardware 100 operates as follows. Voltage signals from receiver coil 14A are amplified by pre-amplifier 104 and input to PSDs 106, 107. An analogue form of the transmitter signal is also input to PSD 107, and an analogue transmitter signal phase-shifted by 90° is also input to PSD 106, for use as reference pulses. Signals output from the PSDs 106, 107 correspond respectively to the imaginary and real parts of the signal received from coil 14A, and are digitised by ADCs 108, 109 and passed to the microprocessor 106. Digital output signals from circuit modules associated with the receiver coils 14B, 14C, 14D are also passed to the microprocessor 106. FIG. 5 shows a software block-diagram illustrating processing of signals received from circuit modules, such as 102A, associated with each of the receiver coils 14A, 14B, 14C, 14D, within the microprocessor 106. Two digital output signals from the ADCs within a circuit module associated with a particular receiver coil are first read (202) and then decimated (204) to produce a signal of reduced bandwidth. Each digital signal has an unwanted dc offset due to slight imbalance between the coil portions of a given detector coil, as well as inherent offsets in the circuit modules. These are removed with a simple algorithm (206) well-known to those skilled in the art. Phase correction (208) is then carried out to compensate for phase shifts within the analogue electronics associated with the transmitter coil and within the circuit modules. This is achieved by a calibration procedure (carried out before the apparatus 10 is operated) in which an object of known phase response is placed near each receiver coil in turn. Two signals, orthogonal in phase, are recorded from each circuit modules (e.g. 102A) and a simple rotation matrix can adjust the phase of the calibration signal to any chosen value. A suitable calibration target is non-conducting ferrite, as this has a zero phase response to a transmitted magnetic field. Predetermined thresholds (21A, 21B in FIG. 3) are compared to the signal to determine whether the signal is stronger than a threshold. The thresholds 21A, 21B are set so that noise, and metal objects too small to be of interest, are rejected (210). The phase of the signal from the receiver coil with respect to the transmitted signal is then established (212); this may be used identify the particular metal involved. A known algorithm (214) then establishes whether the metal is ferrous or non-ferrous. A fitting algorithm (216) may then used to establish the position of a metal object across the width of the conveyor belt 11 to a greater precision than the separation of coil portions in the ĉ direction. Data generated by the microprocessor 106 regarding the nature and position of metal objects on the conveyor belt 11 is time-stamped (218) and may be passed to rejection means to effect separation of metal objects in the input stream on the conveyor belt 11. Signals output from each of the receiver coils 14A, 14B, 14C, 14D are processed in a common manner. Although the apparatus 10 comprises a transmitter coil, this is not essential in all circumstances. For example, if it is desired to only to extract ferrous objects from the input stream, this may be achieved by subjecting the input stream to a magnetic field before it enters the apparatus 10. Magnetised ferrous objects may then induce signals in the receiver coils by virtue of relative movement between the objects and the receiver coils, obviating the need for a transmitter coil. Where a transmitter coil is used, a single coil arranged around all the receiver coils is particularly advantageous in terms of reduced cost and complexity, although the use of individual transmitter coils with the receiver coils is also possible. Where a transmitter coil is used, neither ferrous nor non-ferrous objects need to be moving with respect to the detector coils in order to be detected, although obviously in the processing of a continuous input stream this is desirable, and it is immaterial whether the waste stream moving with respect to static detecting coils or whether the detecting coils are moved with respect to a static waste stream. Although the use of printed circuit boards mentioned above is particularly convenient, it is not essential. The differential receiver coils may be formed in a more conventional manner by winding wire onto one or more formers. In a variant of the apparatus 10, the coil portion 15 is offset with respect to the coil portion 16 by a distance s+x (x=s/4) in the â direction, and also by a distance s/2 in the ĉ direction, and remaining detector coils of the variant apparatus are similarly arranged. Detector coils in the variant apparatus provide a greater spatial resolution (s/2) although for a given conveyor belt width, a greater number of individual detector coils is required than is the case in the apparatus 10, in which coil portions are offset in the ĉ direction by a distance s. Some of the geometries discussed above are summarised in Table 1 below. TABLE 1 Bp · â Bp · ĉ cos−1 â · {circumflex over (b)} s s 45.0° s s/2 26.5° 5s/4 s 38.6° 5s/4 s/2 21.8° 3s/2 s 33.7° 3s/2 s/2 18.4° In other embodiments of the invention, the coil portions of the differential receiver coils may have shapes other than square. FIG. 6 indicates two possible arrangements of circular coil portions of a differential receiver coil in which BP·ĉ equals D or D/2 (D is the diameter of a circular coil portion.) FIGS. 6A and 6B show how consecutive detectors coils would be arranged in the first and second of these cases respectively. FIGS. 7 illustrates two possible arrangements for differential receiver coil having elliptical coil portions. Generally, in embodiments of the invention, the coil portions of a differential receiver coil need to be of generally similar size and shape, and provided 0 < cos - 1 ⁢ a ^ · b ^ < π 2 the benefits of the invention are achieved, i.e. even if the coil portions of respective receiver coils overlap in a plane parallel to that of the conveyor belt 11. However it is preferable that B is such that B·ĉ is either s or s/2, where s is the approximate dimension of a coil portion in the ĉ direction, and simultaneously B·â>t, where t is the approximate dimension of a coil portion in the â direction, as this simultaneously provides a significant detecting width across the conveyor belt and an output signal from which the position of a metal object across the belt 11 can be accurately obtained. Also it will be appreciated that the planes of the coil portions of a receiver coil must be arranged so that there is flux linkage sufficient to generate a useful signal in the receiver coil when a metal object is conveyed past it. For example, if it is desired to detect and separate ferrous objects only, these objects may be magnetised in a direction normal to the plane of FIG. 1, prior to their passage past the detector array; the planes of the coil portions of the receiver coils are then preferably substantially parallel to the plane of the conveyor belt 11. The detector array may also be positioned above the conveyor belt 11, rather than below it, although in that case it would need to be ensured that the spacing between the belt 11 and the array was sufficient to allow the passage of objects comprised in the input stream. Although the foregoing description relates to CW metal-detection, other embodiments of the invention may employ pulse-induction detection. In such embodiments, the metal-detecting coils would have the same configuration but the electronic processing hardware would be adapted to this other method of metal-detection.

20060420

20070410

20070111

95912.0

G01N2772

LEDYNH, BOT L

APPARATUS AND METHOD FOR ESTABLISHING THE POSITIONS OF METAL OBJECTS IN AN INPUT STREAM

UNDISCOUNTED

ACCEPTED

G01N

ACCEPTED

Method for producing a ketone

A process for preparing a ketone, in particular cyclododecanone, by reacting cyclododecatriene with dinitrogen monoxide to obtain cyclododecadienone and hydrogenating the resulting cyclododecadienone, in particular to give cyclododecanone.

1. A process for preparing a ketone comprising the reaction of cyclododecatriene with dinitrogen monoxide to obtain cyclododecadienone. 2. A process as claimed in claim 1, wherein the dinitrogen monoxide source is at least one dinitrogen monoxide-containing offgas of at least one industrial process. 3. A process as claimed in claim 2, wherein the dinitrogen monoxide source is the offgas of an adipic acid plant and/or of a dodecanedioic acid plant and/or of a hydroxylamine plant and/or of a nitric acid plant operated with the offgas of an adipic acid plant and/or of a dodecanedioic acid plant and/or of a hydroxylamine plant. 4. A process as claimed in claim 1, wherein cyclododecatriene is reacted with a gas mixture containing from 20 to 99.9% by weight of dinitrogen monoxide, based on the total weight of the gas mixture. 5. A process as claimed in claim 1, wherein the dinitrogen monoxide or the gas mixture containing dinitrogen monoxide is used in liquid form. 6. A process as claimed in claim 1, wherein the reaction is carried out at a temperature in the range from 140 to 350° C. and a pressure in the range from 1 to 1000 bar. 7. A process as claimed in claim 1, wherein the reaction has a conversion of cyclododecatriene in the range from 1 to 80% at a selectivity based on cyclododecadienone of at least 90%. 8. A process as claimed in claim 1, wherein the cyclododecatriene is cis,trans,trans-1,5,9-cyclododecatriene and is reacted in (ii) with dinitrogen monoxide to give cyclododeca-4,8-dienone. 9. A process as claimed in claim 1, wherein the cyclododecadienone obtained from the reaction of cyclododecatriene with dinitrogen monoxide is hydrogenated to obtain cyclododecanone. 10. A process as claimed in claim 9, wherein the hydrogenation is carried out in the presence of a hydrogenation catalyst at a temperature in the range from 0 to 250° C. and a pressure in the range from 1 to 325 bar. 11. A process for preparing cyclododecanone, comprising the steps (I) and (II) (I) reacting cyclododecatriene with dinitrogen monoxide to obtain cyclododecadienone; (II) hydrogenating the cyclododecadienone obtained in (I) to obtain cyclododecanone. 12. A process as claimed in claim 11, wherein the dinitrogen monoxide source used is at least one offgas comprising dinitrogen monoxide from at least one industrial process. 13. A process as claimed in claim 12, wherein the dinitrogen monoxide source is the offgas of an adipic acid plant and/or of a dodecanedioic acid plant and/or of a hydroxylamine plant and/or of a nitric acid plant operated with the offgas of an adipic acid plant and/or of a dodecanedioic acid plant and/or of a hydroxylamine plant. 14. A process as claimed in claim 11, wherein cyclododecatriene is reacted with a gas mixture containing from 20 to 99.9% by weight of dinitrogen monoxide, based on the total weight of the gas mixture. 15. A process as claimed in claim 11, wherein the dinitrogen monoxide or the gas mixture containing dinitrogen monoxide is used in liquid form. 16. A process as claimed in claim 11, wherein the reaction in (I) is carried out at a temperature in the range from 140 to 350° C. and a pressure in the range from 1 to 1000 bar. 17. A process as claimed in claim 11, wherein the reaction in (I) has a conversion of cyclododecatriene in the range from 1 to 80% at a selectivity based on cyclododecadienone of at least 90%. 18. A process as claimed in claim 11, wherein the cyclododecatriene used is cis,trans,trans-1,5,9-cyclododecatriene and is reacted in (I) with dinitrogen monoxide to give cyclododeca-4,8-dienone. 19. A process as claimed in claim 11, wherein the hydrogenation in (II) is carried out in the presence of a heterogeneous hydrogenation catalyst at a temperature in the range from 0 to 250° C. and a pressure in the range from 1 to 325 bar. 20. A process for preparing a ketone comprising the reaction of cyclododecatriene with dinitrogen monoxide to obtain cyclododecadienone wherein the dinitrogen monoxide source is the offgas of an adipic acid plant and/or of a dodecanedioic acid plant and/or of a hydroxylamine plant and/or of a nitric acid plant operated with the offgas of an adipic acid plant and/or of a dodecanedioic acid plant and/or of a hydroxylamine plant, wherein the dinitrogen monoxide or the gas mixture containing dinitrogen monoxide is used in liquid form, and wherein the cyclododecatriene is cis,trans,trans-1,5,9-cyclododecatriene and is reacted in (ii) with dinitrogen monoxide to give cyclododeca-4,8-dienone.

The present invention relates to a process for preparing a ketone by oxidizing cyclododecatriene to cyclododecadienone by reacting with dinitrogen monoxide. In a preferred embodiment, the cyclododecadienone is hydrogenated in a further step to cyclododecanone. Cyclododecanone is an important intermediate for the preparation of, for example, laurolactam, dodecanedicarboxylic acid and polyamides derived therefrom, for example nylon-12 or nylon-6,12. Cyclododecanone is prepared in the common industrial process by air oxidation of cyclododecane in the presence of boric acid to give cyclododecyl borate, hydrolysis of the borate to give cyclododecanol and subsequent dehydrogenation of the cyclododecanol. Cyclododecane itself is also obtained by fully hydrogenating cyclododecatriene (CDT). One description of this industrial process for synthesizing cyclododecanone can be found in T. Schiffer, G. Oenbrink, “Cyclododecanol, Cyclododecanon and Laurolactam” in Ullmann's Encyclopedia of Industrial Chemistry, 6th Edition, 2000, Electronic Release, Wiley VCH. However, the industrial process mentioned has a series of disadvantages. First, the oxidation of cyclododecane with oxygen only ensures acceptable selectivity at low conversions. Even with the addition of boric acid, which protects the cyclododecanol formed from further oxidation in the form of boric ester, the cyclododecane conversion must not be above 30%. After the oxidation, the boric esters have to be hydrolyzed in a separate step, and both the boric acid and the unconverted cyclododecane have to be recycled into the oxidation. Additionally, boron containing waste products are formed, which are difficult to dispose. The main products formed are cyclododecanol and cyclodecanone in a ratio of 10:1. Secondly, the mixture of cyclododecanol and cyclododecanone which is formed has to be separated by distillation and the cyclododecanol has to be converted to cyclododecanone by dehydrogenation. This dehydrogenation is endothermic and likewise affords only partial conversion. The unconverted cyclododecanol then in turn has to be removed by distillation and recycled into the process. As a consequence of the incomplete conversion, the conventional process includes several large recycle streams and a series of technically costly and inconvenient distillative separations. It is an object of the present invention to provide a novel process for preparing cyclododecanone which does not have the disadvantages of the prior art process. We have found that this object is achieved by a process for preparing cyclododecanone in which cyclododecanone is prepared by hydrogenating cyclododecadienone. This inventive solution presents the problem of how the cyclododecadienone which is used as the reactant of the hydrogenation can be prepared in a very simple and effective manner. According to the invention, this problem is solved by a process in which the cyclododecatriene is oxidized to cyclododecadienone by a one-stage reaction with dinitrogen monoxide. The oxidation of an olefinic compound to an aldehyde or a ketone by means of dinitrogen monoxide is described, for example, in GB 649,680 or in the equivalent U.S. Pat. No. 2,636,898. However, the cyclic olefinic compounds described there are only cyclopentene, cyclohexene, cyclooctene, and cyclooctatetraene. Cyclic compounds having more than 8 carbon atoms or cyclic compounds having 3 C—C double bonds are not described there. The more recent scientific articles of G. L. Panov et al., “Non-Catalytic Liquid Phase Oxidation of Alkenes with Nitrous Oxide. 1. Oxidation of Cyclohexene to Cyclohexanone”, React. Kinet. Catal. Lett. Vol. 76, No. 2 (2002) p. 401-405, and K. A. Dubkov et al., “Non-Catalytic Liquid Phase Oxidation of Alkenes with Nitrous Oxide. 2. Oxidation of Cyclopentene to Cyclopentanone”, React. Kinet. Catal. Lett. Vol. 77, No. 1 (2002) p. 197-205 likewise describe oxidations of olefinic compounds with dinitrogen monoxide. However, the disclosures on this subject are restricted exclusively to cyclopentene and cyclohexene. Also, the scientific article “Liquid Phase Oxidation of Alkenes with Nitrous Oxide to Carbonate Compounds” of E. V. Starokon et al. in “Advanced Synthetic Catalysis” 2004, 346, 268-274 gives a mechanistic study of the oxidation of alkenes with dinitrogen monoxide in the liquid phase. The preparation of cyclododeca-4,8-dienone from 1,5,9-cyclododecatriene has hitherto only been possible by a two-stage synthesis in which 1,5,9-cyclododecatriene was epoxidized to 1,2-epoxycyclododeca-5,9-diene in a first step and the epoxide was catalytically rearranged in a second step to cyclododeca-4,8-dienone. This process is described, for example, in U.S. Pat. No. 3,063,986. This conventional process has two decisive disadvantages: first, it is difficult to achieve a selective monoepoxidation. Secondly, the process necessarily has two stages. In comparison, the above-described preferred embodiment of the process according to the invention offers the possibility of starting from 1,5,9-cyclododecatriene to obtain cyclododeca-4,8-dienone in a single step with high selectivity. The overall process according to the invention for preparing cyclododecanone accordingly comprises two steps, a first step involving the reaction of cyclododecatriene with dinitrogen monoxide to obtain cyclododecadienone and a second step the hydrogenation of cyclododecadienone to obtain cyclododecanone. Compared to the above-described common process which necessarily comprises the four steps of full hydrogenation of cyclododecatriene to cyclododecane; air oxidation of the cyclododecane in the presence of boric acid to give cyclododecyl borate; hydrolysis of the borate to cyclododecanol; dehydrogenation of the cyclododecanol to obtain cyclododecanone, one feature of the process according to the invention for preparing cyclododecanone is that, starting from the same reactant, cyclododecatriene, the cyclododecanone product can be prepared while saving two reaction stages, thus halving the number of reaction stages. The present invention accordingly relates to a process for preparing cyclododecanone, comprising the steps (I) and (II) (I) reacting cyclododecatriene with dinitrogen monoxide to obtain cyclododecadienone; (II) hydrogenating the cyclododecadienone obtained in (I) to obtain cyclododecanone. The present invention likewise relates to a process for preparing a ketone by reacting cyclododecatriene with dinitrogen monoxide to obtain cyclododecadienone. The dinitrogen monoxide used for the reaction may in principle be used in pure form or in the form of a suitable gas mixture comprising dinitrogen monoxide. Moreover, the dinitrogen monoxide may in principle stem from any desired source. The term “gas mixture” as used in the context of the present invention refers to a mixture of two or more compounds which are in the gaseous state at ambient pressure and ambient temperature. The gas mixture can also have another aggregation with varying temperature or varying pressure, for example a liquid or hypercritic condition, preferably liquid, and is still classified as a gas mixture in the context of the present invention. When a gas mixture is used, its dinitrogen monoxide content is essentially arbitrary, as long as it is ensured that the reaction according to the invention is possible. In a preferred embodiment of the process according to the invention, a gas mixture containing at least 10% by volume of dinitrogen monoxide is used, and the dinitrogen monoxide content in the mixtures is preferably in the range from 20 to 99.9% by volume, more preferably in the range from 40 to 99.5% by volume, more preferably in the range from 60 to 99.5% by volume and especially preferably in the range from 80 to 99.5% by volume. In the context of the present invention the composition of the gas mixtures is given in volume percent. All values given refer to the composition of the gas mixture at ambient pressure and ambient temperature. Accordingly, the present invention also relates to a process as described above, wherein cyclododecatriene is reacted with a gas mixture containing from 20 to 99.9% by weight of dinitrogen monoxide, based on the total weight of the gas mixture. The term “gas mixture” as used in the context of the present invention also refers to mixtures which, in addition to dinitrogen monoxide, contain at least one further component, preferably one further gas. The component can also be a gas which is for example liquid under the conditions chosen. In this context, essentially all gases are conceivable, as long as it is ensured that the reaction of cyclododecatriene with dinitrogen monoxide is possible. Preference is accordingly given in particular to gas mixtures which, in addition to dinitrogen monoxide, contain at least one inert gas. The term “inert gas” as used in the context of the present invention refers to a gas which behaves inertly with regard to the reaction of dinitrogen monoxide with cyclododecatriene. Useful inert gases are, for example, nitrogen, carbon dioxide, carbon monoxide, hydrogen, water, argon, methane, ethane and propane. Equally, the gas mixture may also contain components, preferably gases which do not behave as inert components, preferably as inert gases in the reaction of N2O with cyclododecatriene. Useful such gases include NOx or, for example, oxygen. The term “NOx,”as used in the context of the present invention, relates to all compounds NaOb except dinitrogen monoxide, wherein a is 1 or 2 and b is a number from 1 to 6. Instead of the term “NOx,”the term “nitrogen oxides” is also used in the context of the present invention. In such a case, preference is given to using those gas mixtures whose content of these gases is in the range from 0 to 0.5% by volume, based on the total volume of the gas mixture. Accordingly, the present invention also describes a process as described above, wherein the gas mixture contains from 0 to 0.5% by volume of oxygen or from 0 to 0.5% by volume of nitrogen oxides or both from 0 to 0.5% by volume of oxygen and from 0 to 0.5% by volume of nitrogen oxides, based in each case on the total volume of the gas mixture. In this context, a value of, for example, 0.5% by volume relates to a total content of all possible nitrogen oxides apart from dinitrogen monoxide of 0.5% by volume. In principle, the composition of the gas mixture can be determined for every method known to the person skilled in the art in the context of the present invention. In the context of the present invention, the composition of the gas mixtures is preferably determined by gas chromatography. It can also be determined by UV-spectroscopy, IR-spectroscopy or by chemical methods. According to the present invention, dinitrogen monoxide or the gas mixture containing dinitrogen monoxide can be used in every form, in particular as a gas or in liquid form. Dinitrogen monoxide or the gas mixture containing dinitrogen monoxide can be liquidified by all methods known to the person skilled in the art, preferably by chosing a suitable pressure and a suitable temperature. According to the present invention, it is also possible that dinitrogen monoxide or the gas mixture containing dinitrogen monoxide is first absorbed in a suitable solvent and then added to the reaction. In a preferred embodiment of the present invention, the dinitrogen monoxide source is at least one dinitrogen monoxide-containing offgas of a chemical process. The scope of the present invention also includes embodiments in which the dinitrogen monoxide source used is at least two nitrogen monoxide-containing offgases of a single plant. Likewise included are embodiments in which the dinitrogen monoxide source used is at least one dinitrogen monoxide-containing offgas of one plant and at least one further dinitrogen monoxide-containing offgas of at least one further plant. The present invention accordingly also relates to a process as described above, wherein the dinitrogen monoxide source used is at least one dinitrogen monoxide-containing offgas of at least one industrial process. In the context of the present invention, it is also possible that dinitrogen monoxide used in the process according to the invention is prepared for the process. Preference is given to the preparation by thermal decomposition of NH4NO3 as disclosed, for example, in U.S. Pat. No. 3,656,899 whose contents on this subject is fully incorporated by reference into the context of the present application. Likewise preferred is a preparation by catalytic oxidation of ammonia, as disclosed for example in U.S. Pat. No. 5,849,257 or in WO 98/25698, whose contents on this subject are fully incorporated by refernce into the context of the present application. In the context of the present invention, the term “dinitrogen monoxide source” relates both to embodiments in which the offgas mentioned is used in unmodified form in the inventive conversion of cyclododecatriene, and embodiments in which at least one of the offgases mentioned is subjected to a modification. The term “modification” as used in this context within the scope of the present invention relates to any suitable process by which the chemical composition of an offgas is changed. Accordingly, the term “modification” relates, among other embodiments, to those in which a dinitrogen monoxide-containing offgas is concentrated with respect to the dinitrogen monoxide content in at least one suitable process. Such processes are described, for example, in DE-A 27 32 267, EP 1 076 217 A2 or WO 00/73202 A1, whose contents on this subject are fully incorporated by reference into the context of the present application. In the context of the present invention, the gas mixture can also be the subject of a modification to reduce the concentration of inert or non-inert compounds in the gas mixture. According to the present invention, this modification can for example be an absorption of the gas mixture in a suitable solvent and subsequent desorption to purify the gas mixture from inert components. A suitable solvent for the absorption is, for example, water, as disclosed in DT 20 40 219. According to the present invention, the modification of the gas mixture can also comprise a further purification step, for example a step for separating of NOx from the gas mixture. Suitable processes for separating of NOx are in principle known from the state of the art. According to the present invention, all processes for separating of NOx known to the person skilled in the art can be used. According to the invention, it is preferred that the offgases are subjected to treatment comprising the absorption in a suitable solvent and subsequent desorption to remove inert compounds. A suitable solvent is, for example, water, as disclosed in DT 20 40 219. In an example of a preferred embodiment of the process according to the invention, it is possible to concentrate the abovementioned dinitrogen monoxide-containing offgas by feeding it to at least one adsorption column and dissolving the dinitrogen monoxide in at least one organic solvent. An example of suitable solvent for this purpose is cyclododecatriene. This inventive process variant offers the advantage that the resulting solution of dinitrogen monoxide in cyclododecatriene can be fed without further workup to the conversion according to the invention. This solution of dinitrogen monoxide in cyclododecatriene may contain dinitrogen monoxide in all conceivable concentrations up to saturation. In other embodiments, at least one further solvent or a mixture of cyclododecatriene and at least one further solvent may be used for adsorption. Such further solvents are, for example, all suitable common organic solvents. Preferred solvents include N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, propylene carbonate, sulfolane and N,N-dimethylacetamide. When at least one further solvent or a mixture of cyclododecatriene and at least one further solvent is used, a further preferred embodiment involves at least partly, preferably substantially fully, obtaining the dinitrogen monoxide from the solution enriched with dinitrogen monoxide in at least one suitable desorption step, and feeding it to the conversion according to the invention. In a further embodiment, the chemical composition of an offgas may also be changed by adding pure dinitrogen monoxide to the offgas. In a further preferred embodiment of the present invention, the at least one dinitrogen monoxide-containing offgas stems from an adipic acid plant, a dodecanedioic acid plant, a hydroxylamine plant and/or a nitric acid plant, in which case the latter is in turn preferably operated with an offgas of an adipic acid plant, of a dodecanedioic acid plant or of a hydroxylamine plant. In a preferred embodiment, the offgas stream used is from an adipic acid plant in which oxidation of cyclohexanol/cyclohexanone mixtures with nitric acid generally forms from 0.8 to 1.0 mol of N2O per mole of adipic acid formed. As described, for example, in A. K. Uriarte et al., Stud. Surf. Sci. Catal. 130 (2000) p. 743-748, the offgases of adipic acid plants also contain, in varying concentrations, further constituents including nitrogen, oxygen, carbon dioxide, carbon monoxide, nitrogen oxides, water and volatile organic compounds. The abovementioned dodecanedioic acid plant is a substantially identical type of plant. An example of a typical composition of an offgas of an adipic acid plant or of a dodecanedioic acid plant is reproduced in the following table: Component Concentrations/% by weight NOx 19-25 N2O 20-28 N2 30-40 O2 7-10 CO2 2-3 H2O ˜7 The offgas stream of an adipic acid plant or of a dodecanedioic acid plant may be used directly in the process according to the invention. Preference is given to cleaning the offgas stream of the adipic acid plant or of a dodecanedioic acid plant before use for converting the cyclododecatriene. For example, it is advantageous to adjust the oxygen and/or nitrogen oxides content of the offgas stream to contents in the range of each from 0 to 0.5% by volume. The above-cited document of A. K. Uriarte et al. discloses various possibilities of how such an offgas stream can be cleaned for use in catalytic benzene hydroxylation. The document describes absorption processes, for example pressure swing absorption, membrane separation processes, low temperature distillation or a combination of selective catalytic reduction with ammonia followed by catalytic removal of oxygen. All of these cleaning methods can also be applied in order to clean the dinitrogen monoxide-containing offgas stream of an industrial plant, for example of an adipic acid plant or of a dodecanedioic acid plant or of a nitric acid plant. Very particular preference is given to the distillative cleaning and therefore distillative concentration of the offgas stream of an adipic acid plant or of a dodecanedioic acid plant or of a nitric acid plant. Particular preference is given in the context of the present invention to purifying the offgas stream of an adipic acid plant or of a dodecanedioic acid plant in the case that it contains in each case more than 0.5% by volume of oxygen and/or nitrogen oxides. Accordingly, the present invention also describes a process as described above, wherein the cyclododecatriene is converted using the offgas stream of an adipic acid plant or of a dodecanedioic acid plant. Accordingly, the present invention further describes a process as described above, wherein the offgas stream, which has preferably been distillatively cleaned if necessary, of the adipic acid plant or of a dodecanedioic acid plant contains oxygen and/or nitrogen oxides in the range of in each case from 0 to 0.5% by volume. In a likewise preferred embodiment, the offgas stream used is of a nitric acid plant which is supplied, entirely or partly, with offgases comprising dinitrogen monoxide and nitrogen oxides from other processes. In such nitric acid plants, nitrogen oxides are adsorbed and converted for the most part to nitric acid, whereas the dinitrogen monoxide is not converted. For example, such a nitric acid plant may be supplied with nitrogen oxides which are prepared by selective combustion of ammonia, and with offgases of an adipic acid plant and/or with offgases of a dodecanedioic acid plant. It is equally possible to supply such a nitric acid plant solely with offgases of an adipic acid plant and/or with offgases of a dodecanedioic acid plant. The offgases of such nitric acid plants always contain different concentrations of further constituents including nitrogen, oxygen, carbon dioxide, carbon monoxide, nitrogen oxides, water and volatile organic compounds. An example of a typical composition of an offgas of such a nitric acid plant is reproduced in the table which follows: Component Concentrations/% by wt. NOx <0.1 N2O 8-36 N2 57-86 O2 3-9 CO2 1-4 H2O ˜0.6 The offgas stream of a nitric acid plant may be used directly in the process according to the invention. Preference is given to purifying the offgas stream of the nitric acid plant before using it to convert the cyclododecatriene. For example, it is advantageous to adjust the content of oxygen and/or nitrogen oxides in the offgas stream to contents in the range of in each case from 0 to 0.5% by volume. Suitable processes by which these values can be attained are described above in the context of the adipic acid plant and dodecanedioic acid plant. Very particular preference is also given in the context of the offgases of the nitric acid plant to distillative purification and therefore to distillative concentration. Particular preference is given in the context of the present invention to purifying the offgas stream of a nitric acid plant in the case that it contains in each case more than 0.5% by volume of oxygen and/or nitrogen oxides. The present invention accordingly also relates to a process as described above, wherein the cyclododecatriene is converted using the dinitrogen monoxide-containing offgas stream of a nitric acid plant. The present invention accordingly further relates to a process as described above, wherein the offgas stream of the nitric acid plant, which has preferably been purified by distillation if necessary, contains oxygen and/or nitrogen oxides in a range from 0 to 0.5% by volume. In a likewise preferred embodiment of the process according to the invention, the offgas stream of a hydroxylamine plant is used, in which, for example, ammonia is initially oxidized with air or oxygen to NO and small amounts of dinitrogen monoxide are by-produced. The NO is subsequently hydrogenated with hydrogen to give hydroxylamine. Since dinitrogen monoxide is inert under the hydrogenation conditions, it accumulates in the hydrogen circuit. In preferred process versions, the purge stream of a hydroxylamine plant contains dinitrogen monoxide in the range from 9 to 13% by volume in hydrogen. This purge stream may be used as such for the conversion according to the invention. It is equally possible to suitably concentrate this stream with respect to the dinitrogen monoxide content as described above. The present invention accordingly also relates to a process as described above, wherein the dinitrogen monoxide source is the offgas of an adipic acid plant and/or of a dodecanedioic acid plant and/or of a hydroxylamine plant and/or of a nitric acid plant operated with the offgas of an adipic acid plant and/or of a dodecanedioic acid plant and/or of a hydroxylamine plant. The present invention likewise relates to an integrated process for preparing cyclododeca-4,8-dienone, which comprises at least the following steps (i) and (ii): (i) providing a dinitrogen monoxide-containing gas mixture containing in each case from 0 to 0.5% by volume of oxygen and/or nitrogen oxides and based on at least one offgas stream of at least one adipic acid plant and/or of at least one dodecanedioic acid plant and/or of at least one hydroxylamine plant and/or of at least one nitric acid plant operated with the offgas of an adipic acid plant and/or of a dodecanedioic acid plant and/or of a hydroxylamine plant; (ii) reacting cyclododecatriene with the gas mixture provided in (i) to obtain cyclododeca-4,8-dienone. It is equally possible in the context of the process according to the invention to selectively prepare dinitrogen monoxide for use in the process. Preference is given, inter alia, to the preparation via the thermal decomposition of NH4NO3, as described, for example, in U.S. Pat. No. 3,656,899, whose contents on this subject are fully incorporated by reference into the context of the present application. Preference is likewise also given to the preparation via the catalytic oxidation of ammonia, as described, for example, in U.S. Pat. No. 5,849,257 or in WO 98/25698, whose contents on this subject are fully incorporated by reference into the context of the present application. In the inventive reaction of cyclododecatriene with dinitrogen monoxide, at least one suitable solvent or diluent may be used. These include cyclododecane or cyclododecanone or saturated aliphatic or aromatic, unsubstituted or alkyl-substituted hydrocarbons, although substantially all common solvents and/or diluents are suitable, with the proviso that they have neither a C—C double bond nor a C—C triple bond nor an aldehyde group. In general, it is not necessary to add a solvent or diluent in the inventive reaction with dinitrogen monoxide. There are generally no particular restrictions with regard to the reaction conditions of the conversion of cyclododecatriene, as long as it is ensured that cyclododeca-4,8-dienone is obtained from the reaction. The temperatures in the reaction of cyclododecatriene with dinitrogen monoxide are preferably in the range from 140 to 350° C., more preferably in the range from 160 to 275° C. or in the range from 200 to 310 ° C. and particularly preferably in the range from 180 to 250° C. or in the range from 250 to 300 ° C. It is possible in the process according to the invention to carry out the reaction at two or more temperatures, i.e. in two or more temperature ranges which are each within the abovementioned limits. Temperature changes in the course of the reaction may be implemented continuously or else discontinuously. The pressures in the reaction of cyclododecatriene-with dinitrogen monoxide are preferably higher than the autogenous pressure of the reactant or product mixture at the selected reaction temperature or the selected reaction temperatures. The pressures are preferably in the range from 1 to 1000 bar, more preferably in the range from 40 to 300 bar and particularly preferably in the range from 50 to 200 bar. It is possible in the process according to the invention to carry out the reaction at two or more pressures, i.e. in two or more pressure ranges which are each within the abovementioned limits. Pressure changes in the course of the reaction can be implemented continuously or else discontinuously. Accordingly, the present invention also relates to a process as described above, wherein the reaction in (ii) is carried out at a temperature in the range from 140 to 350° C. and a pressure in the range from 1 to 1000 bar. With regard to the reactors which can be used for the conversion, there are no particular restrictions. In particular, the conversion may be in batch mode or in continuous mode. Accordingly, the reactors used may be, for example, at least one CSTR (continuous stirred tank reactor) having at least one internal and/or at least one external heat exchanger, at least one tubular reactor or at least one loop reactor. It is equally possible to configure at least one of these reactors in such a way that it has at least two different zones. Such zones may differ, for example, in reaction conditions, for example the temperature or the pressure and/or in the geometry of the zone, for example the volume or the cross section. When the reaction is carried out in two or more reactors, two or more of the same reactor types or at least two different reactor types may be used. In a preferred embodiment, the inventive reaction with dinitrogen monoxide is carried out in a single reactor. Preference is given, for example, to the reaction in continuous mode. The residence time of the reactants in the at least one reactor is generally in the range of up to 20 h, preferably in the range from 0.1 to 20 hours, more preferably in the range from 0.2 to 15 hours and particularly preferably in the range from 0.25 to 10 h. In the feed which is fed to the reaction of dinitrogen monoxide with cyclododecatriene, the molar ratio of dinitrogen monoxide to cyclododecatriene is generally in the range from 0.05 to 4, preferably in the range from 0.06 to 1, more preferably in the range from 0.07 to 5 and in particular from 0.1 to 0.4. According to an alternative embodiment of the present invention, preferred ranges are in the range from 0.2 to 4, preferably in the range from 0.3 to 3, more preferably in the range from 0.4 to 2 and particularly preferably in the range from 0.4 to 1.5. In a particularly preferred embodiment, the process according to the invention is carried out in such a way that a conversion of cyclododecatriene in the range of up to 95%, preferably in the range from 1 to 80%, more preferably in the range from 5 to 50%, especially preferably in the range from 8 to 25%. According to an alternative embodiment, preferred ranges are from 10 to 80%, more preferably in the range from 21 to 75% and especially preferably in the range from 20 to 50% is achieved at a very high selectivity with respect to cyclododecadienone. The selectivity based on cyclododecadienone is generally at least 90%, preferably at least 92.5% and more preferably at least 95%. The present invention accordingly also relates to a process as described above, wherein the reaction of dinitrogen monoxide with cyclododecatriene has a conversion of cyclododecatriene in the range from 1 to 80%, preferably in the range from 5 to 30% at a selectivity based on cyclododecadienone of at least 90%. In the context of the present invention, in principle any cyclododecatriene or any mixture of two or more different cyclododecatrienes with dinitrogen monoxide may be converted. These include, for example, 1,5,9-cyclododecatrienes, for example cis,trans,trans-1,5,9-cyclododecatriene or cis,cis,trans-1,5,9-cyclododecatriene or all-trans-1,5,9-cyclododecatriene. In a very particularly preferred embodiment of the process according to the invention, the cyclododecatriene used is cis,trans,trans-1,5,9-cyclododecatriene. The present invention accordingly also relates to a process as described above, wherein the cyclododecatriene used is cis,trans,trans-1,5,9-cyclododecatriene. In particular, the present invention therefore also relates to a process as described above, wherein cis,trans,trans-1,5,9-cyclododecatriene is reacted with dinitrogen monoxide to give cyclododeca-4,8-dienone. The inventive reaction of cis,trans,trans-1,5,9-cyclododecatriene with dinitrogen monoxide generally results in a cyclododeca-4,8-dienone isomer mixture which comprises at least two of the cis,trans-cyclododeca-4,8-dienone, trans,cis-cyclododeca-4,8-dienone and trans,trans-cyclododeca-4,8-dienone isomers. Preference is given in accordance with the invention for obtaining an isomer mixture in which trans,cis isomer and cis,trans isomer are formed in about the same amounts and the trans,trans isomer is formed only in small amounts compared to the two other isomers. An example of a typical isomer mixture accordingly has the isomers in molar ratios of about 1:1:0.08. The inventive conversion of at least one cyclododecatriene, preferably the conversion of at least one 1,5,9-cyclododecatriene and especially preferably the conversion of cis,trans,trans-1,5,9-cyclododecatriene may in principle be effected in the presence of a catalyst. In a preferred embodiment of the process according to the invention, the reaction with dinitrogen monoxide is carried out without the addition of a catalyst. The present invention accordingly also describes a process as described above, wherein the reaction of cyclododecatriene with dinitrogen monoxide is carried out without the addition of a catalyst. In general, it is not necessary to add a solvent or diluent in the inventive reaction with dinitrogen monoxide. The 1,5,9-cyclododecatriene which is used with preference may be prepared, for example, by trimerizing pure 1,3-butadiene, as described, for example, in T. Schiffer, G. Oenbrink, “Cyclodecatriene, Cyclooctadiene, and 4-Vinylcyclohexene”, Ulmann's Encyclopedia of Industrial Chemistry, 6th Edition (2000), Electronic Release, Wiley VCH. In the case of trimerization in the presence of Ziegler catalysts, this process results, for example, in cis,trans,trans-1,5,9-cyclododecatriene, cis,cis,trans-1,5,9-cyclododecatriene and all-trans-1,5,9-cyclododecatriene, as described, for example, in H. Weber et al. “Zur Bildungsweise von cis,trans,trans-Cyclododecatrien-(1.5.9) mittels titanhaltiger Katalysatoren” in: Liebigs Ann. Chem. 681 (1965) p.10-20. While all of these cyclododecatrienes may be oxidized by means of dinitrogen monoxide, individually or as a mixture of two or more thereof, in the process according to the invention, particular preference is given in the present process according to the invention, as described above, to converting cis,trans,trans-1,5,9-cyclododecatriene. This cis,trans,trans-1,5,9-cyclododecatriene is more preferably prepared in accordance with the abovementioned article by Weber et al., whose contents on this subject are fully incorporated by reference into the context of the present application. The present invention accordingly also relates to a process as described above, wherein the cyclododecatriene used as a reactant is prepared by trimerizing 1,3-butadiene using a titanium catalyst. While all suitable titanium catalysts may in principle be used for trimerization, particular preference is given to the titanium tetrachloride/ethylaluminum sesquichloride catalyst described in the article by Weber et al. The butadiene used for the trimerization especially preferably has a degree of purity determined by gas chromatography of at least 99.6% and more preferably of at least 99.65%. Especially preferably, the 1,3-butadiene used, within the precision of detection, contains no 1,2-butadiene and no 2-butyne. This preferred trimerization generally results in mixtures which contain at least 95% by weight, preferably at least 96% by weight and more preferably at least 97% by weight, of cis,trans,trans-1,5,9-cyclododecatriene. For example, the mixtures especially preferably contain about 98% by weight of cis,trans,trans-1,5,9-cyclododecatriene. This cis,trans,trans-1,5,9-cyclododecatriene-containing mixture may be used as such for the reaction with dinitrogen monoxide. It is equally possible to remove the cis,trans,trans-1,5,9-cyclododecatriene from the mixture by at least one suitable method, for example and with preference by at least one distillation, and use it in the reaction with dinitrogen monoxide. There is preferably no such purification in the process according to the invention. With regard to further details on the trimerization, reference is made to the article by Weber et al. The inventive reaction of cyclododecatriene with dinitrogen monoxide generally results in a mixture which comprises cyclododecadienone, preferably cyclododeca-4,8-dienone, and in some cases unconverted reactant and/or in some cases at least one by-product. Depending on the further utilization and/or workup, the cyclododecadienone, preferably the cyclododeca4,8-dienone, may be removed from this mixture. In the case that the mixture comprises cyclododecadienone and, for example, a diketone such as cyclododecenedione, it is possible to remove the cyclododecadienone, preferably the cyclododeca4,8-dienone, in a simple manner, and feed it to a further process step, for example the partial hydrogenation to cyclododecenone or preferably to the hydrogenation to cyclododecanone. It is possible to remove the cyclododeca-4,8-dienone from this mixture by at least one suitable method. Preference is given in this context to distillative removal. The distillation is effected at a pressure in the range of generally from 0.001 to 2 bar, preferably in the range from 0.01 to 1 bar and especially preferably in the range from 0.03 to 0.5 bar, for example from 0.04 to 0.5 bar or 0.05 to 0.5 bar. The cyclododecadienone obtained in accordance with the invention from the reaction of cyclododecatriene with dinitrogen monoxide may be fed to one or more of any further processes. For example, the keto group of cyclododecadienone may be subjected to a chemical reaction. Equally, at least one of the C—C double bonds may be subjected to a chemical reaction. For example and with preference, at least one C—C double bond, preferably both C—C double bonds, may be hydrogenated. Irrespective of which regioisomer of cyclododecadienone or which mixture of at least two regioisomeric cyclododecadienones is obtained from the inventive reaction with dinitrogen monoxide, this regioisomer or this regioisomer mixture is preferably hydrogenated to cyclododecanone. In a preferred embodiment of the process according to the invention, cyclododeca-4,8-dienone is hydrogenated to cyclododecanone. The present invention accordingly also relates to a process as described above, wherein the cyclododecadienone obtained from the reaction of cyclododecatriene with dinitrogen monoxide is hydrogenated to obtain cyclododecanone. For the hydrogenation of cyclododecadienone and especially preferably cyclododeca-4,8-dienone, all suitable catalysts may be used. In particular, at least one homogeneous or at least one heterogeneous or both at least one homogeneous and at least one heterogeneous catalyst can be used. The catalysts which can be used preferably contain at least one metal from the 7th, the 8th, the 9th, the 10th or the 11th transition group of the Periodic Table of the Elements. Preference is further given to the catalysts which can be used in accordance with the invention containing at least one element selected from the group consisting of Re, Fe, Ru, Co, Rh, Ir, Ni, Pd, Pt, Cu and Au. Particular preference is given to the catalysts which can be used in accordance with the invention containing at least one element selected from the group consisting of Fe, Ni, Pd, Pt and Cu. Especially preferably, the catalyst used according to the present invention contains Pd. Homogeneous catalysts used with preference in the process according to the invention preferably contain at least one element of the 8th, 9th or 10th transition group. Preference is further given to homogeneous catalysts which contain Ru, Rh, Ir and/or Ni. Examples include RhCI(TTP)3 or Ru4H4(CO)12. Particular preference is given to those homogeneous catalysts which contain Ru. For example, homogeneous catalysts are used as described in U.S. Pat. Nos. 5,180,870, 5,321,176, 5,177,278, 3,804,914, 5,210,349, 5,128,296, U.S. B 316,917 and in D. R. Fahey in J. Org. Chem. 38 (1973) p. 80-87, whose disclosure content on this subject is fully incorporated by reference into the context of the present application. Such catalysts are, for instance, (TPP)2(CO)3Ru, [Ru(CO)4]3, (TPP)2Ru(CO)2Cl2, (TPP)3(CO)RuH2, (TPP)2(CO)2RuH2, (TPP)2(CO)2RuClH or (TPP)3(CO)RuCl2. Particular preference is given in the process according to the invention to using at least one heterogeneous catalyst, in which case at least one of the abovementioned metals may be used as the metal as such, as a Raney catalyst and/or applied to a customary support. Preferred support materials are, for instance, activated carbons or oxides, for example aluminum oxides, silicon oxides, titanium oxides or zirconium oxides. Support materials likewise include bentonites. When two or more metals are used, these may be separate or an alloy. It is possible in this context to use at least one other metal as such and at least one other metal as a Raney catalyst or at least one metal as such and at least one other metal applied to at least one support or at least one metal as the Raney catalyst and at least one other metal applied to at least one support or at least one metal as such and at least one other metal as the Raney catalyst and at least one other metal applied to at least one support. The catalysts used in the process according to the invention may also be, for example, precipitation catalysts. Such catalysts may be prepared by precipitating their catalytically active components from their salt solutions, in particular from the solutions of their nitrates and/or acetates, for example by adding solutions of alkali metal and/or alkaline earth metal hydroxide and/or carbonate solutions, for example sparingly soluble hydroxides, oxide hydrates, basic salts or carbonates, subsequently drying the resulting precipitates and then converting them by calcining at generally from 300 to 700° C., in particular from 400 to 600° C., to the corresponding oxides, mixed oxides and/or mixed-valence oxides, which are reduced by treatment with hydrogen or hydrogen-containing gases in the range of generally from 50-700° C., in particular from 100 to 400° C., to the metals in question and/or oxidic compounds of lower oxidation state and converted to the actual catalytically active form. Reduction is generally effected until no more water is formed. In the preparation of precipitation catalysts which contain a support material, the catalytically active components may be precipitated in the presence of the support material in question. The catalytically active components may advantageously be precipitated from the salt solutions in question at the same time as the support material. Preference is given to using hydrogenation catalysts in the process according to the invention which contain the metals or metal compounds catalyzing the hydrogenation deposited on a support material. Apart from the abovementioned precipitation catalysts which, apart from the catalytically active components, additionally also contain a support material, suitable support materials for the process according to the invention are generally those in which the catalytically hydrogenating component has been applied to a support material, for example by impregnation. The way in which the catalytically active metal is applied to the support is generally not critical and may be brought about in various ways. The catalytically active metals may be applied to these support materials, for example by saturation with solutions or suspensions of the salts or oxides of the elements in question, drying and subsequent reduction of the metal compounds to give the metals in question or compounds of lower oxidation state by means of a reducing agent, preferably with hydrogen or complex hydrides. Another means of applying the catalytically active metals to these supports is to impregnate the supports with solutions of salts which readily decompose thermally, for example with nitrates or complexes which readily decompose thermally, for example carbonyl or hydrido complexes of the catalytically active metals, and to heat the support saturated in this way to temperatures in the range from 300 to 600° C. to thermally decompose the adsorbed metal compounds. This thermal decomposition is preferably carried out under a protective gas atmosphere. Suitable protective gases are, for example, nitrogen, carbon dioxide, hydrogen or noble gases. In addition, catalytically active metals may be deposited on the catalyst support by vapor deposition or by flame spraying. The catalytically active metals content of these supported catalysts is in principle not critical for the success of the process according to the invention. In general, higher catalytically active metals contents of these supported catalysts lead to higher space-time conversions than lower contents. In general, supported catalysts are used whose catalytically active metals content is in the range from 0.1 to 90% by weight, preferably in the range from 0.5 to 40% by weight, based on the total weight of the catalyst. Since these contents specifications relate to the entire catalyst including support material, but the different support materials have very different specific weights and specific surface areas, it is also conceivable that these data may also be lower or higher than the specifications without this having a disadvantageous effect on the result of the process according to the invention. It will be appreciated that a plurality of catalytically active metals may also be applied to the particular support material. In addition, the catalytically active metals may be applied to the support, for example, by the process of DE-A 25 19 817 or EP 0 285 420 A1. In the catalysts according to the abovementioned documents, the catalytically active metals are an alloy which are generated by thermally treating and/or reducing the, for example, by impregnating with a salt or complex of the aforementioned metals. Both the precipitation catalysts and the supported catalysts may be activated in situ at the beginning of the reaction by the hydrogen present. Preference is given to separately activating these catalysts before their use. Useful support materials are generally the oxides of aluminum and titanium, zirconium dioxide, silicon dioxide, clay earths, for example montmorillonites, silicates, for example magnesium or aluminum silicates, zeolites, for example the ZSM-5 or ZSM-10 structure types, or activated carbon. Preferred support materials are aluminum oxides, titanium dioxides, silicon dioxide, zirconium dioxide and activated carbon. It will be appreciated that mixtures of different support materials may also serve as the support for catalysts which can be used in the process according to the invention. The at least one heterogeneous catalyst may be used, for example, as a suspension catalyst and/or as a fixed bed catalyst. When the hydrogenation in the process according to the invention is carried out, for example, with at least one suspension catalyst, preference is given to hydrogenating in at least one tubular reactor or in at least one bubble column or in at least one packed bubble column or in a combination of two or more identical or different reactors. The term “different reactors” in the present context refers either to different reactor types or to reactors of the same type which differ, for example, by their geometry, for example their volume and/or their cross section and/or by the hydrogenation conditions in the reactors. When, for example, the hydrogenation in the process according to the invention is carried out with at least one fixed bed catalyst, preference is given to using at least one tubular reactor, for example at least one shaft reactor and/or at least one tube bundle reactor, in which case a single reactor can be operated in liquid phase or trickle mode. When two or more reactors are used, at least one may be operated in liquid phase mode and at least one in trickle mode. In a preferred embodiment of the process according to the invention, the at least one catalyst used for the hydrogenation is removed from the product mixture of the hydrogenation. Depending on the catalyst used, this removal may be effected by any suitable process. When the catalyst used in the hydrogenation is, for example, a heterogeneous catalyst as a suspension catalyst, preference is given to removing it in the present invention by at least one filtration step. The catalyst removed in this way may be recycled into the hydrogenation or fed to at least one of any other processes. It is equally possible to work up the catalyst, for example in order to recover metal present in the catalyst. When the catalyst used in the hydrogenation is, for example, a homogeneous catalyst, preference is given to removing it by at least one distillation step in the process according to the invention. In the course of this distillation, one or two or more distillation columns may be used. The catalyst removed in this way may be recycled into the hydrogenation or fed to at least one of any other processes. It is equally possible to work up the catalyst, for example in order to recover metal present in the catalyst. Before use in any process, for example recycling into the process according to the invention, either the at least one homogeneous or the at least one heterogeneous catalyst, should this be necessary, are regenerated by at least one suitable process. Heat may be removed from the reactor used in accordance with the invention internally, for example using cooling coils, and/or externally, for example using at least one heat exchanger. When, for example and with preference, at least one tubular reactor is used for hydrogenating, preference is given to conducting the reaction via external circulation in which the removal of heat is integrated. When, in a preferred embodiment of the process according to the invention, the hydrogenation is carried out continuously, preference is further given to using at least two reactors, more preferably at least two tubular reactors, more preferably at least two tubular reactors connected in series and especially preferably two tubular reactors connected in series. The hydrogenation conditions in the reactors used may in each case be the same or different and are each within the above-described ranges. When the hydrogenation is carried out over at least one suspended catalyst, the residence time is generally in the range from 0.5 to 50 h, preferably in the range from 1 to 30 h and more preferably in the range from 1.5 to 25 h. It is unimportant in accordance with the invention whether one reactor or at least 2 reactors connected in series are used. For all of these embodiments, the total residence time is within the above-specified ranges. When in the process according to the invention, the hydrogenation is carried out in continuous mode over at least one fixed bed catalyst, the residence time is generally in the range from 0.1 to 20 h, preferably in the range from 0.2 to 15 h and more preferably in the range from 0.3 to 10 h. It is unimportant in accordance with the invention whether one reactor or at least 2 reactors connected in series are used. For all of these embodiments, the total residence time is within the above-specified ranges. The mixture which is obtained from the first tubular reactor contains cyclododecanone in a proportion, based on the total content of C12 components in the mixture, which is preferably in the range from 50 to 99.9% by weight and more preferably in the range from 70 to 99.5% by weight. This mixture is, optionally after at least one suitable intermediate treatment, fed to the second tubular reactor. The mixture which is obtained from the second tubular reactor contains cyclododecanone in a proportion which is preferably in the range of at least 99.5%, especially in the range of 99.9% and especially preferably of 99.99% by weight, more preferably in the range of at least 99.9% and especially preferably of at least 99.99% by weight. The hydrogen pressure in the hydrogenation according to the invention is generally in the range from 1 to 325 bar, preferably in the range from 1.5 to 200 bar, more preferably in the range from 2 to 100 bar and especially preferably in the range from 2.5 to 50 bar. The hydrogenation temperature is generally in the range from 0 to 250° C., preferably in the range from 20 to 200° C., for example in the range from 30 to 180° C., more preferably in the range from 30 to 150° C., more preferably in the range from 40 to 170 and especially preferably in the range from 40 to 140° C. The present invention accordingly also relates to a process as described above, wherein the hydrogenation is carried out in the presence of a hydrogenation catalyst, preferably of a heterogeneous hydrogenation catalyst, at a temperature in the range from 0 to 250° C. and a pressure in the range from 1 to 325 bar. In the hydrogenation according to the invention, at least one suitable solvent or diluent may be used. Useful solvents and diluents include cyclododecanone or cyclododecane and also in principle any solvents and diluents which are not hydrogenated or converted in any other way under the hydrogenation conditions. In a preferred embodiment of the process according to the invention, the hydrogenation is carried out without the addition of a solvent or diluent. The hydrogenation according to the invention generally results in a mixture which, in addition to cyclododecanone, in some cases comprises at least one by-product and/or at least one unconverted reactant and/or at least one further compound which has been fed to the hydrogenation via, for example, a mixture comprising reactant. The cyclododecanone may be removed from this mixture by at least one suitable method, for example and with preference by at least one distillation. One advantage of the above-described process according to the invention for preparing cyclododecanone is that cyclododecanone and also cyclododecadienone are obtained in few steps and simultaneously with high selectivity. A further considerable advantage is the fact that the reactant used for the process according to the invention may be dinitrogen monoxide-containing offgases from preferably industrial plants which firstly are available without great cost and secondly enable the integration of the process according to the invention into an existing integrated plant system, allowing the transport path for the reactant to be kept to a minimum, and which also, as potential greenhouse gases, do not have to be fed to a special treatment for disposal, but rather flow directly into a product of value. The cyclododecanone which is especially preferably obtained in accordance with the invention and has optionally been removed from the product mixture may more preferably, for example, be used to prepare dodecanedicarboxylic acid and/or laurolactam and/or polymers derived therefrom, for example polyamides such as nylon-12 or nylon-6,12. The present invention is illustrated by the examples which follow. EXAMPLES Example 1 Oxidation of cis,trans,trans-1,5,9-cyclododecatriene with N2O A 250 ml autoclave was initially charged with 92.67 g (0.56 mol) of cis,trans,trans-1,5,9-cyclododecatriene (approx. 98%, commercially available from-DuPont). The autoclave was then sealed and purged with N2. Subsequently, the autoclave was pressurized with N2O up to 30 bar. The temperature was then increased to 225° C. (maximum pressure during the reaction: 55 bar). After a reaction time of 50 h, the autoclave was cooled and decompressed. The product (96 g) was analyzed by means of quantitative GC and GC-MS. The conversion of cis,trans,trans-1,5,9-cyclododecatriene was 45%. The selectivity for cyclododeca4,8-dienone as an isomer mixture was 92% (molar cis,trans:trans,cis:trans,trans isomer ratios 1:1:0.1). Only small amounts of diketocyclododecenes were formed, of which GC-MS was used to detect a total of five different isomers, and traces of dodeca-4,8,11-trienal (as an isomer mixture). Example 2 Oxidation of cis,trans,trans-1,5,9-cyclododecatriene with N2O A 250 ml autoclave was initially charged with 94.30 g (0.57 mol) of cis,trans,trans-1,5,9-cyclododecatriene (approx. 98%, commercially available from DuPont). The autoclave was then sealed and purged with N2. Subsequently, the autoclave was pressurized with N2O up to 50 bar. The temperature was then increased to 200° C. (maximum pressure during the reaction: 81 bar). After a reaction time of 10 h, the autoclave was cooled and decompressed. The product (102.2 g) was analyzed by means of quantitative GC and GC-MS. The conversion of cis,trans,trans-1,5,9-cyclododecatriene was 35%. The selectivity for cyclododeca-4,8-dienone as an isomer mixture was 92% (molar cis,trans:trans,cis:trans,trans isomer ratios 1:1:0.08). Only small amounts of diketocyclododecenes were formed, of which GC-MS was used to detect a total of five different isomers, and traces of dodeca-4,8,11-trienal (as an isomer mixture). Example 3 Oxidation of cis,trans,trans-1,5,9-cyclododecatriene with N2O A 250 ml autoclave was initially charged with 91.5 g (0.56 mol) of cis,trans,trans-1,5,9-cyclododecatriene (approx. 98%, commercially available from DuPont). The autoclave was then sealed and purged with N2. Subsequently, the autoclave was pressurized with N2O up to 50 bar. The temperature was then increased to 200° C. (maximum pressure during the reaction: 92 bar). After a reaction time of 5 h, the autoclave was cooled and decompressed. The product (99.4 g) was analyzed by means of quantitative GC and GC-MS. The conversion of cis,trans,trans-1,5,9-cyclododecatriene was 30%. The selectivity for cyclododeca-4,8-dienone as an isomer mixture was 95% (molar cis,trans:trans,cis:trans,trans isomer ratios 1:1:0.08). Only small amounts of diketocyclododecenes were formed, of which GC-MS was used to detect a total of five different isomers, and traces of dodeca-4,8,11-trienal (as an isomer mixture). Example 4 Oxidation of recovered cis,trans,trans-1,5,9-cyclododecatriene with N2O The effluents from Examples 1 to 3 were collected and distilled under reduced pressure. The first fraction which boiled at 111° C. (20 mbar, Thead) consisted substantially of cis,trans,trans-1,5,9-cyclododecatriene. The second fraction which boiled at 140° C. (20 mbar, Thead) consisted substantially of cyclododeca-4,8-dienone. Fraction 1 was oxidized under the conditions of Example 3. Both conversion and selectivity remained unchanged compared to Example 3. Example 5 Hydrogenation of cyclododeca-4,8-dienone to cyclododecanone 50 g of cyclododeca-4,8-dienone (isomer mixture, fraction 2 from Example 4) and 1 g of Pd/C catalyst (10% by weight of Pd, commercially available from Degussa under the product number E 101 N/D) were introduced into a 100 ml autoclave. 5 bar of hydrogen were injected with stirring. At a reaction temperature of 50° C., further hydrogen was supplied (10 h) until no more hydrogen was absorbed. After cooling, decompressing and filtering off the catalyst, the effluent was analyzed by gas chromatography. The conversion of cyclododeca-4,8-dienone was quantitative. Cyclododecanone was obtained in a substantially quantitative yield (>98%). The only impurities which could be detected by GC-MS were traces of cyclododecane, cyclododecenone and dodecanal. Example 6 Hydrogenation of cyclododeca-4,8-dienone to cyclododecanone A 30 ml tubular reactor having liquid circulation was charged with 28 ml of Pd/C catalyst (5% by weight of Pd, commercially available from Degussa under the product number E 101 ND/W). After flushing with nitrogen, a hydrogen pressure of 10 bar was established, the autoclave was heated to 60° C. and 150 ml of methanol (as a startup aid) were pumped into the system by means of a feed pump. The circulation pump was subsequently switched on (circulation: about 100 ml/h) and then the feed was switched to 10 ml/h of cyclododeca-4,8-dienone (trickle mode). After 24 h, the effluent was found to contain, in addition to 1% by weight of methanol, about 98% by weight of cyclododecanone and about 1% of unsaturated compounds. After a further 24 h and a temperature increase to 70° C., 99.5% by weight of cyclododecanone and 0.5% by weight of unsaturated compounds were found. Subsequently, the plant was modified in such a way that a tubular reactor (postreactor, 10 ml capacity) was additionally installed and was likewise operated at 70° C. In the effluent of the postreactor, no further unsaturated compounds were found and the yield of cyclododecanone was substantially quantitative (>98%). Example 7 2000 g/h cis,trans,trans-1,5,9-cyclododecatriene and 68 g/h of liquid dinitrogen monoxide are pumped into a turbular reactor (diameter inside 6 mm, length 36 m) via a static mixer. The reactor is heated to 280 ° C. The pressure in the reactor is regulated to 100 bar. After passing through the reaction zone, the reaction mixture is decompressed into two flash containers to 3 bar and subsequently to 600 mbar to separate off N2 formed during the process and unreacted N2O. The liquid product is subsequently distillated at 60 mbar (seven theoretical separation steps, Tbottom=170° C., Thead=130° C.). The product obtained via the head of the distillation column is unreacted cis,trans,trans-1,5,9-cyclododecatriene, which is recycled into the reaction. The product obtained via bottom, which contains mostly cyclododecane-4,8-dienone is distilled in a second column with at least 12 theoretical separation steps at 45 mbar. Cyclododeca-4,8-dienone is distilled off as a mixture of isomers via the head of the column (Tbottom=193° C., Thead=160° C.) On average, 209 g/h cyclododeca-4,8-dienone are obtained. The selectivity of cyclododeca-4,8-dienone is 95% (based on cis,trans,trans-1,5,9-dodecatriene).